882825.book of Abstracts Web PDF

BOOK OF
ABSTRACTS
IMPRESSUM
ORGANIZER
Croatian Chemical Society, Zagreb, Croatia
Section of Medicin al/ Pharmaceutical Chemistry
www.hkd.hr
PUBLISHED BY
EDITORS
Danijel Namjesnik, Nikola Basarić,
Višnja Stepanić, Ivana Perković
DESIGN
Danijel Namjesnik
TEXT PREPARED BY
Authors, who are fully responsible for the abstracts
CONFERENCE VENUE
Sheraton Dubrovnik Riviera Hotel
Šetalište dr. F. Tuđmana 17 - 20207,
Srebreno, Mlini, Croatia
www.sheratondubrovnikriviera.com
Tel: +385 (0)20 601 500
ISBN 978-953- 55232-8- 4

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ORGANIZER
Section of Medicinal/Pharmaceutical Chemistry

of the Croatian Chemical Society
Zagreb, Croatia
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The 10 th Joint Meeting on Medicinal Chemistry 2017
Dear Participants,
The 10th JMMC follows the tradition created by several European national medicinal
chemistry societies to organize these joint scientific events in the years between the
biennial International Symposia on Medicinal Chemistry (EFMC/ISMC). Various
European cities have hosted the JMMC since the first one 1999 in Taormina: Budapest
(2001 and 2009), Krakow (2003), Vienna (2005), Portorož (2007), Catania (2011),
Lublin (2013) and the most recent one in Athens (2015). The JMMCs is an important
scientific event in the field of medicinal chemistry which gives the opportunity for
networking of the participants coming mainly from the nine middle European
countries: Austria, Croatia, Czech Republic, Greece, Hungary, Italy, Poland, Slovakia
and Slovenia. This leads us to the principal aims of the Meeting: dissemination of
research results, training of young researchers and enhancement of transnational
collaborations between scientists from academia as well as industry.
The 10th JMMC will continue the tradition and will cover drug discovery advances in
the major therapeutic areas, including anti-infectives, neurodegenerative diseases
and oncology. JMMC 2017 will present various topics which will cover advances in
approaches for hit findings and accelerating lead optimization process, exploration of
new chemical entities from nature, discovery of small molecule chemical probes,
optimization of drug delivery and computational medicinal chemistry. Our intention
is to get together scientists from different countries, disciplines and sectors, and in a
relaxed atmosphere discuss and rationalize results and challenges associated with
new drug discovery. As you know, Dubrovnik is one of the most visited spots on the
Croatian coastline, where Mediterranean grace, rich history and culture fusion in a
unique beauty and harmony.
Looking forward to seeing You in Dubrovnik, the Pearl of the Adriatic!
Vesna Gabelica Marković

Head of the Section of Medicinal/Pharmaceutical Chemistry
of the Croatian Chemical Society
6
NATIONAL ORGANIZING COMMITTEE
Vesna Gabelica Marković (Chair)

Croatian Chemical Society, Zagreb
Nikola Basarić
Ruđer Bošković Institute, Zagreb
Ivanka Jerić
Sanja Koštrun
Fidelta Ltd., Zagreb
Danijel Namjesnik
Faculty of Science, University of Zagreb
Ivana Perković
Faculty of Pharmacy and Biochemistry, University of Zagreb
Silvana Raić-Malić
Faculty of Chemical Engineering and Technology, University of Zagreb
Rosana Ribić
Faculty of Science, University of Zagreb
Višnja Stepanić
Ines Vujasinović
Fidelta Ltd., Zagreb
7
I N TE RNA T I ON AL OR GA NI Z IN G CO MM I T TEE
Vesna Gabelica Marković (Chair)

Schnürch Michael
Vienna University of Technology, Vienna, Austria
Jarmila Vinšová
Charles University in Prague, Prague, Czech Republic
Emmanuel Mikros
National and Kapodistrian University of Athens, Athens, Greece
János Wölfling
University of Szeged, Szeged, Hungary
Girolamo Cirrincione
University of Palermo, Palermo, Italy
Katarzyna Kieć-Kononowicz
Jagiellonian University Medical College, Kraków, Poland
Andrej Boháč
Comenius University in Bratislava, Bratislava, Slovakia
Marko Anderluh
University of Ljubljana, Ljubljana, Slovenia
8
I N TE R N A T I O N A L S C I E N T I F I C C O M M I T T E E
Marko Mihovilovic
Vienna University of Technology, Vienna, Austria
Višnja Stepanić
Ruđer Bošković Institute, Zagreb, Croatia
Jarmila Vinšová
Charles University in Prague, Prague, Czech Republic
Anna Tsantili
National and Kapodistrian University of Athens, Athens, Greece
Péter Mátyus
Semmelweis University, Budapest, Hungary
Gabriele Costantino
University of Parma, Parma, Italy
Dariusz Matosiuk
Medical University of Lublin, Poland
Milan Remko
Comenius University in Bratislava, Bratislava, Slovakia
Danijel Kikelj
University of Ljubljana, Ljubljana, Slovenia
9
PLENARY LECTURERS
Nenad Ban (ETH Zürich, CH)

Beyond the Prokaryotic Ribosome: Structural and Functional Insights Into
Eukaryotic and Mitochondrial Ribosomes
Gerhard Klebe (University of Marburg, DE)

What Thermodynamics Can Help to Understand Protein-Ligand Binding in
Medicinal Chemistry
Paul Brennan (University of Oxford, UK)

Chemical Probes in Target Discovery
Margot Ernst (Medical University Vienna, AT)

GABAA Receptor Subtypes: A Structure Guided Path to Selective Compounds
Ivo Piantanida (Ruđer Bošković Institute, HR)

Design of Small Molecular Probes for Proteins and
DNA / RNA
Martin Krátký (Charles University, CZ)

Oligotuftsin-based Carriers for Novel Antimycobacterial Active Agents and
Their Conjugates
10
PLENARY LECTURERS
Grigoris Zoidis (National and Kapodistrian University of Athens, GR)

Metal Chelating Agents Against Viruses and Parasites
János Wölfling (University of Szeged, HU)

Old Scaffolds in New Role: Steroids as Antiproliferative Agents
Girolamo Cirrincione (University of Palermo, IT)

Marine Environment Inspires Kinases Inhibitors
Jadwiga Turlo (Medical University of Warsaw, PL)

Polysaccharides as Biological Response Modifiers: Structure-Activity
Relationship
Stanislav Gobec (University of Ljubljana, SI)

New Hits and Leads for Neurodegenerative Disorders
11
KEYNOTE LECTURERS
Hannes Mikula (Technical University Vienna, AT)

Pretargeted Prodrug Activation Through Bioorthogonal Elimination
Vesna Eraković Haber (Fidelta Ltd., HR)

Patient Derived Testing Systems – Reaching Beyond Targed Based Drug
Discovery
Robert Vianello (Ruđer Bošković Institute, HR)

Computational Insight into the Catalytic Activity of Monoamine Oxidase
Enzyme for Targeting Neurological Diseases
Marta Kučerová-Chlupáčová (Charles University, CZ)

Antimicrobial Potential of 1,2,4-Oxadiazoles and Their Synthesis
Radim Nencka (Czech Academy of Sciences, CZ)

Rational Design of PI4KB Inhibitors as Potential Broad-spectrum Antiviral
Agents
Nektarios Aligiannis (National and Kapodistrian University of Athens, GR)

Can Multivariate Statistics Aid to the Reveal of Bioactive Compounds? An NMR
and HPTLC Approach
Vasiliki Sarli (Aristotle University of Thessaloniki, GR)

New Drug Conjugates Based on Azasteroids or Peptides for Targeted Drug
Delivery in Cancer Therapy
Marco Macchia (University of Pisa, IT)

Endocannabinoid System Modulation: Therapeutic Implications and Future
Perspectives
12
KEYNOTE LECTURERS
Gianluca Sbardella (University of Salerno, IT)

A "Library-on-Library" Screening Approach to Identify Small-Molecule Ligands
of Methyl-Lysine Reader Proteins
Krzysztof Kaminski (Jagiellonian University, PL)

Hybrid Compounds in the Search for the New Highly Effective Anticonvulsants
Maciej Dawidowski (Medical University of Warsaw, PL)

Application of Ugi Multicomponent Reaction in Synthesis of Novel 2,6-Diketo-
piperazine Derivatives with High and Broad Activity in Animal Models of
Epilepsy
Magdaléna Májeková (Slovak Academy of Sciences, SK)

Ligand-based Drug Design of Novel Aldose Reductase Inhibitors from
Databases of Indole-1-Acetic Acids
Pavol Jakubec (Slovak University of Technology, SK; Harward University, USA)

A Platform for the Discovery of New Macrolide Antibiotics
Matej Sova (University of Ljubljana, SI)

Design and Synthesis of Novel Modulators of Toll-like Receptors and Inhibitors
of Indoleamine 2,3-Dioxygenase (IDO1)
Nace Zidar (University of Ljubljana, SI)

Discovery of N-phenylpyrrolamides as ATPase Inhibitors of DNA Gyrase and
Topoisomerase IV
13
KEYNOTE LECTURERS
SUNDAY, JUNE 25
14:00-17:00 Registration
17:00-17:30 Opening of the Meeting
A WAY FORWARD TO NEW ANTI-INFECTIVES
Moderator: Gabriele Costantino (Italy)
Nenad Ban (ETH Zürich, CH)
17:30-18:15 PL-1 Beyond the Prokaryotic Ribosome: Structural and Functional Insights Into Eukaryotic and
Mitochondrial Ribosomes
Pavol Jakubec (Slovak University of Technology, SK; Harward University, USA)
18:15-18:45 KL-1
A Platform for the Discovery of New Macrolide Antibiotics
Martin Krátký (Charles University, CZ)
18:45-19:25 PL-2
Oligotuftsin-based Carriers for Novel Antimycobacterial Active Agents and Their Conjugates
19:30 Welcome party
MONDAY, JUNE 26
RATIONAL APPROACH TO THE DESIGN OF NOVEL DRUGS
Moderator: Margot Ernst (Austria)
Gerhard Klebe (University of Marburg, DE)
9:00-9:45 PL-3 What Thermodynamics Can Help to Understand Protein-Ligand Binding in Medicinal
Chemistry
Nace Zidar (University of Ljubljana, SI)
9:45-10:15 KL-2
Discovery of N-phenylpyrrolamides as ATPase Inhibitors of DNA Gyrase and Topoisomerase IV
10:15-10:45 Coffee break
ANTI-INFECTIVE CASE STUDIES
Moderator: Marko Anderluh (Slovenia)
Grigoris Zoidis (National and Kapodistrian University of Athens, GR)
10:45-11:25 PL-4
Metal Chelating Agents Against Viruses and Parasites
Marta Kučerová-Chlupáčová (Charles University, CZ)
11:25-11:55 KL-3
Antimicrobial Potential of 1,2,4-Oxadiazoles and Their Synthesis
Radim Nencka (Czech Academy of Sciences, CZ)
11:55-12:25 KL-4
Rational Design of PI4KB Inhibitors as Potential Broad-spectrum Antiviral Agents
12:25-15:00 Lunch – POSTER SESSION I
FILLING THE GAP IN THE DISCOVERY OF NEW ANTI-CANCER DRUGS
Moderator: Ivo Piantanida (Croatia)
Girolamo Cirrincione (University of Palermo, IT)
15:00-15:40 PL-5
Marine Environment Inspires Kinases Inhibitors
Matej Sova (University of Ljubljana, SI)
15:40-16:10 KL-5 Design and Synthesis of Novel Modulators of Toll-like Receptors and Inhibitors of Indoleamine
2,3-Dioxygenase (IDO1)
János Wölfling (University of Szeged, HU)
16:30-17:10 PL-6
Old Scaffolds in New Role: Steroids as Antiproliferative Agents
Vasiliki Sarli (Aristotle University of Thessaloniki, GR)
17:10-17:40 KL-6 New Drug Conjugates Based on Azasteroids or Peptides for Targeted Drug Delivery in Cancer
Therapy
18:30 Trip to Dubrovnik
14
TUESDAY, JUNE 27
LOOKING AT THE EPIGENETIC LEVEL
Moderator: János Wölfling (Hungary)
Paul Brennan (University of Oxford, UK)
9:00-9:45 PL-7
Chemical Probes in Target Discovery
Gianluca Sbardella (University of Salerno, IT)
9:45-10:15 KL-7 A "Library-on-Library" Screening Approach to Identify Small-Molecule Ligands of
Methyl-Lysine Reader Proteins
IN SEARCH FOR NOVEL BIOLOGICALLY ACTIVE MOLECULES
Moderator: Jadwiga Turlo (Poland)
Margot Ernst (Medical University Vienna, AT)
10:35-11:15 PL-8
GABAA Receptor Subtypes: A Structure Guided Path to Selective Compounds
Maciej Dawidowski (Medical University of Warsaw, PL)
11:15-11:45 KL-8 Application of Ugi Multicomponent Reaction in Synthesis of Novel 2,6-Diketopiperazine
Derivatives with High and Broad Activity in Animal Models of Epilepsy
Krzysztof Kaminski (Jagiellonian University, PL)
11:45-12:15 KL-9
Hybrid Compounds in the Search for the New Highly Effective Anticonvulsants
Nektarios Aligiannis (National and Kapodistrian University of Athens, GR)
12:15-12:45 KL-10 Can Multivariate Statistics Aid to the Reveal of Bioactive Compounds?
An NMR and HPTLC Approach
12:45-14:00 Lunch
TARGETING NEURODEGENERATIVE DISORDERS
Moderator: Vesna Eraković Haber (Croatia)
Stanislav Gobec (University of Ljubljana, SI)
14:00-14:40 PL-9
New Hits and Leads for Neurodegenerative Disorders
Marco Macchia (University of Pisa, IT)
14:40-15:10 KL-11
Endocannabinoid System Modulation: Therapeutic Implications and Future Perspectives
Robert Vianello (Ruđer Bošković Institute, HR)
15:10-15:40 KL-12 Computational Insight into the Catalytic Activity of Monoamine Oxidase Enzyme for
Targeting Neurological Diseases
15:40-17:00 Coffee break – POSTER SESSION II
ORAL PRESENTATIONS – section I
Moderator: Magdaléna Májeková (Slovak Republic)
Manabu Kawada (Institute of Microbial Chemistry - BIKAKEN, JP)
17:00-17:15 OP-1
Anti-Helicobacter Pylori Activity of a Novel Derivative of Intervenolin
Nela Malatesti (University of Rijeka, HR)
17:15-17:30 OP-2 In vitro Photodynamic Activity of a New Tri-Cationic Amphiphilic Porphyrin Against Herpes
Simplex Virus 1, Bacteria And Cancer Cells
Giannamaria Annunziato (University of Parma, IT)
17:30-17:45 OP-3 Discovery of New, Potential Anti-Infective Compounds Based on Carbonic Anhydrase
Inhibitors by Rational Target-Focus Repurposing Approach
Michaela Barančoková (University of Ljubljana, SI)
17:45-18:00 OP-4 Discovery of Novel Gyrase B Inhibitors and Gyrase B/Topoisomerase IV (ParE) Dual Inhibitors
with In Vitro Antibacterial Activity
Tommaso Felicetti (University of Perugia, IT)
18:00-18:15 OP-5
Fighting Antimicrobial Resistance by Breaking Resistance Mechanisms
Dmitry Tsvelikhovsky (The Hebrew University of Jerusalem, IL)
18:15-18:30 OP-6
α-Enaminones: New Building Blocks for Direct Synthesis of Biologically Active Alkaloids
Marcin J. Cieślak (Polish Academy of Sciences, PL)
18:30-18:45 OP-7 Novel Benzo[b]furan Derivatives – Biological Activity and Protein Target Identification in
Leukemic Cells
Moran Shubely (Bar-Ilan University, IL)
18:45-19:00 OP-8
Development of Novel Drug Candidate Against Prostate Cancer
15
ORAL PRESENTATIONS – section II

Moderator: Jarmila Vinšová (Czech Republic)
Rafał Kurczab (Polish Academy of Sciences, PL)
17:00-17:15 OP-9 Evaluation of Halogen Bonding Hot Spots by Virtual Screening of Commercial Databases –
a Case Study of 5-HT7R
Jaroslaw Polanski (University of Silesia, PL)
17:15-17:30 OP-10
Big Data: Avogadro Stoichiometry Explains Hyperbolic Ligand Efficiency Trend
Vassilios Myrianthopoulos (University of Athens, GR)
17:30-17:45 OP-11 From Public Domain Compound Collections to Cell-Active Epigenetic Modulators.
The Case of the NCI Repository
Thavendran Govender (University of KwaZulu Natal, ZA)
17:45-18:00 OP-12
Mass Spectrometric Imaging as a Preclinical Tool for Medicinal Chemists
David Chan Bodin Siebert (Technical University Vienna, AT)
18:00-18:15 OP-13
Pyrazoloquinolinones, Revisited GABA A Receptor Tool Compounds
Svetlana Maklakova (Lomonosov Moscow State University, RU)
18:15-18:30 OP-14
Synthesis of Tissue-Specific Conjugates for Targeted Drug Delivery Into Hepatic Cells
Rosana Leiva (Universitat de Barcelona, ES)
18:30-18:45 OP-15
Novel Polycyclic N-acylpyrrolidines as 11β-HSD1 Inhibitors
Maria Majellaro (University of Santiago de Compostela, ES)
18:45-19:00 OP-16
Enantiospecific Modulation Of A2B Adenosine Receptor
20:00 Gala Dinner
WEDNESDAY, JUNE 28
LIGAND-BASED APPROACH
Moderator: Gianluca Sbardella (Italy)
Jadwiga Turlo (Medical University of Warsaw, PL)
9:00-9:40 PL-10
Polysaccharides as Biological Response Modifiers: Structure-Activity Relationship
Magdaléna Májeková (Slovak Academy of Sciences, SK)
9:40-10:10 KL-13 Ligand-based Drug Design of Novel Aldose Reductase Inhibitors from Databases of
Indole-1-Acetic Acids
Hannes Mikula (Technical University Vienna, AT)
10:10-10:40 KL-14
Pretargeted Prodrug Activation Through Bioorthogonal Elimination
FROM MOLECULAR PROBES TO CLINICS
Moderator: Hannes Mikula (Austria)
Ivo Piantanida (Ruđer Bošković Institute, HR)
11:00-11:40 PL-11
Design of Small Molecular Probes for Proteins and DNA / RNA
Vesna Eraković Haber (Fidelta Ltd., HR)
11:40-12:10 KL-15
Patient Derived Testing Systems – Reaching Beyond Targed Based Drug Discovery
12:15-12:45 WINNING POSTERS FLASH PRESENTATIONS

12:45-13:00 CLOSING
16
C O N TE N T S
PLENARY LECTURES
PL-1 BEYOND THE PROKARYOTIC RIBOSOME: STRUCTURAL AND FUNCTIONAL INSIGHTS INTO EUKARYOTIC AND
MITOCHONDRIAL RIBOSOMES
Nenad Ban .................................................................................................................................................................. 31
PL-2 OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCOBACTERIAL ACTIVE AGENTS AND
THEIR CONJUGATES
Martin Krátký, Zsuzsa Baranyai, Szilvia Bősze, Nóra Szabó and Jarmila Vinšová....................................................32
PL-3 WHAT THERMODYNAMICS CAN HELP TO UNDERSTAND PROTEIN-LIGAND BINDING IN MEDICINAL
CHEMISTRY
Gerhard Klebe ............................................................................................................................................................33
PL-4 METAL CHELATING AGENTS AGAINST VIRUSES AND PARASITES
Grigoris Zoidis ............................................................................................................................................................34
PL-5 MARINE ENVIRONMENT INSPIRES KINASES INHIBITORS
Girolamo Cirrincione..................................................................................................................................................35
PL-6 OLD SCAFFOLDS IN NEW ROLE: STEROIDS AS ANTIPROLIFERATIVE AGENTS
János Wölfling, Éva Frank, Erzsébet Mernyák, Gyula Schneider, Mihály Szécsi and István Zupkó .......................36
PL-7 CHEMICAL PROBES IN TARGET DISCOVERY
Paul Brennan ..............................................................................................................................................................37
PL-8 GABAA RECEPTOR SUBTYPES: A STRUCTURE GUIDED PATH TO SELECTIVE COMPOUNDS
Konstantina Bampali, David Siebert, Marko D. Mihovilovic, Michael Schnürch, and Margot Ernst ......................38
PL-9 NEW HITS AND LEADS FOR NEURODEGENERATIVE DISORDERS
Urban Košak, Damijan Knez, Boris Brus, Stanislav Gobec .......................................................................................39
PL-10 POLYSACCHARIDES AS BIOLOGICAL RESPONSE MODIFIERS: STRUCTURE-ACTIVITY RELATIONSHIP
Jadwiga Turlo .............................................................................................................................................................40
PL-11 DESIGN OF SMALL MOLECULAR PROBES FOR PROTEINS AND DNA / RNA
Ivo Piantanida ............................................................................................................................................................41
PL-12 FROM EXCEPTIONAL KINASE CONFORMATION TO DUAL KINASE INHIBITORS -
CHEMISTRY OF 2-AMINOOXAZOLES
Andrej Boháč, Peter Šramel, Juraj Dobiaš, Miroslav Murár, Matúš Hlaváč, Maroš Smolíček and
Gilles Hanquet ...........................................................................................................................................................42
KEYNOTE LECTURES
KL-1 A PLATFORM FOR THE DISCOVERY OF NEW MACROLIDE ANTIBIOTICS
Ian B. Seiple, Ziyang Zhang, Pavol Jakubec, Peter M. Wright, Audrey Langlois-Mercier, Daniel T. Hog, Kazuo
Yabu, Senkara Rao Allu, Takehiro Fukuzaki, Peter N. Carlsen, Yoshiaki Kitamura, Xiang Zhou, Matthew L.
Condakes, Filip Szczpinski, William D. Green and Andrew G. Myers ...................................................................... 44
KL-2 DISCOVERY OF N-PHENYLPYRROLAMIDES AS ATPASE INHIBITORS OF DNA GYRASE AND
TOPOISOMERASE IV
Nace Zidar .................................................................................................................................................................. 45
KL-3 ANTIMICROBIAL POTENTIAL OF 1,2,4-OXADIAZOLES AND THEIR SYNTHESIS
Marta Kučerová-Chlupáčová, Anastasia Katirtzi, Pavlina Dzamova, Lucie Kolcarkova, Klara Konecna,
Ondrej Jandourek and Veronika Opletalova ............................................................................................................ 46
17
KL-4 RATIONAL DESIGN OF PI4KB INHIBITORS AS POTENTIAL BROAD-SPECTRUM ANTIVIRAL AGENTS

Radim Nencka, Ivana Mejdrová, Dominika Chalupská, Pavla Plačková, Christin Müller, Michal Šála, Eliška
Procházková, Adriana Baumlová, Milan Dejmek, Dmytro Strunin, Jan Weber, Gary Lee, Helena Mertlíková-
Kaiserová, John Ziebuhr, Gabriel Birkus and Evzen Boura.......................................................................................47
KL-5 DESIGN AND SYNTHESIS OF NOVEL MODULATORS OF TOLL-LIKE RECEPTORS AND
INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE (IDO1)
Matej Sova, Urban Švajger, Kaja Rožman, Damijan Knez, Samo Lešnik, Janez Konc and Stanislav Gobec ........... 48
KL-6 NEW DRUG CONJUGATES BASED ON AZASTEROIDS OR PEPTIDES FOR TARGETED DRUG DELIVERY IN
CANCER THERAPY
Vasiliki Sarli................................................................................................................................................................. 49
KL-7 A "LIBRARY-ON-LIBRARY" SCREENING APPROACH TO IDENTIFY SMALL-MOLECULE LIGANDS OF
METHYL-LYSINE READER PROTEINS
Gianluca Sbardella .....................................................................................................................................................50
KL-8 APPLICATION OF UGI MULTICOMPONENT REACTION IN SYNTHESIS OF NOVEL 2,6-DIKETOPIPERAZINE
DERIVATIVES WITH HIGH AND BROAD ACTIVITY IN ANIMAL MODELS OF EPILEPSY
Maciej Dawidowski ....................................................................................................................................................51
KL-9 HYBRID COMPOUNDS IN THE SEARCH FOR THE NEW HIGHLY EFFECTIVE ANTICONVULSANTS
Krzysztof Kaminski .....................................................................................................................................................52
KL-10 CAN MULTIVARIATE STATISTICS AID TO THE REVEAL OF BIOACTIVE COMPOUNDS?
AN NMR AND HPTLC APPROACH
V. I. Boka, K. Stathopoulou, D. Benaki, E. Gikas, E. Mikros and N. Aligiannis..........................................................53
KL-11 ENDOCANNABINOID SYSTEM MODULATION: THERAPEUTIC IMPLICATIONS AND FUTURE PERSPECTIVES
Marco Macchia ..........................................................................................................................................................54
KL-12 COMPUTATIONAL INSIGHT INTO THE CATALYTIC ACTIVITY OF MONOAMINE OXIDASE ENZYME FOR
TARGETING NEUROLOGICAL DISEASES
Robert Vianello ..........................................................................................................................................................55
KL-13 LIGAND-BASED DRUG DESIGN OF NOVEL ALDOSE REDUCTASE INHIBITORS FROM
DATABASES OF INDOLE-1-ACETIC ACIDS
Magdaléna Májeková, Jana Ballekova, Marta Soltesova Prnova and Milan Stefek ...............................................56
KL-14 PRETARGETED PRODRUG ACTIVATION THROUGH BIOORTHOGONAL ELIMINATION
Hannes Mikula ...........................................................................................................................................................57
KL-15 PATIENT DERIVED TESTING SYSTEMS – REACHING BEYOND TARGED BASED DRUG DISCOVERY
Vesna Eraković Haber ................................................................................................................................................58
ORAL PRESENTATIONS
OP-1 ANTI-HELICOBACTER PYLORI ACTIVITY OF A NOVEL DERIVATIVE OF INTERVENOLIN
Manabu Kawada, Tomokazu Ohishi, Hikaru Abe, Chigusa Hayashi, Chiharu Sakashita, Shun-ichi Ohba, Hiroyuki
Inoue, Masayuki Igarashi, Takumi Watanabe and Masakatsu Shibasaki ................................................................60
OP-2 IN VITRO PHOTODYNAMIC ACTIVITY OF A NEW TRI-CATIONIC AMPHIPHILIC PORPHYRIN
AGAINST HERPES SIMPLEX VIRUS 1, BACTERIA AND CANCER CELLS
Nela Malatesti, Maja Cokarić Brdovčak, Lara Djaković, Igor Jurak, Anđelo Šuvak, Ivana Gobin, Anja Harej and
Sandra Kraljević Pavelić ............................................................................................................................................. 61
OP-3 DISCOVERY OF NEW, POTENTIAL ANTI-INFECTIVE COMPOUNDS BASED ON CARBONIC ANHYDRASE
INHIBITORS BY RATIONAL TARGET-FOCUS REPURPOSING APPROACH
G. Annunziato, A. Angeli, F. D’Alba, A. Bruno, M. Pieroni, D. Vullo, V. De Luca, C. Capasso, C. T. Supuran and
G. Costantino .............................................................................................................................................................62
OP-4 DISCOVERY OF NOVEL GYRASE B INHIBITORS AND GYRASE B/TOPOISOMERASE IV (PARE)
DUAL INHIBITORS WITH IN VITRO ANTIBACTERIAL ACTIVITY
Michaela Barančoková, Janez Ilaš, Tihomir Tomašič, Nace Zidar, Andraž Lamut, Davide Benedetto Tiz, Päivi
Tammela, Antonio Felici, Vanesa Garrido and Danijel Kikelj ...................................................................................63
18
OP-5 FIGHTING ANTIMICROBIAL RESISTANCE BY BREAKING RESISTANCE MECHANISMS

Tommaso Felicetti, Rolando Cannalire, Giuseppe Manfroni, Maria Letizia Barreca, Sabatini Stefano, and
Violetta Cecchetti ......................................................................................................................................................64
OP-6 Α-ENAMINONES: NEW BUILDING BLOCKS FOR DIRECT SYNTHESIS OF BIOLOGICALLY ACTIVE ALKALOIDS
David Lankri, Ghassan Albarghouti and Dmitry Tsvelikhovsky ................................................................................65
OP-7 NOVEL BENZO[B]FURAN DERIVATIVES – BIOLOGICAL ACTIVITY AND PROTEIN TARGET
IDENTIFICATION IN LEUKEMIC CELLS
Marcin J. Cieślak, Karolina Królewska, Julia Kaźmierczak-Barańska, Milena Sobczak, Bożena Kuran, Mariola
Napiórkowska, Jerzy Kossakowski, Iwona Wybrańska and Barbara Nawrot ..........................................................66
OP-8 DEVELOPMENT OF NOVEL DRUG CANDIDATE AGAINST PROSTATE CANCER
Moran Shubely, Dhanoop Manikoth Ayyathan, Michael Shokhen, Michael Blank and Arie Gruzman.................67
OP-9 EVALUATION OF HALOGEN BONDING HOT SPOTS BY VIRTUAL SCREENING OF COMMERCIAL DATABASES
– A CASE STUDY OF 5-HT7R
Rafał Kurczab, Grzegorz Satała and Andrzej J. Bojarski ...........................................................................................68
OP-10 BIG DATA: AVOGADRO STOICHIOMETRY EXPLAINS HYPERBOLIC LIGAND EFFICIENCY TREND
Jaroslaw Polanski, Urszula Kucia, Aleksandra Tkocz, Roksana Duszkiewicz and Anna Pedrys ..............................69
OP-11 FROM PUBLIC DOMAIN COMPOUND COLLECTIONS TO CELL-ACTIVE EPIGENETIC MODULATORS.
THE CASE OF THE NCI REPOSITORY
Vassilios Myrianthopoulos, Nadine Martinet, Christian Bronner, Jessica Ann Downs, Susanne Müller,
Stefan Knapp and Emmanuel Mikros .......................................................................................................................70
OP-12 MASS SPECTROMETRIC IMAGING AS A PRECLINICAL TOOL FOR MEDICINAL CHEMISTS
Thavendran Govender ...............................................................................................................................................71
OP-13 PYRAZOLOQUINOLINONES, REVISITED GABAA RECEPTOR TOOL COMPOUNDS
David Chan Bodin Siebert, Xenia Simeone, Konstantina Bampali, Marko Mihovilovic, Michael Schnürch and
Margot Ernst ..............................................................................................................................................................72
OP-14 SYNTHESIS OF TISSUE-SPECIFIC CONJUGATES FOR TARGETED DRUG DELIVERY INTO HEPATIC CELLS
S. Yu. Maklakova, V. V. Hapko, R. A. Petrov, T. S. Zatsepin, T. O. Abakumova, O. V. Sergeeva,
E. K. Beloglazkina, N. V. Zyk, V. E. Koteliansky and A. G. Majouga .......................................................................... 73
OP-15 NOVEL POLYCYCLIC N-ACYLPYRROLIDINES AS 11Β-HSD1 INHIBITORS
Rosana Leiva, Constantí Seira, Andrew McBride, Margaret Binnie, Axel Bidon-Chanal, F. Javier Luque,
Scott P. Webster and Santiago Vázquez ...................................................................................................................74
OP-16 ENANTIOSPECIFIC MODULATION OF A2B ADENOSINE RECEPTOR
Maria Majellaro, Jhonny Azuaje, Carlos Carbajales, Abel Crespo, Angela Stefanachi, Cosimo Altomare,
Saverio Cellamare, María I. Loza, José Brea, María I. Cadavid, Hugo Gutiérrez de Terán and Eddy Sotelo.......... 75
POSTERS
P-1 FREE RADICAL SCAVENGING POTENCY OF DIHYDROCAFFEIC ACID: THERMODYNAMICS OF 2H+/2e–
PROCESSES
Ana Amić, Zoran Marković, Jasmina Dimitrić Marković, Bono Lučić and Dragan Amić ......................................... 77
P-2 RADICAL SCAVENGING AND COX-2 INHIBITION BY COLON METABOLITES OF POLYPHENOLS:
A THEORETICAL APPROACH
Ana Amić, Zoran Marković, Jasmina M. Dimitrić Marković, Svetlana Jeremić, Bono Lučić and Dragan Amić ...... 78
P-3 CYTOTOXICITY OF A KOJIC ACID DERIVATIVE ON A375 HUMAN MALIGNANT MELANOMA AND HGF1
FIBROBLAST CELLS
M. D. Aytemir, G. Karakaya, A. Ercan and S. Öncül .................................................................................................. 79
P-4 DESIGN AND SYNTHESIS OF NOVEL TARGETED CHEMICAL CHAPERONES AS A BASIS FOR AMYOTROPHIC
LATERAL SCLEROSIS (ALS) TREATMENT
Salome Azoulay-Ginsburg, Tamar Getter, Edward Korshin and Arie Gruzman......................................................80
19
P-5 MULTICOMPONENT SYNTHESIS OF NOVEL ANDROSTANO-PYRIMIDINES AND THEIR PHARMACOLOGICAL

EVALUATION IN VITRO
Ádám Baji, Éva Frank and Mónika Kiricsi ..................................................................................................................81
P-6 A COMPARATIVE MOLECULAR MODELLING STUDY OF MAO-A, MAO-B AND SSAO INHIBITORS
Balázs Balogh, Michela Contu, Elias Maccioni and Péter Mátyus ........................................................................... 82
P-7 IDENTIFICATION OF NEW KDM4 INHIBITORS THROUGH A HTS AND HIT REFINEMENT STRATEGY
A. L. Balzano, F. Sarno, C. Milite, G. Franci, I. Forné, L. Altucci, A. Ihmof, S. Castellano and G. Sbardella ............ 83
P-8 SYNTHESIS AND ANTIOXIDATIVE ACTIVITY OF SOME QUATERNARY 3-HYDROXYQUINUCLIDINIUM SALTS
DETERMINED BY DPPH METHOD
Linda Bazina, Matilda Šprung, Barbara Soldo and Renata Odžak ........................................................................... 84
P-9 PHYTOCHEMICAL COMPOSITION AND BIOLOGICAL ACTIVITY OF THE EXTRACTS OF
SATUREJA SUBSPICATA VIS. GROWING IN BOSNIA AND HERZEGOVINA
Mejra Bektašević, Ivana Carev, Marin Roje, Mladenka Jurin and Olivera Politeo..................................................85
P-10 NOVEL ANTICANCER DRUGS DISPIRO-OXINDOLE SERIES BASED ON VARIOUS TYPES OF HETEROCYCLES:
SYNTHESIS AND BIOLOGICAL TESTING
A. A. Beloglazkina, A. A.Barashkin, G. A. Kotovskii, M. A. Kunin, N. A. Karpov, M. E. Kukushkin, E. K.
Beloglazkina, N. V. Zyk D. A. Skvortsov, N. A. Vorobyeva and A. G. Majouga ........................................................86
P-11 OSTEOBLASTIC CELL BEHAVIOUR ON DIFFERENT TITANIUM - SURFACE ANALYSIS
M. Lukaszewska-Kuska, R. Majchrowski and B. Dorocka-Bockowska ..................................................................... 87
P-12 A NOVEL CLASS OF HIGHLY POTENT SMALL MOLECULE INHIBITORS OF RHINOVIRUS REPLICATION:
6-{[2-(METHYLCARBAMOYL)PYRIDIN-4-YL]OXY}BENZO[B]THIOPHENE-2-CARBOXYLIC ESTER DERIVATIVES
S. B. Han, J. W. Kim, U.-K. Jung, J. Y. Lee, C. Kim and Y.-S. Jung ..............................................................................88
P-13 SYNTHESIS, DOCKING AND ANTI-CANDIDA ACTIVITY OF SOME NEW 1,4-PHENYLENE-BISTHIAZOLES AS
INHIBITORS OF LANOSTEROL 14α-DEMETHYLASE
Anca-Maria Borcea, Ilioara Oniga, Gabriel Marc, Dan C Vodnar, Adrian Pîrnău, Laurian Vlase,
Andreea Pricopie, Brîndușa Tiperciuc and Ovidiu Oniga .........................................................................................89
P-14 SCREENING OF BIOLOGICAL ACTIVITY OF CENTAUREA SPECIES AQUEOUS EXTRACTS
Ivana Carev, Anja Golemac, Sanda Raić, Jelena Žarković, Ana Kelavić, Maria Šarić, François-Xavier Pellay and
Olivera Politeo............................................................................................................................................................90
P-15 ANTIOXIDANT ACTIVITY AND LIPOPHILICITY EVALUATION OF SOME NEW THIAZOLYL-TRIAZOLE
SCHIFF BASES
Cezar Login, Daniela Benedec, Ioana Ionuţ, Cristina Nastasă, Anca Stana, Ovidiu Oniga and Brîndușa Tiperciuc ....... 91
P-16 NOVEL 2,4-DIAMINOPYRIMIDINE BEARING FUSED TRICYCLIC RING MOIETY FOR ANAPLASTIC
LYMPHOMA KINASE (ALK) INHIBITOR
Chang-Soo Yun, Chong Ock Lee, Hyoung Rae Kim, Chi Hoon Park, Pilho Kim and Jong Yeon Hwang ..................92
P-17 TARGETED DELIVERY OF CYTOTOXIC AGENTS VIA cRGD PEPTIDE IN CANCER THERAPY AND
THERANOSTICS
Theodora Chatzisideri, Savvas Thysiadis, Sotirios Katsamakas, Theodore Lazarides and Vasiliki Sarli .................93
P-18 METHODS OF SYNTHESIS OF BIOLOGICALLY ACTIVE ANALOGUES AND HOMOLOGUES
AMINOPHOSPHONATES AND AMINOBISHOSPHONATES
Ewa Chmielewska, Joanna Wietrzyk and Paweł Kafarski.........................................................................................94
P-19 MOLECULAR MODELING AND DYNAMICS STUDIES OF LIGAND-DEPENDENT CONFORMATIONAL
MACROSTATES OF A2A ADENOSINE RECEPTOR
Yoonji Lee, Changbong Hyeon and Sun Choi............................................................................................................ 95
P-20 NEW DICARBOXIMIDE DERIVATIVES – ANTICANCER ACTIVITY AND MECHANISM OF ACTION
Julia Kaźmierczak-Barańska, Karolina Królewska, Marcin J Cieślak, Milena Sobczak, Bożena Kuran, Mariola
Napiórkowska, Jerzy Kossakowski and Barbara Nawrot ..........................................................................................96
P-21 ANTIPROLIFERATIVE ACTIVITY OF QUINONE METHIDES WITH BODIPY CHROMOPHORE
Matej Cindrić, Nikola Basarić, Irena Martin Kleiner, Lidija Uzelac and Marijeta Kralj............................................ 97
P-22 MEPHEDRONE METABOLITES AND DERIVATIVES
Daniela Cintulova, Laurin Wimmer, Harald H. Sitte and Marko D. Mihovilovic .....................................................98
20
P-23 NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2-OXAADAMANTANE MOIETY I:

PIPERIDINE DERIVATIVES
Sandra Codony, Javier Pizarro, Elena Valverde, Eugènia Pujol, M. Isabel Loza, J. Manuel Brea, Elena Sáez,
Julen Oyarzábal, Belén Pérez, Rosana Leiva, Manuel Vázquez-Carrera and Santiago Vázquez ............................99
P-24 NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2-OXAADAMANTANE MOIETY II:
AROMATIC DERIVATIVES
Eugènia Pujol, Javier Pizarro, Elena Valverde, Sandra Codony, Tiziana Ginex, M. Isabel Loza, J. Manuel Brea, Belén
Pérez, Elena Sáez, Julen Oyarzábal, F. Javier Luque, Rosana Leiva, Manuel Vázquez-Carrera, Santiago Vázquez..........100
P-25 BIOLOGICAL ACTIVITIES OF EXTRACTS FROM THYME (THYMUS VULGARIS) LEAVES
Biljana Damjanović-Vratnica, Slađana Krivokapić, Snežana Pantović and Svetlana Perović................................101
P-26 SYNTHESIS, ANTICANCER ACTIVITY AND DOCKING STUDIES OF NEW PHENYLAMINOPYRIMIDINE
DERIVATIVES
Aslı Demirci, İrem Durmaz, Rengül Çetin Atalay, and İlkay Küçükgüzel ................................................................102
P-27 RADIOLABELED 1,2,4,5-TETRAZINES AS BIOORTHOGONAL IMAGING TOOLS
Christoph Denk, Martin Wilkovitsch, Thomas Wanek, Claudia Kuntner Hannes, Dennis Svatunek and Hannes Mikula103
P-28 IDENTIFICATION OF EXPANDED CAG REPEATS LIGANDS TO COUNTERACT HUNTINGTON’S DISEASE
Jenny Desantis, Kenji Schorp, Serena Massari, Anna Bochicchio, Frank Matthes, Judith Schilling, Stephanie
Weber, Nina Offermann, Paolo Carloni, Kamyar Hadian, Giulia Rossetti, Oriana Tabarrini and Sybille Krauss .104
P-29 SYNTHESIS OF SOME NEW BENZOTHIAZOLONE DERIVATIVES AND INVESTIGATION OF THEIR
CHOLINESTERASE INHIBITOR ACTIVITIES
Deniz S. Doğruer, Merve Erdoğan and Burcu Kılıç .................................................................................................105
P-30 LONG-CHAIN DERIVATIVES OF (TRIFLUOROMETHYLPHENYL)PIPERAZINES – SYNTHESIS AND EVALUATION
OF THE ACTIVITY TOWARDS 5-HT RECEPTORS
Anna Drabczyk, Jolanta Jaśkowska, Damian Kułaga, Grzegorz Satała and Magdalena Malinowska ...................106
P-31 SYNTHESIS AND EVALUATION OF THE ACTIVITY TOWARDS 5-HT RECEPTORS OF NEW LIGANDS FROM THE
LCAPS GROUP
Anna Drabczyk, Jolanta Jaśkowska, Damian Kułaga, Grzegorz Satała and Magdalena Malinowska ...................107
P-32 SYNTHESIS OF PHOTOSWITCHABLE INHIBITORS FOR CNS APPLICATIONS
D. Dreier, M. Holy, K. Jäntsch, H. H. Sitte and M. D. Mihovilovic ..........................................................................108
P-33 AER METHOD: A GOOD WAY TO OBTAIN APIs AS IONIC LIQUIDS
E. Alcalde, I. Fallon, F. Roig, J. Esquena, M. J. García-Celma and I. Dinarès..........................................................109
P-34 SYNTHESIS OF SOME NEW BENZOXAZOLONE DERIVATIVES AND EVALUATION OF THEIR CHOLINESTERASE
INHIBITOR ACTIVITIES
Merve Erdoğan, Burcu Kılıç and Deniz S. Doğruer .................................................................................................110
P-35 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW SERIES OF DIHYDROXYLATED
2,6-DIPHENYL-4-CHLOROPHENYLPYRIDINES: DNA NON-INTERCALATIVE CATALYTIC
TOPOISOMERASE I & IIα DUAL INHIBITOR
Eung-Seok Lee, Ganesh Bist, Til Bahadur Thapa Magar, Aarajana Shrestha, Pramila Katila and Youngjoo Kwon......111
P-36 SYNTHESIS OF RING A-FUSED PYRAZOLE REGIOISOMERS IN THE ANDROSTANE SERIES AND AN
EVALUATION OF THEIR CELL-GROWTH INHIBITORY EFFECTS IN VITRO
Éva Frank, Ádám Baji, Gergő Mótyán and István Zupkó ........................................................................................112
P-37 SYNTHESIS, CYTOSTATIC AND ANTIBACTERIAL EVALUATIONS OF N-4-BENZOYLCYTOSINE–1,2,3-TRIAZOLE
AND 7-DEAZAPURINE–1,2,3-TRIAZOLE HYBRIDES
Maja Stipković Babić, Mande Miošić, Moris Mihovilović, Marijana Jukić, Ljubica Glavaš-Obrovac, Domagoj
Drenjančević, Silvana Raić-Malić and Tatjana Gazivoda Kraljević .........................................................................113
P-38 STERANE-FUSED PYRAZOLES: AN EFFICIENT MICROWAVE-ASSISTED SYTHESIS ON RING A
Gergő Mótyán, Réka Kiss-Faludy, János Wölfilng and Éva Frank ..........................................................................114
P-39 BROADLY EFFECTIVE METAL CHELATORS, AS INFLUENZA PA ENDONUCLEASE AND HEPATITIS C VIRUS INHIBITORS
Erofili Giannakopoulou, Annelies Stevaert, Efseveia Frakolaki, Vassilios Myrianthopoulos, Emmanuel Mikros,
Ralf Bartenschlager, Niki Vassilaki, Lieve Naesens and Grigoris Zoidis .................................................................115
21
P-40 ORGANOCATALYSIS MEETS BETA LACTAMS

Thavendran Govender, Tricia Naicker, Hendrik G. Kruger and Per I. Arvidsson ..................................................116
P-41 SEARCH FOR 5-HT6 RECEPTOR AGENTS AMONG TRIAZINE DERIVATIVES OF HYDANTOIN
Jadwiga Handzlik, Rafał Kurczab, Dorota Łażewska, Małgorzata Więcek, Angelika Nowakowska, Grzegorz
Satała, Andrzej J. Bojarski and Katarzyna Kieć-Kononowicz ..................................................................................117
P-42 NOVEL SYNTHESIS OF (+)-DIENOMYCIN C AND ANALOGOUS COMPOUNDS WITH ANTIBACTERIAL ACTIVITY
Hajime Yokoyama, Yuko Hayashi, Hiromi Ejiri, Masahiro Miyazawa and Yoshiro Hirai .......................................118
P-43 NOVEL para SUBSTITUTED N-ARYL 3-HYDROXYPYRIDIN-4-ONE MANNOSIDES: SYNTHESIS,
HEMAGGLUTINATION INHIBITORY PROPERTIES AND MOLECULAR MODELING
V. Petrović Peroković, Ž. Car, K. Meglić, R. Ribić, T. Tandarić, R. Vianello and S. Tomić ......................................119
P-44 ANTIBACTERIAL AND ANTIPROLIFERATIVE ACTIVITY OF NOVEL 2-BENZIMIDAZOLYL AND 2-
BENZOTHIAZOLYL SUBSTITUED BENZOTHIENO-2-CARBOXAMIDES
Maja Cindrić, Mihaela Perić, Marijeta Kralj, Irena Martin Kleiner, Hana Čipčić Paljetak, Mario Matijašić,
Donatella Verbanac, Grace Karminski-Zamola and Marijana Hranjec ..................................................................120
P-45 SYNTHESIS OF DIPEPTIDES CONTAINING PHOTOCHEMICALLY REACTIVE MODIFIYED TYROSINE AND
EVALUATION OF THEIR DNA BINDING
Antonija Husak, Josipa Matić, Ivo Piantanida and Nikola Basarić .........................................................................121
P-46 TARGETED DEGRADATION OF ANAPLASTIC LYMPHOMA KINASE (ALK) BY APPLYING THE PROTEOLYSIS
TARGETING CHIMERAS (PROTAC)
Jong Yeon Hwang, Chi-Hoon Park, Dong Ho Lee, Chung Hyo Kang, Chong Ock Lee and Jae Du Ha ...................122
P-47 LIPOPHILICITY EVALUATION AND IN SILICO ADME-TOX STUDIES OF SOME NOVEL THIOSEMICARBAZONE
AND 1,3,4-THIADIAZOLINE DERIVATIVES
Ioana Ionuț, Gabriel Marc, Ovidiu Oniga and Brîndușa Tiperciuc .........................................................................123
P-48 SYNTHESIS OF NOVEL RING STRUCTURES AS GABAA RECEPTOR LIGANDS WITH
FUNCTIONAL SELECTIVITY
Maria Teresa Iorio, Laurin Wimmer, Konstantina Bampali, Margot Ernst and Marko Mihovilovic ....................124
P-49 SYNTHESIS AND BIOLOGICAL EVALUATION OF CHALCONE DERIVATIVES AS NEUROPROTECTIVE AGENTS
FOR PARKINSON’S DISEASE
Bo Ko Jang, Ji Won Choi, Jong-Hyun Park, Seul Ki Yeon, Si Won Kim, Yerim Lee, Su Jeong Shin, Hyeon Jeong
Kim, Hyeon Ji Kim, Yong Gu Kang, Ae Nim Pae and Ki Duk Park ...........................................................................125
P-50 SYNTHESIS, STRUCTURE-ACTIVITY RELATIONSHIPS, AND MOLECULAR MODELING STUDIES OF NEW LONG-
CHAIN CHLOROARYLPIPERAZINES DERIVATIVES AS 5-HT7 AND 5-HT1A RECEPTOR LIGANDS
Jolanta Jaśkowska, Paweł Śliwa, Zbigniew Majka, Anna K. Drabczyk, Damian Kułaga, Magdalena Malinowska
and Grzegorz Satała .................................................................................................................................................126
P-51 NEW METHODS FOR SYNTHESIS OF THE TRAZODONE ANTIDEPRESSANT
Przemysław Zaręba, Jolanta Jaśkowska and Zbigniew Majka................................................................................127
P-52 PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS NOVEL POTENT ANTI-INFLAMMATORY AGENTS
Hui Rak Jeong, Sun Yeung Kim and Jae Yeol Lee ....................................................................................................128
P-53 DESIGN, SYNTHESIS AND EVALUATION OF INDOLE DERIVATIVES AS MULTIFUNCTIONAL AGENTS AGAINST
ALZHEIMER’S DISEASE
Jacques Joubert, Ireen Denya and Sarel F. Malan..................................................................................................129
P-54 3,4-DIHYDROQUINAZOLINE DERIVATIVES AS NOVEL AND SELECTIVE BUTYRYLCHOLINESTERASE INHIBITORS
Da Woon Jung, Jin Han Kim, Hong Bin Yoon and Jae Yeol Lee ..............................................................................130
P-55 HIGH THROUGHPUT SCREENING FOR DIPEPTIDYL PEPTIDASE III INTERACTING PROTEINS
Snježana Jurić, Katarzyna Kliza, Koraljka Husnjak and Mihaela Matovina ............................................................131
P-56 IN VITRO, IN VIVO AND MOLECULAR MODELING STUDIES OF N-(3-{4-[3-(TRIFLUOROMETHYL)PHENYL]-
PIPERAZIN-1-YL}PROPYL)-1H-INDAZOLE-3-CARBOXAMIDE (D2AAK3) AS A POTENTIAL ANTIPSYCHOTIC
Agnieszka A. Kaczor, Katarzyna M. Targowska-Duda, Marta Kruk-Słomka, Andrea G. Silva, Peter Kolb,
Antti Poso, Grażyna Biała and Marian Castro.........................................................................................................132
22
P-57 DIRECT PHOSPHONYLATION OF HETEROAROMATIC COMPOUNDS AS A MEAN TO SYNTHESIZE CYTOTOXIC

AGENTS
Ewa Chmielewska, Monika Prokopowicz, Natalia Wojtowicz, Joanna Wietrzyk, Piotr Młynarz and
Paweł Kafarski ..........................................................................................................................................................133
P-58 EVALUATION OF ANTIMYCOBACTERIAL ACTIVITY FOR A RANGE OF POLYCYCLIC AMANTADINE AND
PENTACYCLOUNDECANE DERIVATIVES
Erika Kapp, Jacques Joubert, Samantha L. Sampson, Margaretha de Vos and Sarel F. Malan............................134
P-59 DEVELOPMENT OF A DISINFECTANT PRODUCT CONTAINING THE ESSENTIAL OIL EXTRACTED FROM
ROSMARINUS OFFICINALIS L.
Fetta Kessal, Amina Dahmoune, Amina Azzam, Boumrar Silia and Boualem Samia............................................135
P-60 DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF D-RING OPENED 17-β ESTRADIOL
ANALOGUES AS ESTROGEN RECEPTOR SUBTYPE-SELECTIVE LIGANDS
Sun Young Lee, Yun Seon Song, Minsun Chang and Hee-Doo Kim .......................................................................136
P-61 SYNERGISTIC ANTICANCER EFFECT OF T-TYPE CALCIUM CHANNEL BLOCKER AND
CHEMOTHERAPEUTIC AGENTS IN HUMAN LUNG CANCER
Jin Han Kim, Hong Bin Yoon, Da Woon Jung and Jae yeol Lee ..............................................................................137
P-62 DISCOVERY OF PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS NOVEL AND SELECTIVE mPGES-1
INHIBITORS
Sun Young Kim, Hui Rak Jeong and Jae yeol Lee ....................................................................................................138
P-63 RUTHENIUM-BASED CATALYSTS FOR ASYMMETRIC TRANSFER HYDROGENATION
Andrea Kišić, Michel Stephan, Barbara Mohar, Andrej Emanuel Cotman, and Dominique Cahard ...................139
P-64 THE PREPARATION OF THE FOUR STEREOISOMERS OF 16-HYDROXYMETHYL-13-EPI-ESTRA-
1,3,5(10)-TRIEN-17-OL-3-METHYL-, AND 3-BENZYLETHERS
Anita Kiss, János Wölfling and Gyula Schneider .....................................................................................................140
P-65 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF CXCR3 AND CXCR4 MODULATORS WITH
PYRAZOLOPYRIDINE SCAFFOLD
Anja Kolarič, Urban Švajger, Tihomir Tomašič, Nikola Minovski, Nuška Tschammer and Marko Anderluh .......141
P-66 CHEMICAL PROTEOMICS IN THE EVALUATION OF THE EGFRI LAPATINIB PHARMACOLOGY
Tatjana Kovačević, Krunoslav Nujić and Milan Mesić ............................................................................................142
P-67 MEDICAL CHEMICAL DEFENCE AGAINST CHEMICAL NERVE AGENT THREATS
Zrinka Kovarik, Nikolina Maček-Hrvat and Tamara Zorbaz....................................................................................143
P-68 ANTITUMOR ACTIVITY OF ANTHROLS THAT PHOTOCHEMICALLY GENERATE QUINONE METHIDES OR
REACTIVE OXYGEN SPECIES AND THEIR SELECTIVITY TOWARDS CANCER STEM CELLS
Lidija Uzelac, Đani Škalamera, Kata Mlinarić-Majerski, Nikola Basarić and Marijeta Kralj ..................................144
P-69 SURFACE INTERACTIONS BETWEEN OLIGOPEPTIDE DERIVATIVES OF SALICYLIC ACID AND
CALCITE AS A MODEL OF AN INORGANIC DRUG DELIVERY SYSTEM
Marko Ukrainczyk, Lara Štajner, Zlatko Brkljača, Robert Stepić, David Smith, Ana Sunčana Smith, Matija
Gredičak, Ivanka Jerić, Andreja Jakas and Damir Kralj ...........................................................................................145
P-70 OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCO-BACTERIAL ACTIVE AGENTS AND THEIR CONJUGATES
Krátký Martin, Baranyai Zsuzsa, Szilvia Bősze, Szabó Nóra, Vinšová Jarmila........................................................146
P-71 NOVEL 1,2,3-TRIAZOLYL-7-SUBSTITUTED COUMARINS AND BIS(COUMARIN-TRIAZOLYL)BENZENES:
SYNTHESIS, PHOTOPHYSICAL PROPERTIES AND CYTOSTATIC EVALUATION
Kristina Bobanović, Ema Horak, Lidija Furač, Marijeta Kralj, Lidija Uzelac, Ivana Murković Steinberg and
Svjetlana Krištafor ....................................................................................................................................................147
P-72 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL POTENT MDM2/P53 SMALL
MOLECULE INHIBITORS
M. E. Kukushkin, V. K. Novotortsev, V. E. Filatov, A. A. Beloglazkina, N. A. Vorobyeva, D. A. Skvortsov,
E. K. Beloglazkina, N. V. Zyk and A. G. Majouga .....................................................................................................148
P-73 SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL LONG CHAIN ARYLOPIPERAZINES (LACPs) WITH
PYRIDYL MOIETY AS LIGANDS FOR SEROTONIN RECEPTORS
Damian Kułaga, Jolanta Jaśkowska, Anna Drabczyk, Grzegorz Satała and Magdalena Malinowska ...................149
23
P-74 DIFFERENT ROLES OF HALOGEN SUBSTITUENTS IN LIGAND-RECEPTOR INTERACTIONS –

A CLASS A GPCRS CASE STUDY
Rafał Kurczab............................................................................................................................................................150
P-75 SYNTHESIS AND BIOLOGICAL POTENTIAL OF SERIES A AND B MODIFIED STEROIDAL D-LACTONES
Ivana Kuzminac, Marina Savić, Dimitar Jakimov, Olivera Klisuric, Andrea Nikolić and Marija Sakač ..................151
P-76 IN SILICO & IN VITRO EVALUATION OF NOVEL INHIBITORS OF MITOCHONDRIAL F1F0-ATPASE
Dimitrios Karagiannis, Panagiotis Efentakis, George Lambrinidis, Ioanna Andreadou and Emmanuel Mikros..152
P-77 3-AROYL-1,4-DIARYLPYRROLES INHIBIT CHRONIC MYELOID LEUKEMIA CELL GROWTH THROUGH AN
INTERACTION WITH TUBULIN
Giuseppe La Regina, Valentina Naccarato, Antonio Coluccia, Addolorata Maria Luce Coluccia,
Ernest Hamel and Romano Silvestri........................................................................................................................153
P-78 INHIBITION OF DENGUE VIRUS BY NOVEL INHIBITORS OF RNA-DEPENDENT RNA POLYMERASE AND
PROTEASE ACTIVITIES
Giuseppe La Regina, Valeria Famiglini, Domiziana Masci, Antonio Coluccia, Jin-Ching Lee, John Hiscott and
Romano Silvestri ......................................................................................................................................................154
P-79 PHENOXYMETHYL DERIVATIVES OF 1,3,5-TRIAZINE AS NOVEL CLASS OF 5-HT6 RECEPTOR LIGANDS
Dorota Łażewska, Małgorzata Więcek, Michał Stelmasiński, Grzegorz Satała, Rafał Kurczab,
Andrzej J. Bojarski, Katarzyna Kieć-Kononowicz and Jadwiga Handzlik ................................................................155
P-80 BLOCKADE OF RAS ACTIVITY BY INHIBITORS OF THE ENZYME ISOPRENYLCYSTEINE CARBOXYL
METHYLTRANSFERASE (ICMT)
S. Ortega-Gutiérrez, M. Martín-Fontecha, N. Marín-Ramos, F.J. Ortega, A. Gil, M. Balabasquer, I. Cushman,
I.R. Torrecillas, L. Pardo, P.J. Casey, M.R. Philips and M.L. López-Rodríguez .......................................................156
P-81 STUDY FOR THE DEVELOPMENT OF NEW PURINE ANALOGUES AS HIGHLY SPECIFIC LIGANDS AGAINST
FUNGAL NUCLEOBASE TRANSPORTERS
Efthymios-Spyridon Gavriil, Spyridon Dimitrakis, Nikolaos Lougiakis, George Lambrinidis, Emmanuel Mikros,
Panagiotis Marakos, Nicole Pouli and George Diallinas.........................................................................................157
P-82 SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL SMALL-MOLECULE PSMA-TARGETED PACLITAXEL
CONJUGATES
A. E. Machulkin, A. P. Ber, I. V. Saltykova, E. K. Beloglazkina, N. V. Zyk, V. E Koteliansky and A. G. Majouga ....158
P-83 DESIGN, SYNTHESIS AND IN VITRO EVALUATION OF MODULATORS OF PFKFB3 AUTOREGULATORY
DOMAIN
H.Macut, X.Hu, D.Tarantino, S.Pellegrino and M.L.Gelmi .....................................................................................159
P-84 ISOXAZOLE DERIVATIVES AS IMMUNOMODULATORS
Marcin Mączyński, Angelika Drynda, Stanisław Ryng and Bożena Obmińska-Mrukowicz ..................................160
P-85 PYRROLYL NON-DKA DERIVATIVES AS NOVEL INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE-ASSOCIATED
RIBONUCLEASE H FUNCTION
V. N. Madia, F. Saccoliti, G. Pupo, V.Tudino, F. Esposito, A. Corona, N. Grandi, E. Tramontano,
R. Costi and R.Di Santo ............................................................................................................................................161
P-86 NOVEL ANTIMALARIALS FROM NATURE: EVOLUTIONARY GENERATED VIRTUAL COMPOUND LIBRARIES
FROM NATURAL PRODUCTS WITH ANTIPLASMODIAL ACTIVITIES
Samuel Egieyeh, James Syce, Alan Christoffels and Sarel F. Malan ......................................................................162
P-87 THE SYNTHESIS OF NEW ARYLPIPERAZINES FOR CNS DISORDERS
Magdalena Malinowska, Jolanta Jaśkowska, Anna Drabczyk and Damian Kułaga...............................................163
P-88 BIOLOGICAL EVALUATIONS OF AMIDINE AND AMIDOXIME SUBSTITUTED HETEROCYCLES WITH
1,2,3-TRIAZOLYL SPACER
Silvija Maračić, Petra Grbčić, Mirela Sedić, Sandra Kraljević Pavelić and Silvana Raić-Malić ..............................164
P-89 DESIGN, SYNTHESIS AND CYTOTOXIC ACTIVITY EVALUATION OF NEW AMINOSUBSTITUTED

PYRAZOLOPYRIDINES
Nikolaos Lougiakis, Vasiliki Giannouli, Ioannis K. Kostakis, Panagiotis Marakos, Nicole Pouli,
Orestis Argyros and Constantin Tamvakopoulos ...................................................................................................165
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P-90 IN VITRO CITOTOXITY AND ANTI-TUMOR INVESTIGATION OF PHENYLBORONIC ACID

Maja Marasović, Mladen Miloš, Siniša Ivanković and Ranko Stojković ................................................................166
P-91 MICROWAVE ASSISTED SYNTHESIS OF SOME NEW THIAZOLIDINE-2,4-DIONE DERIVATIVES AS POTENTIAL
ANTIMICROBIAL AGENTS
Gabriel Marc, Ioana Ionuț, Dan Vodnar, Adrian Pîrnău, Brîndușa Tiperciuc and Ovidiu Oniga...........................167
P-92 WEB-4D-QSAR OF 17β-HYDROXYSTEROID DEHYDROGENASE TYPE 3 INHIBITORS
Eduardo B. de Melo, Tuanny P. Schmidt and João Paulo A. Martins ....................................................................168
P-93 WEB-4D-QSAR OF URACIL DERIVATIVES DESCRIBED AS THYMIDINE PHOSPHORYLASE INHIBITORS
João Paulo A. Martins and Eduardo B. de Melo.....................................................................................................169
P-94 SYNTHESIS AND DETERMINATION OF PHYSICOCHEMICAL PROPERTIES OF NEW POTENTIAL
ANTIMYCOBACTERIAL DRUGS
Pavlína Marvanová, Tereza Padrtová, Klára Odehnalová, Otakar Humpa and Petr Mokrý.................................170
P-95 EXPLORATION OF NEW ANTICANCER CHEMOTHERAPEUTIC AGENTS BASED ON ANTITUMOR NATURAL
PRODUCT ANDRASTINS
Shuqiang Yin, Quan Li, Aki Kohyama, Kenji Sugimoto and Yuji Matsuya ..............................................................171
P-96 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL PYRROLE-BASED AS EZH2 INHIBITORS
R. Mazzone, C. Zwergel, M. Tafani, A. Nebbioso, L. Altucci, A. Mai and S. Alente ...............................................172
P-97 SYNTHESIS OF NOVEL 13α-ESTRONE DERIVATIVES AS POTENTIAL 17β-HSD1 INHIBITORS
Ildikó Bacsa, Rebeka Jójárt, János Wölfling, Gyula Schneider, Bianka Edina Herman, Mihály Szécsi and
Erzsébet Mernyák ....................................................................................................................................................173
P-98 ANTITUMORAL AND ANTIVIRAL ACTIVITIES OF NOVEL 1,2,3-TRIAZOLYL APPENDED L-ASCORBIC ACID
DERIVATIVES
Andrijana Meščić, Anja Harej, Višnja Stepanić, Sandra Kraljević Pavelić, Dominique Schols and
Silvana Raić-Malić ....................................................................................................................................................174
P-99 IDENTIFICATION OF NEW INHIBITORS OF PRMTs BY A MULTI-SUBSTRATE-ADDUCT APPROACH
C. Milite, D. Rescigno, A. Feoli, S. Castellano and G. Sbardella .............................................................................175
P-100 SYNTHESIS AND EVALUATION OF NEW N-ACYLETHANOLAMINES PPAR-α LIGANDS PLANNED FROM
CARDANOL
Camila de Oliveira Miranda, Carolyn Cummins and Luiz A Soares Romeiro ........................................................176
P-101 DEVELOPMENT OF NOVEL REAGENTS FOR GENERATING ISLETS Β-CELLS AND ENHANCING THEIR FUNCTION
BASED ON CLUSTERED NANOFORMULATION OF NEUROLIGIN-2 MIMETICS
Munder Anna, Shtriker Efrat, Viskind Olga, Korshin Edward, Chessler Steven, and Gruzman Arie ....................177
P-102 TARGETING PLASMODIUM FALCIPARUM GLUCOSE-6-PHOSPHATE DEHYDROGENASE IN THE PURSUIT OF
NOVEL ANTIMALARIAL AGENTS
Diego Muñoz-Torrero, Nelson Alencar, Irene Sola, María Linares, Caterina Pont, Luca Di Palma, Carla
Barbaraci, Cristina Sampedro, Jordi Juárez-Jiménez, Paloma Abad, Susana Pérez-Benavente, Jerónimo
Lameira, José M. Bautista and F. Javier Luque .......................................................................................................178
P-103 A SYNTHESIS OF “DUAL WARHEAD” β ARYL ETHENESULFONYL FLUORIDES AND ONE-POT REACTION TO β
SULTAMS
Praveen K. Chinthakindi, Kimberleigh B. Govender, A. Sanjeeva Kumar, Hendrik G. Kruger, Thavendran
Govender, Tricia Naicker and Per I. Arvidsson .......................................................................................................179
P-104 SYNTHESIS AND CYTOTOXIC PROPERTIES OF NEW DERIVATIVES OF BENZOFURANS
M. Napiórkowska, M. Cieślak, K. Królewska, J. Kaźmierczak-Barańska and B. Nawrot ........................................180
P-105 INVESTIGATION OF THE ANTIPROLIFERATIVE AND ANTIHYPERGLYCEMIC ACTIVITIES OF NEW
THIAZOLIDINEDIONE DERIVATIVES
Cristina Nastasă, Daniel Scherman, Alina Pârvu, Ovidiu Oniga and Brîndușa Tiperciuc ......................................181
P-106 ANTICARCINOGENIC POTENTIAL OF PLUM (Prunus domestica L.) KERNEL EXTRACTS OBTAINED BY
SUBCRITICAL WATER
Nataša Nastić, Slavica Ražić, Ana Damjanović, Aleksandra Cvetanović, Višnja Gaurina Srček, Igor Slivac, Kristina
Radošević and Jaroslava Švarc-Gajić.......................................................................................................................182
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P-107 IN VITRO SCREENING OF ANTICARCINOGENIC PROPERTIES OF CHERRY STEM EXTRACTS OBTAINED BY

SUBCRITICAL WATER
Nataša Nastić, Višnja Gaurina Srček, Kristina Radošević, Igor Slivac, Aleksandra Cvetanović, Vesna Novakov and
Jaroslava Švarc-Gajić................................................................................................................................................183
P-108 DESIGN, SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW PIPERAZINAMIDES DERIVED FROM 3-
ISOBUTYL-2,5-DIOXOPYRROLIDIN-1-YL-ACETIC ACID
Jolanta Obniska, Małgorzata Góra, Sabina Rybka, Krzysztof Kamiński and Anna Rapacz ....................................184
P-109 IDENTIFICATION OF 3-[3, 4-BIS-(TERT-BUTYL-DIMETHYL-SILANYLOXY)-PHENYL]-PROPIONIC ACID AS
AN ADIPONECTIN EXPRESSION ENHANCER
Tsutomu Oikawa, Motomu Inoue, Yurie Ueno, Atsuko Motojima, Nobuyasu Matsuura, Tomio Saito and
Hiroyuki Osada .........................................................................................................................................................185
P-110 SYNTHESIS AND BIOLOGICAL ACTIVITY OF 3-AMINOTHYMOQUINONE
Una Glamočlija, Subhash Padhye, Selma Špirtović-Halilović, Amar Osmanović, Elma Veljović, Sunčica Roca,
Irena Novaković, Sandra Kraljević Pavelić, Anja Harej and Davorka Završnik.......................................................186
P-111 SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW PHENOXYACETHAMIDE DERIVATIVES OF
AMINES, AMINOALKANOLS OR AMINO ACIDS
Katarzyna Pańczyk, Anna Waszkielewicz, Dorota Żelaszczyk, Ewa Żesławska, Karolina Słoczyńska, Paulina
Koczurkiewicz, Elżbieta Pękala and Henryk Marona..............................................................................................187
P-112 THEORETICAL PREDICTION OF LIPOPHILICITY OF THIOSEMICARBAZIDE DERIVATIVES
Agata Paneth, Tomasz Plech, Dominika Janowska, Szymon Kosiek, Nazar Trotsko, and Monika Wujec ...........188
P-113 NOVEL SPIRO CARBOCYCLIC HYDANTOIN-DERIVATIVES WITH POTENT ANTITRYPANOSOMAL ACTIVITY
Vasiliki Pardali, Martin C. Taylor, John M. Kelly and Grigoris Zoidis......................................................................189
P-114 SYNTHESIS AND BIOLOGICAL EVALUATION OF HYDROXAMATE COMPOUNDS AS HDAC6 INHIBITORS
Hui Yeon Mok, Han Pyo Son, Seung Yeop Baek, Hyun-Ju Park and Young Hoon Jung ........................................190
P-115 DRUG DESIGN AND SYNTHESIS OF NEW INDOLYLARYLSULFONES AS HIV-1 NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
S. Passacantilli, V. Famiglini, G. La Regina, A. Coluccia, D.Masci, J. A. Estè, G. Maga and R. Silvestri .................191
P-116 NEW (AMINOMETHYLENE)BISPHOSPHONATES OBTAINED FROM HETEROCYCLIC AMINES AND THEIR
BIOLOGICAL ACTIVITY
Patrycja Miszczyk, Ewa Chmielewska, Błażej Dziuk, Joanna Wietrzyk and Paweł Kafarski..................................192
P-117 IS N-A ISOMERIZATION OF HUMAN SERUM ALBUMIN STILL IMPORTANT FOR THE INTERACTION WITH
LIGANDS?
Mariola Chudzik, Bartosz Pawełczak and Małgorzata Maciążek-Jurczyk..............................................................193
P-118 THE INFLUENCE OF FATTY ACIDS ON THEOPHYLINE BINDING TO GLYCATED SERUM ALBUMIN
Agnieszka Szkudlarek, Bartosz Pawełczak, Małgorzata Maciążek-Jurczyk ...........................................................194
P-119 SYNTHESIS, ANTIBACTERIAL ACTIVITY AND SAR STUDY OF NOVEL AMIDINO 2-SUBSTITUTED
BENZIMIDAZOLE DERIVATIVES
Nataša Perin, Marijana Hranjec, Mihaela Perić, Hana Čipčić Paljetak, Mario Matijašić, Višnja Stepanić,
Donatella Verbanac, Grace Karminski-Zamola and Kristina Starčević ..................................................................195
P-120 CHEMICAL COMPOSITION AND BIOACTIVE EFFECTS OF LAVENDER ESSENTIAL OIL FROM
MONTENEGRO
Svetlana Perović, Snežana Pantović, Valentina Šćepanović, Andrej Perović and
Biljana Damjanović-Vratnica .................................................................................................................................196
P-121 NOVEL СONJUGATES OF DOXORUBICIN WITH ASGP-RECEPTOR LIGANDS FOR TARGETED DELIVERY
R. A. Petrov, S. A. Petrov, E. E. Ondar, S. Yu. Maklakova, I. V. Saltykova, E. K. Beloglazkina,
A. G. Majouga and V. E. Koteliansky .......................................................................................................................197
P-122 SYNTHESIS, CHARACTERIZATION AND CYTOTOXICITY OF PHENOLIC COPPER(II) COMPLEXES
Vladimir P. Petrović, Dušica Simijonović, Zorica D. Petrović, Marko N. Živanović and Snežana D. Marković.....198
P-123 THIOSEMICARBAZIDE DERIVATIVES WITH 4-NITROPHENYL GROUP AS MULTI-TARGET DRUGS
Monika Pitucha, Małgorzata Miazga-Karska, Agnieszka A. Kaczor, Katarzyna Klimek, Zbigniew Karczmarzyk,
Maciej Woś, Waldemar Wysocki, Grazyna Ginalska, Zofia Urbanczyk-Lipkowska and Maja Morawiak.............199
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P-124 DESIGN AND SYNTHESIS OF NEW SUBSTITUTED NUCLEOSIDES AS POTENTIAL ANTI-HCMV AGENTS
Maria Gerasi, Georgios Papadakis, Nikolaos Lougiakis, Panagiotis Marakos and Nicole Pouli ...........................200
P-125 SCREENING PHYSIOLOGICALLY RELEVANT SUBSTRATES OF ALDOSE REDUCTASE: ENZYME
ACTIVITIES AND DIFFERENTIAL INHIBITION
Marta Soltesova Prnova, Jana Ballekova, Yoel Rodriguez, Magdaléna Májeková and Milan Stefek...................201
P-126 POST HEROIN DOSE TISSUE DISTRIBUTION OF 6-MONOACETYLMORPHINE (6-MAM) WITH MALDI IMAGING
Belin G Teklezgi, Annapurna Pamreddy, Sooraj Baijnath, Nirmala D Gopal, Tricia Naicker,
Hendrik G Kruger and Thavendran Govender ........................................................................................................202
P-127 RATIONAL DESIGN OF NEW POTENT NON-NUCLEOSIDE INHIBITORS OF TERMINAL DEOXYNUCLEOTIDYL
TRANSFERASE ACTIVE IN LEUKEMIC CELLS
G. Pupo, A. Coluccia, A. Messore, V. N. Madia, F.Saccoliti, L. Pescatori, R. Costi, G. Maga, E. Crespan and R. Di Santo..203
P-128 SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL 2-(HETERO)ARYL-6-(2-IMIDAZOLINYL)BENZO-
THIAZOLES AS ANTICANCER AGENTS
Livio Racané, Lucija Ptiček, Mirela Sedić, Petra Grbčić, Sandra Kraljević Pavelić, Irena Sović,
Grace Karminski-Zamola..........................................................................................................................................204
P-129 NEW PRIMAQUINE AMIDES WITH HYDROXYPHENYL AND HALOGENPHENYL SUBSTITUENTS
Zrinka Rajić Džolić, Maja Beus and Branka Zorc .....................................................................................................205
P-130 SYNTHESIS AND EVALUATION OF MULTI-TARGET LIGANDS PLANNED FROM CARDANOL FOR THE
TREATMENT OF ALZHEIMER'S DISEASE
Giselle de Andrade Ramos, Luiz A. Soares Romeiro, Manuela Bartolini, Paul E. Fraser and Ling Wu ................206
P-131 DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL G9A INHIBITORS FROM A SCAFFOLD
HOPPING APPROACH
D. Rescigno, C. Milite, M. Viviano, S. Castellano and G. Sbardella ........................................................................207
P-132 SYNTHESIS OF MULTIANTENNARY MANNOSE DERIVED DESMURAMYL PEPTIDES
Rosana Ribić, Marija Paurević, Nora Tir and Srđanka Tomić .................................................................................208
P-133 MOLECULAR MODELING AND SYNTHESIS OF PYRUVATE DEHYDROGENASE KINASE INHIBITORS AS A
POTENTIAL ANTICANCER TARGETS
Agata Rosińska, Urszula Kijkowska-Murak and Dariusz Matosiuk ........................................................................209
P-134 DISCOVERY OF NOVEL DIARYL SULFIDE DERIVATIVES AS INHIBITORS OF TRYPANOTHIONE REDUCTASE ENZYME
F. Saccoliti, V. N. Madia, G. Pupo, V. Tudino, G. Colotti, G. Angiulli, A. Fiorillo, P. Baiocco, T. Di Muccio, M.
Gramiccia, L. Scipione, R. Costi, A. Ilari and R. Di Santo.........................................................................................210
P-135 PSORALENE DERIVATIVES INHIBITORS OF THE β5i SUBUNIT OF THE IMMUNOPROTEASOME
Eva Shannon Schiffrer, Izidor Sosič, Martina Gobec, Irena Mlinarič-Raščan and Stanislav Gobec .....................211
P-136 THE APPLICATION OF FMO-EDA CALCULATION TO STUDY THE SELECTIVITY OF 2-CHLOROPHENYL-
PIPERAZIN DERIVATIVE TO SEROTONIN AND DOPAMINE RECEPTORS
Paweł Śliwa, Jolanta Jaśkowska and Rafał Kurczab ................................................................................................212
P-137 AN ASPARTATE-AMINE SALT BRIDGE – THE ETS-NOCV STUDY
Paweł Śliwa, Rafał Kurczab and Andrzej J. Bojarski................................................................................................213
P-138 STEROID RECEPTOR BINDING AFFINITIES OF SELECTED MODIFIED STEROIDS- A SCREENING TOOL FOR
IDENTIFICATION OF POTENTIAL THERAPEUTICS
Sofija S. Bekić, Marija N. Sakač, Suzana S. Jovanović-Šanta, Edward T. Petri and Andjelka S. Ćelić....................214
P-139 DEVELOPMENT OF BIOORTHOGONAL 2-NITROIMIDAZOLE BASED HYPOXIA SENSITIVE PROBES
Barbara Sohr, Christoph Denk, Thomas Wanek and Hannes Mikula ....................................................................215
P-140 NEUROPROTECTIVE POTENTIAL OF LINEZOLID: A QUANTITATIVE AND DISTRIBUTION STUDY VIA MASS
SPECTROMETRY
Sooraj Baijnath, Chivonne Moodley, Bongani Ngcobo, Sanil D. Singh, Gert Kruger, Per I. Arvidsson, Tricia
Naicker, Alexander Pym and Thavendran Govender .............................................................................................216
P-141 SYNTHESIS, ANTITUMOR AND ANTIOXIDATIVE ACTIVITY OF NITRO AND AMINO SUBSTITUTED
BENZIMIDAZOLE AND BENZOTHIAZOLE 2-CARBOXAMIDES
Irena Sović, Ida Boček, Petra Roškarić, Marijeta Kralj, Irena Martin Kleiner, Kristina Starčević and
Marijana Hranjec .....................................................................................................................................................217
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P-142 ESTIMATION OF BINDING AFFINITY FOR SOME SYNTHESIZED COUMARIN DERIVATIVES WITH RECEPTORS
IMPORTANT FOR BACTERIAL GROWTH AND DEVELOPMENT
Selma Špirtović-Halilović, Elma Veljović, Mirsada Salihović, Aida Šapčanin, Amar Osmanović, Nihada Škrijelj and
Davorka Završnik ......................................................................................................................................................218
P-143 ANTIBACTERIAL THIAZOLIN-4-ONES AS POTENTIAL DNA GYRASE AND TOPOISOMERASE IV INHIBITORS
Anca Stana, Radu Tamaian, Dan C. Vodnar, Ovidiu Oniga and Brîndușa Tiperciuc..............................................219
P-144 DESIGN, SYNTHESIS, X-RAY STUDIES AND BIOLOGICAL EVALUATION OF NOVEL CHALCONE DERIVATIVES –
POTENTIAL MICROTUBULE TARGETING AGENTS
Tomasz Stefanski, Rafał Kurczab, Artur Korzanski, Katarzyna Skonieczka, Barbara Grolik, Emilia Kania, Barbara Bojko,
Zbigniew Dutkiewicz, Agnieszka Gielara-Korzańska, Renata Mikstacka, Adam Hogendorf and Maciej Kubicki.........220
P-145 NOVEL DPDPE ANALOGUES INCORPORATING A XYLENE BRIDGE: SYNTHESIS AND BIOLOGICAL PROFILE
Azzurra Stefanucci, Giorgia Macedonio, Stefano Pieretti, Ferenc Zador, Sandor Benyhe and Mollica Adriano 221
P-146 IDENTIFICATION OF NOVEL STAT3 INHIBITORS AND SYNTHESIS-ASSISTED ELUCIDATION OF MOLECULAR
MECHANISM
Seungbeom Lee, Changjin Lim, Joonseong Hur and Young-Ger Suh ....................................................................222
P-147 HIGHLY REACTIVE DIENOPHILES FOR BIOORTHOGONAL TETRAZINE LIGATIONS
Dennis Svatunek, Maximilian Haider and Hannes Mikula .....................................................................................223
P-148 SYNTHESIS AND CYTOTOXIC ACTIVITY OF NEW DERIVATIVE OF ISOTHIAZOLOPYRIDINE
Piotr Świątek, Agnieszka Matera-Witkiewicz, Karolina Królewska-Golińska, Julia Kaźmierczak-Barańska, Marcin
Cieślak and Barbara Nawrot ....................................................................................................................................224
P-149 STUDIES ON ARYL-SUBSTITUTED PHENYLALANINES: SYNTHESIS, ACTIVITY AND DIFFERENT BINDING
MODES AT AMPA RECEPTORS
Ewa Szymańska, Birgitte Nielsen, Darryl S. Pickering and Tommy N. Johansen...................................................225
P-150 NOVEL AND EFFICIENT BICYCLIC GUANIDINE CATALYST FOR THE CYCLOTRIMERIZATION OF ISOCYANATES.
A QUANTUM CHEMICAL STUDY.
Tana Tandarić and Robert Vianello.........................................................................................................................226
P-151 DESIGN AND SYNTHESIS OF DUAL G9A METHYLTRANSFERASE/LSD1 DEMETHYLASE OR SELECTIVE
LSD1 INHIBITORS BY STRUCTURAL MANIPULATION OF THE QUINAZOLINE SCAFFOLD
Daniela Tomaselli, Alessia Lucidi, Mariantonietta Forgione, Gebremedhin Solomon Hailu, Valentina Speranzini,
Biagina Marrocco, Simona Pilotto, Andrea Mattevi, Dante Rotili and Antonello Mai .........................................227
P-152 HOMOLOGY MODELLING, STRUCTURE- AND LIGAND-BASED DRUG DESIGN OF NOVEL CALCIUM
CHANNEL BLOCKERS WITH LEISHMANICIDAL ACTIVITIES
Carlos Henrique Tomich de Paula da Silva, Leonardo Bruno Federico, Laura M. Alcântara, Carolina B. Moraes,
Lucio H. Freitas-Júnior and Joaquín M. Campos Rosa ...........................................................................................228
P-153 NOVEL D- GLUCOSAMINE N- PEPTIDYL DERIVATIVES ENDOWED WITH SELECTIVE ACTIVITY TOWARDS
IKK ALPHA
V. Tudino, V. N. Madia, F. Saccoliti, G. Pupo, R. Cocchiola, A. Scotto D’Abusco, R. Scandurra, R. Costi and R. Di Santo .229
P-154 MEMANTINE ANALOGUES WITH ACTIVITY AS GLUTAMATE N-METHYL D-ASPARTATE RECEPTOR
ANTAGONISTS
Andreea L.Turcu, Daina Martínez-Falguera, Francesc X. Sureda and Santiago Vázquez .....................................230
P-155 NOVEL THIAZOLES AS TRYPANOCIDAL AGENTS
Santiago Vázquez, Rosana Leiva, Jèssica Rubí, Martin C. Taylor, Belén Pérez and John M. Kelly .......................231
P-156 FLUORINATED PHENYLALANINE DERIVATIVES: VERSATILE BIOLOGICAL ACTIVITY
Martin Krátký, Jarmila Vinšová, Šárka Štěpánková, Jiřina Stolaříková ..................................................................232
P-157 DISCOVERY OF THE FIRST-IN-CLASS CHEMICAL PROBES FOR THE SPINDLIN1 METHYL-LYSINE
READER DOMAIN
M. Viviano, S. Castellano, M. T. Bedford, H. Li and G. Sbardella ...........................................................................233
P-158 HYDRAZINO PEPTIDOMIMETICS AS MODULATORS OF PROTEIN-PROTEIN INTERACTIONS
Kristina Vlahoviček-Kahlina, Luka Kavčič, Marija Marković, Janez Plavec, Ivo Piantanida and
Ivanka Jerić ...............................................................................................................................................................234
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P-159 SALICYLANILIDE MUTUAL PRODRUGS: SYNTHESIS AND BIOLOGICAL ACTIVITY

R. Vosátka, M. Krátký, J. Vinšová.............................................................................................................................235
P-160 SYNTHESIS AND PHARMACOLOGICAL ACTIVITY IN A GROUP OF PHENOXYALKYL DERIVATIVES OF
PIPERAZINE
Anna M. Waszkielewicz, Katarzyna Pańczyk, Karolina Pytka, Anna Rapacz, Monika Głuch-Lutwin, Agata Siwek,
Adam Bucki, Marcin Kołaczkowski and Henryk Marona........................................................................................236
P-161 STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF INTERVENOLIN, A NATURAL QUINOLONE WITH ANTI-
TUMOR AND ANTI-HELICOBACTER PYLORI ACTIVITIES
Takumi Watanabe, Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Shun-ichi Ohba, Hiroyuki Inoue,
Tomokazu Ohishi, Tohru Masuda, Chigusa Hayashi, Masayuki Igarashi and Masakatsu Shibasaki ....................237
P-162 DISCOVERY OF ISOQUINOLINOQUINAZOLINONES AS A NOVEL PPAR GAMMA ANTAGONISTS
Yifeng Jin,Younho Han, Daulat B. Khadka, Kwang Youl Lee and Won-Jea Cho.....................................................238
P-163 SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW S-TRIAZOLE DERIVATIVES
M. Wujec, A. Paneth, Ł. Popiołek, T. Plech, Sz. Kosiek, E. Kędzierska and J. Kotlińska ........................................239
P-164 DEVELOPMENT OF THE METHOD FOR HPLC ASSAY OF THE LIMОNIUM GMЕLINII DRY EXTRACT
G.Е. Zhussupova, D.T. Kassymova, A.I. Zhussupova...............................................................................................240
P-165 STRUCTURE-ACTIVITY AND MECHANISTIC STUDY OF INHIBITORY EFFECTS OF POLYSUBSTITUTED
PYRIMIDINES ON PROSTAGLANDIN E2 PRODUCTION
Zdeněk Zídek, Zlatko Janeba, Petr Jansa, Miloslav Kverka, Eva Kmoníčková, Filip Kalčic and
Viktor Kolman...........................................................................................................................................................241
P-166 DESIGN AND ANTIMYCOBACTERIAL EVALUATION OF COMPOUNDS COMBINING PYRAZINAMIDE AND
PARA AMINOBENZOIC ACID
Jan Zitko and Martin Doležal ...................................................................................................................................242
P-167 BIOLOGICAL ACTIVITY OF NOVEL PRIMAQUINE-CINNAMIC ACID CONJUGATES OF THE
ACYLSEMICARBAZIDE TYPE
K. Pavić, K. Ester, M. Kralj, D. Schols, D. Hadjipavlou-Litina, E. Pontiki and B. Zorc .............................................243
P-168 ANTIMYCOBACTERIAL SCREENING OF FOUR SERIES OF PRIMAQUINE DERIVATIVES
Josef Jampílek, Sarka Pospíšilová, H. Michnová, Kristina Pavić, Ivana Perković and Branka Zorc .......................244
P-169 INSIGHTS INTO ANTIOXIDANT AND CYTOSTATIC ACTIVITY OF THE NOVEL PRIMAQUINE
UREIDOAMIDES
Branka Zorc, Kristina Pavić, Dimitra Hadjipavlou-Litina, Eleni Pontiki, Marijeta Kralj and Katja Ester ................245
INDEX ........................................................................................................................................................................................246
PARTICIPANTS ..........................................................................................................................................................................254
29
PLENARY LECTURES
30
PL-1
BEYOND THE PROKARYOTIC RIBOSOME: STRUCTURAL AND

FUNCTIONAL INSIGHTS INTO EUKARYOTIC AND MITOCHONDRIAL
RIBOSOMES
Nenad Ban
Institute of Molecular Biology and Biophysics, ETH Zürich, Otto-Stern-Weg 5, 8093 Zürich Switzerland
ban@mol.biol.ethz.ch
We are investigating bacterial and eukaryotic ribosomes and their functional complexes to obtain
insights into the process of protein synthesis. Eukaryotic ribosomes are much more complex than
their bacterial counterparts, require a large number of assembly and maturation factors during their
biogenesis, use numerous initiation factors, and are subjected to extensive regulation. We have
investigated the structures of eukaryotic ribosomes and their complexes involved in initiation and
maturation and complexes involved in regulation of protein synthesis.[1-4] These results provide
insights into the architecture of the eukaryotic ribosome and into various eukaryotic-specific aspects
of protein synthesis. Using electron microscopy, we determined the complete molecular structure of
the 55S mammalian mitoribosome. The maps that we calculated between 3.4 and 3.6 Å resolution
allowed de-novo tracing of a large number of mitochondrial specific ribosomal proteins and
visualization of interactions between tRNA and mRNA in the decoding centre, the peptidyl
transferase center, and the path of the nascent polypeptide through the idiosyncratic tunnel of the
mammalian mitoribosome. Furthermore, the structure suggested a mechanism of how mitochondrial
ribosomes, specialized for the synthesis of membrane proteins, are attached to membranes.[5,6]
[1]
J. Rabl, M. Leibundgut, F. Sandro, S.F. Ataide, A. Haag, N. Ban, Nature, 2010, 331(6018). 730.
[2]
S. Klinge, F. Voigts-Hoffmann, M. Leibundgut, S. Arpagaus, N. Ban, Science, 2011, 334, 941.
[3]
J.P. Erzberger et al., Cell, 2014, 158, 1123.
[4]
C.H. Aylett et al. Science, 2016, 351(6268), 48.
[5]
B.J. Greber, D. Boehringer et al., Nature, 2014, 505(7484), 515.
[6]
B.J. Greber, P. Bieri, et al., Science, 2015, 348(6232), 303.
31
PL-2
OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCO-

BACTERIAL ACTIVE AGENTS AND THEIR CONJUGATES
Krátký Martin,[a],* Baranyai Zsuzsa,[b] Szilvia Bősze,[b] Szabó Nóra[c] and

Vinšová Jarmila[a]
[a] Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles
University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
[b] MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter Sétány 1/A, Budapest, H-1117,
Hungary, P.O. Box 32, 1518 Budapest 112, Hungary
[c] Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine,
Pihenő út 1, Budapest, H-1122, Hungary
* martin.kratky@faf.cuni.cz
The global tuberculosis epidemic and increasing emergence of drug-resistant Mycobacterium

tuberculosis (Mtb.) strains as well as non-tuberculous mycobacteria (NTM) call for intensive research
on novel therapeutic interventions. Drug delivery systems (DDS) may help to overcome inconvenient
properties of bioactive molecules, e.g., poor solubility, bioavailability or selectivity. Additionally, they
are useful in targeted drug delivery.[1] We selected tuftsin-based oligopeptides as potential carriers
for small antimycobacterial active molecules. Tuftsin derivatives are non-toxic, non-immunogenic
and biodegradable. They also enhance immune response and target macrophages specifically, thus
increasing cellular uptake, activity and reducing toxicity.[2,3] A pilot study with isoniazid indicates that
this concept is viable.[2]
Salicylanilides (2-hydroxy-N-phenylbenzamides) have exhibited interesting antimicrobial properties
including drug-resistant Mtb. and NTM (MIC ≥ 0.5 µM), but their potential use is prevented due to
limited solubility and comparatively higher toxicity.[4] These obstacles can be overcome, i.a., by
employment of DDS. That is why salicylanilides bearing a carbonyl group were selected as model
compounds for the evaluation of oligotuftsine carriers.
Oligotuftsin-based carriers ([TKPKG]n, n = 1-4) were synthesized by solid-phase synthesis
(Fmoc/tBu strategy, rink amide MBHA resin, diisopropylcarbodiimide/HOBt, NMP). N-Terminus
and/or side chain lysine ε-amino group(s) were substituted to obtain carriers with various properties.
Carboxylic acids (acetic, succinic, palmitic etc.) modify lipophilicity, short peptide spacers (G5, GFLG
cleavable by cathepsin B) were used to control the cellular site where the drug is released, whereas
fluorescein enables to determine cellular uptake by flow cytometry and fluorescent microscopy. One
or more aminooxyacetic acid molecule(s) were coupled with peptides to provide a reactive group for
the attachment of active molecules. After these modifications, peptide carriers were cleaved from
the resin TFA and purified. Then, carriers were coupled with salicylanilide derivatives to form acid
stable oxime bond. Novel conjugates were purified and characterised.[3]
Generally, salicylanilide-oligotuftsin conjugates exhibited a significant extracellular antimyco-
bacterial activity including against drug-resistant Mtb. Moreover, they are more effective against
intracellular mycobacteria than parent salicylanilides. Cellular uptake was enhanced substantially,
too, together with decreased cytostatic and cytotoxic effects on mammalian cells. In conclusion, our
tuftsine peptides are perspective carriers for antimycobacterial agents.
Acknowledgments: This work was supported by the Czech Science Foundation project No. 17-
27514Y.
[1]
G. Tiwari, R. Tiwari, et al., Int. J. Pharm. Invest., 2012, 2, 2.
[2]
K. Horvati, G. Mezo, et al., J. Pept. Sci., 2009, 15, 385.
[3]
Z. Baranyai, M. Krátký, et al., Eur. J. Med. Chem., 2017, under revision.
[4]
Z. Baranyai, M. Krátký, J. Vinšová, et al., Eur. J. Med. Chem., 2015, 101, 692.
32
PL-3
WHAT THERMODYNAMICS CAN HELP TO UNDERSTAND

PROTEIN-LIGAND BINDING IN MEDICINAL CHEMISTRY
Gerhard Klebe
Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, D35032 Marburg, Germany
klebe@mailer.uni-marburg.de
Small-molecule drug discovery involves the optimization of various physicochemical properties of a

ligand, particularly the binding affinity for its target receptor(s). In recent years, there has been
growing interest in using thermodynamic profiling of ligand–receptor interactions in order to select
and optimize those ligands that look most promising to become a drug candidate with desirable
physicochemical properties. The thermodynamics of binding are influenced by multiple factors,
including hydrogen bonding and hydrophobic interactions, desolvation, residual mobility, dynamics
and the local water structure.
How well do we understand these properties on the molecular level? Is it only important that a
sufficient number of hydrogen bonds are formed and the shape of the molecules fit perfectly
together? How much contributes the burial of hydrophobic surface portion and how important are
changes of the degrees of freedom upon complex formation? Both binding partners are
conformationally flexible species and will adapt to one another upon complex formation. However,
who is going to pay for these adaptations? All biological processes occur in water, thus the
ubiquitously present water molecules take an important impact on protein-ligand binding, and even
rearrangements of water molecules on the surface of a formed protein-ligand complex modulate the
affinity of complex formation.
Structural and thermodynamic considerations help to get insight into the driving forces for complex
formation. Water takes in manifold ways influence on the structure and energetics of protein-ligand
complex formation. The impact of such effects is less apparent in a strong modulation of affinity (ΔG)
but, owing to compensatory effects, it strongly shifts the enthalpy/entropy inventory and tunes
binding kinetics. Upon ligand binding water molecules are displaced, rearranged or recruited to
engage in new contacts between protein and ligand. The newly formed complex is coated by a
rearranged water shell. All these processes take influence on the thermodynamic and binding-kinetic
signature of the formed complex. Decisive for the characteristics of the involved hydrophobic effect
is the state of the water molecules before and after ligand binding. The displacement of ordered and
firmly embedded water molecules results in another signature than the displacement of disordered,
partly dynamic water molecules. In case binding occurs in empty or partly solvated but structurally
stable pockets significantly different energetics are observed compared to transient pockets opened
upon binding. The water network created around exposed ligand functional groups in flat solvent-
exposed pockets takes strong impact on the thermodynamic signature of the complex and seems to
govern binding kinetics. As the parameters affinity and binding kinetics are determinant for the
efficacy of binding, they must be optimized individually for each drug in tailored fashion. By closely
linking the results of high resolution X-ray and neutron diffraction, microcalorimetry, binding kinetics
and computer simulations we want to characterize the determining influence of water on the efficacy
of ligand binding.[1]
[1]
G. Klebe, Nat. Rev. Drug Discov. 2015, 14(2), 95.
33
PL-4
METAL CHELATING AGENTS AGAINST VIRUSES AND PARASITES
Zoidis Grigoris
School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National
and Kapodistrian University of Athens, Panepistimioupoli-Zografou, GR-15771, Athens, Greece
zoidis@pharm.uoa.gr
Influenza viruses cause considerable morbidity and mortality, whether in the context of annual
epidemics, sporadic pandemics, or outbreaks of avian influenza virus. For hepatitis C virus (HCV),
an estimated 170 million people are chronically infected worldwide. These individuals are at high risk
of developing progressive liver injury or hepatocellular carcinoma. Another major public health
problem in many areas of sub-Saharan Africa is sleeping sickness (human African trypanosomiasis),
which currently kills ca. 50 000 people each year. Since emerging viral resistance remains high, the
cost threaten the efficacy of currently approved antiviral drugs and the attention of pharmaceutical
industry concerning neglected and relatively unprofitable parasitic disease is little, new antiviral and
antiparasitic drugs are urgently needed.
Metalloenzymes are enzyme proteins containing metal ions (metal cofactors), which are directly
bound to the protein or to enzyme-bound nonprotein components (prosthetic groups). Approximately
one-third of proteins are metalloproteins, which serve to execute a wide array of functions in vivo,
including facilitating matrix degradation, modulating DNA transcription, and many others. Given the
importance of these functions, metalloenzymes play a significant role in human, virus and parasite
physiology. Pathologies for which metalloenzymes are implicated include cancer, heart disease,
influenza A and HCV. Given the impact of these diseases on human health, metalloenzyme inhibition
offers an appealing approach to disease treatment. Indeed, sales of metalloprotein inhibitors account
for billions of dollars in pharmaceutical sales annually.
Hydroxamates act as bidentate ligands and are able to form hydrogen bonds; they can act as potent
inhibitors of any enzyme that contains metal ion and residues able to act as hydrogen-bond donors
or acceptors. Almost all the enzymes that contain M2+ ion are easily coordinated with any hydroxamic
acid derivative. In most of the enzyme proteins containing metal ions, hydroxamates bind bidentately
to their catalytic M2+ ion to create a distorted trigonal bipyramidal geometry around the M2+ as shown
in Figure. Thus, the metal-chelating property and multiple hydrogen-bond formation ability of
hydroxamates have made them an intriguing family of compounds with a wide spectrum of biological
activities, among them antiviral and antiparasitic.[1]-[3]
Figure: The predicted binding orientation of hydroxamates in the catalytic site of PA influenza endonuclease
and HCV polymerase shown in a ribbon representation.
Acknowledgments: Prof. Zoidis would like to thank the National and Kapodistrian University of
Athens (ELKE Account) for financial support.
[1]
G. Zoidis, E. Giannakopoulou, at al., MedChemComm 2016, 7(3), 447.
[2]
C. Fytas, G. Zoidis, at al., J. Med. Chem. 2011, 54 (14), 5250.
[3]
A. Tsatsaroni, G. Zoidis, at al., Tet. Lett. 2013, 54, 3238.
34
PL-5
MARINE ENVIRONMENT INSPIRES KINASES INHIBITORS
Girolamo Cirrincione
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università
degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
girolamo.cirrincione@unipa.it
Marine organisms constitute a very unique source of bioactive molecules belonging to a great variety
of different chemical structural classes. Among marine derived bioactive molecules, over 70 novel
compounds showed significant inhibitory activity against kinases, important enzymes involved in vital
role cell regulation and signal transmission pathways, controlling cell differentiation, proliferation and
apoptosis.[1] Several marine derived molecules are in the pharmaceutical pipeline and have
successfully reached the market. In particular there are six FDA-approved drugs and many others
are under clinical trials.[2]
Bis-indole marine alkaloids, have emerged as important lead compounds for the discovery of new
biologically active derivatives due to their potent biological activities shown. Among them,
nortopsentins A–C having a characteristic 2,4-bis(3’-indolyl)imidazole skeleton, isolated from
Spongosorites ruetzleri, exhibited in vitro cytotoxicity against P388 cells (IC50 values: 4.5–20.7 µm)
and their synthetic analogs in which the imidazole moiety of nortopsentin was replaced by different
5-membered heterocycles, showed improved biological activity against a wide range of human tumor
cell lines with GI50 values reaching sub-micromolar level. In particular, thiazole nortopsentin analogs
1-4, in which one or both indole units of the natural nortopsentins were also manipulated, showed
even better activity and inhibition of cyclin-dependent kinase 1 (CDK1).[3] Many derivatives,
belonging to this class of compounds, revealed significant biological activity also in STO e MesoII
cell lines, derived from human diffuse malignant peritoneal mesothelioma (DMPM), a very
aggressive and resistant form of cancer, inducing a caspase-dependent apoptotic response, with a
concomitant reduction of the expression of the anti-apoptotic protein survivin. The most active
derivatives were also investigated in vivo showing a significant tumor volume inhibition of DMPM
xenografts (range, 58%-75%) at well-tolerated doses, and two complete responses in each treatment
group.
R N R3 S
Y R3
R
N N Z
H X W
N N N N
H H R1 R2
Nortopsentins Thiazole Nortopsentin Analogs
1 X=Y=Z=CH, W=N; 2 X=W=N, Y=Z=CH;
3 X=N, Y=W=Z=CH; 4 X=Y=W=CH, Z=N;
In order to confirm the therapeutic efficacy of this series of compounds, further studies were
performed against cancer stem cells (CSCs) subpopulation freshly isolated from surgical resections
of patients with the aim to identify new molecules potentially useful in therapy. Preliminary data
showed that the treatment of colorectal CSCs, bearing different mutational background, with thiazole
nortopsentin analogs, induced reduction of cells viability at 24 hours, potently induced the exit of
CSCs from dormancy state. This phenomenon rendered the highly resistant CSCs sensitive to
conventional chemotherapy drugs, oxaliplatin and 5FU. These results supported the use of these
compounds as an innovative differentiation therapy that could be used in combination with standard
chemotherapy as additive effect.
[1]
D. Skropeta et al., Mar. Drugs, 2011, 9, 2131.
[2]
B. S. Bharate et al., Chem. Rev., 2013, 113, 6761.
[3]
a) A. Carbone et al., J. Med. Chem., 2013, 56, 7060; b) B. Parrino et al., Mar. Drugs, 2015, 13, 1901; c) A.
Carbone et al., Mar. Drugs, 2015, 13, 460.
35
PL-6
OLD SCAFFOLDS IN NEW ROLE: STEROIDS AS ANTIPROLIFERATIVE

AGENTS
János Wölfling,[a],* Éva Frank,[a] Erzsébet Mernyák,[a] Gyula Schneider,[a]

Mihály Szécsi[b] and István Zupkó[c]
[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8. H-6720, Szeged, Hungary
[b] 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary
[c] Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös utca 6. H-6720,
Szeged, Hungary
* wolfling@chem.u-szeged.hu
One of the main trends in medicinal chemistry is the structural modification of biologically active
natural products with the aim of obtaining drug-like molecules with selective biological action.
Steroids can be found widespread in nature; their function in plants, in human and in animal body is
mostly well-known. They show high selectivity in some of their actions because they are subject to
a special transport system and receptors. The literature reveals several antitumoural steroid
derivatives, but elimination of their hormonal activity and improvement of their tumour selectivity are
frequently ongoing problems. Structural modifications of natural steroids may lead to hormonally
inactive at the same time effective and selective cytostatic derivatives.
The whole arsenal of synthetic organic chemistry is disposable for modifying the molecules of
steroidal sex hormones. As a result of chemical transformations, we synthesized hundreds of new
derivatives, such as homo- or secosteroids, epimeric and/or heteroring-containing compounds. The
formation of steroid hybrids with other steroids or non-steroidal natural products may lead to new
conjugates exhibiting different biological activities from those of the original constituents.
The in vitro antiproliferative activities of the new derivatives were determined on several cancer cells
by using MTT assay. Some of our new compounds display remarkable cytostatic effects against
ovarian and cervical cell lines.
We investigated the antiandrogenic effects of the new compounds by determining their in vitro
inhibition of rat testicular C17,20-lyase, Δ5-3β-hydroxysteroid dehydrogenase (Δ5-3β-HSD) and
17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) activities.
Acknowledgments: The authors are grateful for financial support from the National Research,
Development and Innovation (NKFI) Fund of Hungary (K113150 and K109107).
36
PL-7
CHEMICAL PROBES IN TARGET DISCOVERY
Paul Brennan
University of Oxford, UK
paul.brennan@sgc.ox.ac.uk
Epigenetics is the study of heritable changes in phenotype that are not encoded in an organism’s
DNA. Epigenetic effects due to persistent changes in gene transcription have been linked to chemical
modification of DNA and the proteins that package and regulate DNA in the nucleus, histones. One
of the major post-translational modifications of histones is acetylation of lysine residues prevalent in
histone tails. The principal readers of histone acetyl lysine marks are bromodomains (BRDs), which
are a diverse family of over sixty evolutionary conserved protein-interaction modules. Proteins that
contain BRDs have been implicated in the development of a large variety of diseases, including
cancer and inflammation. In order to decipher the complex biology of bromodomains and provide
evidence linking specific bromodomain targets to disease, we are discovering selective, cell active
small molecule inhibitors of bromodomains.
37
PL-8
GABAA RECEPTOR SUBTYPES: A STRUCTURE GUIDED PATH TO

SELECTIVE COMPOUNDS
Konstantina Bampali,[a] David Siebert,[b] Marko D. Mihovilovic,[b] Michael Schnürch,[b] and

Margot Ernst[a],*
[a] Department of Molecular Neurosciences, Medical University of Vienna, Spitalgasse 4, 1090 Wien,
Austria
[b] TU Wien, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna
* margot.ernst@meduniwien.ac.at
Atomic resolution structures of cys-loop receptors, including one of a GABAA receptor subtype,[1]
allow amazing insights into the structural features of these pentameric ligand-gated ion channels.
Here we present a comprehensive analysis of more than thirty cys-loop receptor structures that
revealed several allosteric binding sites not previously described in GABAA receptors. Four so far
undescribed putative ligand binding sites can be identified in each prototypical GABAA receptor
subunit based on this structural data.[3] The large fragment of the intracellular domain that is present
in the structure of the 5-HT3 receptor[2] can be utilized to generate GABAA receptor models with a
corresponding intracellular domain fragment.[3]
Schematic view of a hetero-pentameric GABAA receptor model [3] with allosteric binding site
localizations indicated by colored regions.
Results of mutational and photoaffinity ligand studies in GABAA
receptors can be analyzed in the light of the model structures. This leads
to an assignment of candidate ligands to proposed novel pockets.
Candidate binding sites for several ligands are presented. The structural
studies can serve as hypotheses generators, and some previously
controversial structural interpretations of biochemical data can be
resolved in the light of the presented multi-template approach to
comparative modeling. Crystal and cryo- EM microscopic structures of
the closest homologues that were solved in different conformational
states[4,5] provided important insights into structural rearrangements of
binding sites during conformational transitions. The impact of structural
variation and conformational motion on the shape of the investigated
binding sites can be studied in this way.
Structure guided approaches to identify new binding sites along with specific ligands for these are
possible, and lead to a new generation of subtype selective allosteric modulators. The structures can
also shed light on the molecular basis that underlies the functional diversity among receptor isoforms.
A showcase of ligand development will be presented.
[1]
P. Miller, A. Aricescu, Nature, 2014, 512, 270.
[2]
G. Hassaine et al., Nature, 2014, 512, 276.
[3]
R. Puthenkalam et al., Front. Mol. Neurosci., 2016, 9, 44.
[4]
T. Althoff et al., Nature, 2014, 512, 333.
[5]
J. Du et al., Nature, 2015, 526, 224.
38
PL-9
NEW HITS AND LEADS FOR NEURODEGENERATIVE DISORDERS
Urban Košak, Damijan Knez, Boris Brus, Stanislav Gobec*

Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
* stanislav.gobec@ffa.uni-lj.si
Alzheimer’s disease (AD) is characterized by severe cholinergic deficit, which results in progressive
and chronic deterioration of memory and cognitive functions. Together with acetylcholinesterase,
butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its
enzymatic activity increases with disease progression, thus classifying BChE as a viable therapeutic
target in advanced AD. In vivo active BChE inhibitors are limited to covalent carbamate inhibitors
with potential reactivity-based toxicities.
In the first step, we developed a selective and highly potent noncovalent BChE inhibitor.[1] In the next
step, this compound was used as a starting point for the synthesis of a comprehensive series of
close structural analogues in order to study the structure-activity relationships and to obtain
compounds with improved on-target activities. More than 100 compounds were synthesized resulting
in improved inhibitors with nano to picomolar inhibition constants. The most promising inhibitor
improved memory, cognitive functions, and learning abilities of mice in a model of the cholinergic
deficit that characterizes AD, without producing acute cholinergic side effects. This inhibitor therefore
provides a promising advanced lead compound for the alleviation of symptoms caused by cholinergic
hypofunction in AD.[2]
Limited clinical efficacy of current symptomatic treatment and minute effect on the progression of AD
has shifted the research focus from targeting single enzyme or receptor towards multi-target-directed
ligands (MTDLs). These ligands are able to interact with multiple pathological processes of AD, and
have the unmet potential to halt the progression or even to cure the disease. Therefore, our potent
BChE inhibitors were used as starting points to develop a new series of multifunctional ligands. The
derivatives designed and synthesized displayed balanced BChE inhibition, antioxidant activity and
inhibition of amyloid β aggregation. The co-crystal structure of typical inhibitor in complex with BChE
explained the molecular basis for its low nanomolar inhibition of the enzyme. The most promising
compounds also showed metal chelating properties, inhibited redox activity of chelated Cu2+ ions,
were non-cytotoxic, and were not substrates of active efflux transport system as determined in Caco2
cells, thereby providing promising lead multifunctional ligands for AD treatment. A series of dual
BChE/monoamine oxidase-B (MAO-B) inhibitors was also developed based on the selective BChE
inhibitors.[3] In addition, nanomolar MAO-A and MAO-B inhibitors with piperidine scaffold were
derived thereof, and they showed promising neuroprotective activity in 6-hydroxydopamine cell
model of Parkinson’s disease.
[1]
B. Brus et al., J. Med. Chem., 2014, 57, 8167.
[2]
U. Košak et al., Sci. Rep., 2016, 6, 39495.
[3]
U. Košak et al., Bioorg. Med. Chem. Lett., 2017, 25, 633.
39
PL-10
POLYSACCHARIDES AS BIOLOGICAL RESPONSE MODIFIERS:

STRUCTURE - ACTIVITY RELATIONSHIP
Jadwiga Turło
Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of
Warsaw, 1 Banacha St., 02-097 Warsaw, Poland
jadwiga.turlo@wum.edu.pl
Polysaccharides are among the best known and most potent macromolecules with antitumor and
immunomodulatory properties. With respect to the mechanism of the pharmacological activity, they
are classified as biological response modifiers (BRMs).
Although the relationship between their activity and the chemical composition has been extensively
investigated over the past three decades, there are some conflicting reports on this topic.[1]
Polysaccharides with strong immunomodulatory activity include neutral and acidic ones; some of
them are bound to protein or peptide residues. In addition to the primary structure of polysaccharides,
higher structure, such as chain conformation, also plays an important role in their activities.[2]
Although structure-activity relationship (SAR) among higher sugars is not clear, it is assumed that
determinants of their immunomodulatory activity are: the monosaccharide composition, water
solubility, molecular weight, branching degrees (DBs) and triple helical conformation [3]. The next
issue to be solved is the mechanism of immunomodulating activity of mushroom polysaccharides.
One possible pathway of host-mediated actions from polysaccharide-drug Lentinan is binding of β-
glucans to iC3b-receptors (CR3, CD11b/CD18) of phagocytic cells and natural killer (NK) cells and
stimulation of phagocytosis and/or cytotoxic degranulation, as suggested by Chihara (1992) [4] and
later modified by Wasser (1999).[5]
The polysaccharide fractions isolated from the natural sources (bacteria, fungi, plants) or obtained
by biotechnological methods are often subjected to structural modifications in order to improve their
pharmacological activity and/or pharmacokinetic properties. Uncertainty of the structural data on the
atomic level considerably hinders this task.
An example of structural modifications of polysaccharides that lead to changes in their biological
activity is incorporation of selenium atoms performed in our laboratory by biotechnological methods.
We have isolated a Se-containing polysaccharide-protein fraction from selenium-enriched mycelial
culture of Lentinula edodes. The results of preliminary tests of immunomodulatory activity of these
fractions were surprising: the effect of Se-polysaccharides on the proliferation of human blood
lymphocytes demonstrated their selective immunosuppresive activity and a very low toxicity at the
same time. This activity is opposite to immunostimulating activity of L. edodes-derived
polysaccharides, described in the literature. We speculate that incorporation of selenium into
exopolysaccharide molecules changes their spatial structure which affects the biological activity.
Acknowledgements: Investigation of structure-activity relationship in Se-enriched polysaccharides

is supported by grant from the Polish National Science Centre DEC-2013/09/B/NZ7/03978
[1]
M. Zhang, S.W. Cui, P.C.K. Cheung, Q. Weng, Trends Food Sci Technol., 2007, 18, 4.
[2]
S.P. Wasser, Appl. Microbiol. Biot., 2002, 10, 13.
[3]
L. Zhang, X. Li, X. Xu, F. Zeng, Carbohydr Res., 2005, 340, 1515.
[4]
G. Cihara, Int J Orient Med., 1992,17, 57.
[5]
S.P. Wasser, A.L. Weiss, Int J Med Mushrooms., 1999,1, 31.
40
PL-11
DESIGN OF SMALL MOLECULAR PROBES FOR PROTEINS AND

DNA / RNA
Ivo Piantanida
Ruđer Bošković Institute, Division of Organic Chemistry & Biochemistry, Zagreb, Croatia
pianta@irb.hr
Small molecules targeting DNA, RNA and/or proteins have attracted significant scientific interest not
only because of their biomedicinal applications, but also due to widespread use of
spectrophotometric markers in the related scientific research. For instance, fluorescent techniques
significantly developed during the last three decades and now represent about 70% of the detection
enabling technologies used in molecular biology and medicine. However, design of small molecule
(Mw<600) for recognition of ds-DNA/RNA sequence or particular protein is very challenging due
limited number of modifications in such restricted molecule size. Quite often, small modifications
lead to change of target preference, for instance from DNA-targeting to protein-targeting molecule.
Scheme: Aggregation-prone dye interacting with various targets and reporting interaction with each target by
sensitive and bio-applicable spectrometric method.
One of our research lines is focused on the generally under-investigated approach: exploitation of
intrinsic property of some dyes for aggregation, whereby monomeric and aggregated dye differ
strongly not only in target recognition but also in spectroscopic properties.[1] Thus, one dye molecule
could bind with similar affinity to several targets (DNA, RNA, protein) giving different spectroscopic
responses for each target: to some polynucleotide sequence dye would bind as monomer, for other
sequence as dimer, and protein binding site would induce different spectroscopic response
(Scheme). The ongoing research endeavours to establish for the low molecular weight dyes the
structure-activity guidelines for fine tuning of DNA - RNA - protein preferences combined with
recognition by set of sensitive and bio-applicable spectrometric methods.
[1]
J. Matić at al, RSC Advances, 2016, 6, 83044; J. Suć at al, Org. Biomol. Chem, 2016, 14, 4865; J.
Gershberg at al, Chem. Eur. J., 2015, 21, 7886; I. Crnolatac at al, Anal. Chim. Acta, 2016, 940, 128; L.-M.
Tumir at al, Chem., Eur. J., 2012, 18, 3859.
41
PL-12
FROM EXCEPTIONAL KINASE CONFORMATION TO DUAL KINASE

INHIBITORS - CHEMISTRY OF 2-AMINOOXAZOLES
Andrej Boháč,[a,b],* Peter Šramel,[a,c] Juraj Dobiaš,[a] Miroslav Murár,[a]

Matúš Hlaváč,[a] Maroš Smolíček[a] and Gilles Hanquet[c]
[a] Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava,
Ilkovičova 6, 842 15 Bratislava, Slovakia
[b] Biomagi, Ltd., Mamateyova 26, 851 04 Bratislava, Slovakia
[c] Université de Strasbourg, Ecole européenne de Chimie, Polyméres et Matériaux (ECPM)
Laboratoire de Synthése et Catalyse (UMR CNRS 7509), 25, rue Becquerel, F-67087 Strasbourg,
France
* andrej.bohac@fns.uniba.sk
The Human Kinom contains 518 Protein Kinases (PKs) collected in 7 major groups. PKs direct the
activity of up to 30 % of cellular proteins and orchestrate the activity of almost all cellular processes.
Many kinases represent important therapeutic targets. Currently PDB database contains around 5
000 structures of human kinases or their complexes. The different conformers of particular kinase
can influence the predictions by false positive or false negative results. This knowledge is important
by development of new inhibitors. By analysis of selected PDB kinases, protein conformers with rare
arrangement of their DFG fragments were identified. Our research focused on rationale development
of series of inhibitors possessing N,5-diaryloxazol-2-amine skeleton was inspired by an exceptional
structure of VEGFR2 TK complex (PDB: 1Y6A; AAZ ligand). (Figure) We have reviewed [1] and
improved the synthesis of aminooxazoles. At about 80 substituted aminooxazoles and their
analogues were prepared. From them 31 compounds reached their IC50 kinase activity below 500
nM. Interactions of aminooxazoles with kinase subdomains, chimera constructs,[2] aminooxazole
isosteric[3] or regioisomeric replacements and some interactions with hepatocellular carcinoma[4]
were / are studied. Recently some of our aminooxazoles were uncovered to be suitable for dual
VEGFR2 / CLK1 inhibition.[5]
N
N
O S O O S O
O O
N N N N
H H
O O
AAZ conformers from PDB: 1Y6A

Figure: The structures of two conformers of AAZ ligand present in the complex with VEGFR2 tyrosine
kinase (PDB: 1Y6A).
Acknowledgements: We are thankful for support to Biomagi, Slovakia and VEGA 1/0634/13.
[1]
L. Lintnerová, L. Kováčiková, G. Hanquet, A. Boháč, J. Het. Chem., 2015, 52, 425.
[2]
L. Lintnerová, M. García-Caballero, F. Gregáň, M. Melicherčík, A.R. Quesada, J. Dobiaš, J. Lác, M. Sališová,
A. Boháč, Eur. J. Med. Chem., 2014, 72, 146.
[3]
M. Vojtičková, J. Dobiaš, G. Hanquet, G. Addová, R. Cetin-Atalay, D.C. Yildirim, A. Boháč, Eur. J. Med.
Chem., 2015, 103, 105.
[4]
D.C. Kahraman, G. Hanquet, L. Jeanmart, S. Lanners, P. Šramel, A. Boháč, R. Cetin-Atalay, RCS
MedChemComm, 2017, 8, 81.
[5]
M. Murár, J. Dobiaš, P. Šramel, G. Addová, G. Hanquet, A. Boháč, Eur. J. Med. Chem., 2017, 126, 754.
42
KEYNOTE LECTURES
43
KL-1
A PLATFORM FOR THE DISCOVERY OF NEW

MACROLIDE ANTIBIOTICS
Ian B. Seiple,[a] Ziyang Zhang,[a] Pavol Jakubec,[a,b],* Peter M. Wright,[a] Audrey Langlois-
Mercier,[a] Daniel T. Hog,[a] Kazuo Yabu,[a] Senkara Rao Allu,[a] Takehiro Fukuzaki,[a] Peter
N. Carlsen,[a] Yoshiaki Kitamura,[a] Xiang Zhou,[a] Matthew L. Condakes,[a] Filip
Szczpinski,[a] William D. Green[a] and Andrew G. Myers[a]
[a] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts
02138, USA.,
[b] Present addresses: Department of Organic Chemistry, Slovak University of Technology,
Radlinského 9, Bratislava 812 37, Slovakia
* pavol.jakubec@stuba.sk
Chemically modifying structurally complex fermentation products, a process referred to as

semisynthesis, has been a primary tool for the discovery and manufacture of antibiotics for the
treatment of human infectious diseases. Many of the medicines obtained in this way are no longer
efficacious as the result of the development of bacterial resistance. Here we present a practical, fully
synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building
blocks, enabling structural diversification not possible by semisynthesis (Figure). More than 300
novel macrolide antibiotic candidates as well as the investigational drug solithromycin were
synthesized by our convergent approach. Evaluation of the novel compounds against a panel of
pathogenic bacteria revealed many antibiotic candidates, with efficacy against strains resistant to
macrolides in current use. The chemistry we describe provides a platform for the discovery of new
macrolide antibiotics and may also serve as a basis for their manufacture.[1]
[1]
I.B. Seiple, Z. Zhang, P. Jakubec, A. Langlois-Mercier, P.M. Wright, D.T. Hog, K. Yabu, S.R. Allu, T.
Fukuzaki, P.N. Carlsen, Y. Kitamura, X. Zhou, M.L. Condakes, F.T. Szczypiński, W.D. Green, A.G. Myers,
Nature, 2016, 533, 338.
44
KL-2
DISCOVERY OF N-PHENYLPYRROLAMIDES AS ATPase INHIBITORS OF

DNA GYRASE AND TOPOISOMERASE IV
Nace Zidar
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
nace.zidar@ffa.uni-lj.si
Bacterial topoisomerases are enzymes that catalyse changes in DNA topology and are clinically
validated targets of antibacterial drugs. DNA gyrase and topoisomerase IV belong to type IIA
topoisomerases and display high structural and functional similarities. They are both
heterotetrameric enzymes composed of two pairs of subunits. DNA gyrase is composed of two GyrA
and two GyrB subunits, while topoisomerase IV is composed of two ParC and two ParE subunits.
The function of DNA gyrase and topoisomerase IV is to catalyse the transient break and reunion of
the DNA double strand, a process crucial for winding and unwiding the DNA molecule during its
replication or transcription. There are currently no GyrB or ParE inhibitors in clinical use.
Using structure-based design and starting from marine alkaloids clathrodin and oroidin, we have
discovered a new, N-phenylpyrrolamide structural class of GyrB and ParE inhibitors. We have
determined the crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B
complex (Figure).[1] Based on this structural information we have designed and prepared novel series
of N-phenyl-4,5-dibromopyrrolamides and N-phenyl-3,4-dichloro-5-methylpyrrolamides and
evaluated them against DNA gyrase from Escherichia coli (E. coli). The most potent inhibitors had
low nanomolar IC50 values against E. coli gyrase. A selected set of compounds was evaluated
against DNA gyrase from Staphylococcus aureus (S. aureus) and against topoisomerase IV from E.
coli and S. aureus. The binding affinities of selected compounds to E. coli gyrase were studied using
surface plasmon resonance (SPR). The structure-activity relationship (SAR) was examined and the
results were rationalised with molecular docking. Antibacterial activities of the most promising
compounds were evaluated against two Gram-positive and two Gram-negative bacterial strains. The
most active compound had a low micromolar minimum inhibitory concentration (MIC90) against
Enterococcus faecalis.[2]-[4]
Arg76
NH2
HN
H NH2 +
O- O Arg136
Asp73 H Gly77 O
O O
O N
H H
Val71 N OH
Br N
Val167 H Pro79
Ile78
Val43 Br O H
Ala47 H
Val120 O
Asn46
NH2
Figure: Structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor of DNA gyrase B and X-ray crystal
structure of the inhibitor in the active site of E. coli GyrB (PDB code: 4ZVI [2]).
[1]
N. Zidar, H. Macut, T. Tomašič, M. Brvar, S. Montalvão, P. Tammela, T. Solmajer, L. Peterlin Mašič, J. Ilaš,
D. Kikelj, J. Med. Chem., 2015, 58, 6179.
[2]
N. Zidar, T. Tomašič, H. Macut, A. Sirc, M. Brvar, S. Montalvão, P. Tammela, J. Ilaš, D. Kikelj, Eur. J. Med.
Chem., 2016, 117, 197.
[3]
M. Gjorgjieva, T. Tomašič, M. Barančokova, S. Katsamakas, J. Ilaš, P. Tammela, L. Peterlin Mašič, D. Kikelj,
J. Med. Chem., 2016, 59, 8941.
[4]
T. Tomašič, M. Mirt, M. Barančokova, J. Ilaš, N. Zidar, P. Tammela, D. Kikelj, Bioorg. Med. Chem., 2017,
25, 338-349.
45
KL-3
ANTIMICROBIAL POTENTIAL OF 1,2,4-OXADIAZOLES AND THEIR

SYNTHESIS
Marta Kucerova-Chlupacova,[a],* Anastasia Katirtzi,[a] Pavlina Dzamova,[b]

Lucie Kolcarkova,[a] Klara Konecna,[c] Ondrej Jandourek[c] and Veronika Opletalova[a]
[a] Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in
Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
[b] Department Pharmaceutical Technology, Faculty of Pharmacy in Hradec Kralove, Charles
University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
[c] Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles
University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
* kucerom@faf.cuni.cz
1,2,4–Oxadiazole ring represents an emerging scaffold in medicinal chemistry used as heterocyclic

bioisoster of amide or ester in the synthesis of peptide building blocks and in the formation of
dipeptidomimetics.[1] In comparison with amide or ester group, the oxadiazole ring showed increased
hydrolytic and metabolic stability.[2] Apart from various biological activities, 1,2,4-oxadiazoles showed
antimicrobial activity. 1,2,4–Oxadiazole moiety seems to perfectly mimic the function of the
morpholinic ring in linezolid derivatives.[3] 1,2,4–Oxadiazoles have been linked to cephalosporins or
carbapenems in order to obtain new efficient antibacterial agents.[4] 1,2,4–Oxadiazole derivatives
have also emerged from a high-throughput virtual screening study on penicillin-binding protein 2a as
novel non-β-lactam bactericidal antibiotics active against Gram-positive bacteria with in vivo efficacy
and 100% oral bioavailability.[5] Antiprotozoal activity has been described as well.[1]
Among various synthetic procedures, amidoxime route and 1,3 dipolar cycloaddition are the most
commonly used,[6] however 1,2,4-oxadiazole derivatives have been identified in nature as well, e.g.
antibacterial metabolite of a fish pathogen Vibrio parahaemolyticus.[7] As 3-pyrazinyl-1,2,4-
oxadiazoles proved to inhibit growth of clinical strains of Mycobacterium,[4] we tried to synthesize 3-
pyrazinyl-5-substituted-1,2,4-oxadiazoles combining amidoximes and reactive carbonyl compounds.
All identified compounds have been tested on antifungal and antibacterial including
antimycobacterial effects.
[1]
Y. Durust, H. Karakus, M. Kaiser, D. Tasdemir, Eur. J. Med. Chem., 2012, 48, 296.
[2]
R: H. Tale, A. H. Rodge, A. P. Keche, G. D. Hatnapure, P. R. Padole, G. S. Gaikwad, S. S. Turkar, J.
Chem. Pharm. Res., 2011, 3, 496.
[3]
C. G. Fortuna, C. Bonaccorso, A. Bulbarelli, G. Caltabiano, L. Rizzi, L. Goracci, G. Musumarra, A. Pace, A.
P. Piccinello, A. Guarcello, P. Pierro, C. E. A. Cocuzza, R: Musumeci, Eur. J. Med. Chem., 2013, 65, 533.
[4]
a) A. Malabarba, B. Cavalleri, M. Berti, V. Arioli, Farmaco Sci., 1977, 32, 650. b) W. J. Wheeler, J. B.
Deeter, D. R. Finley, M. D. Kinnick, R. Koehler, H. E. Obsorne, J. T. Ott, J. K. Swartzendruber, D. G. Wishka,
J. Antibiot. ,1986, 39, 111. c) C.-H. Oh, H.-G. Dong, J.-S. Lee, S.-C. Lee, J. H. Hong, J.-H. Cho, Arch.
Pharm. Pharm. Med. Chem., 2003, 336, 567.
[5]
P. I. O´Daniel, Z. Peng, H. Pi, S. A. Testero, D. Ding, E. Spink, E. Leemans, M. A. Boudreau, T.
Yamaguchi, V. A. Schroeder, W. R. Wolter, L. I. Llarull, W. Song, E. Lastochkin, M. Kumarasiri, N. T.
Antunes, M. Espahbodi, K. Lichtenwalter, M. A. Suckow, S. Vakulenko, S. Mobashery, M. Chang, J. Am.
Chem. Soc., 2014, 136, 3664.
[6]
A. Pace, P. Pierro, Org. Biomol. Chem., 2009, 7, 4337.
[7]
A. Pandey, M. M. Naik., S. K. Dubey, Afric. J. Biotechnol., 2010, 9, 7134.
[8]
D. Pancechowska-Ksepko, H. Foks, M. Janowiec, Z. Zwolska-Kwiek, Acta Polon. Pharm., 1986, 43, 211.
46
KL-4
RATIONAL DESIGN OF PI4KB INHIBITORS AS POTENTIAL BROAD-

SPECTRUM ANTIVIRAL AGENTS
Radim Nencka,[a],* Ivana Mejdrová,[a] Dominika Chalupská,[a] Pavla Plačková,[a] Christin

Müller,[b] Michal Šála,[a] Eliška Procházková,[a] Adriana Baumlová,[a]
Milan Dejmek,[a] Dmytro Strunin,[a] Jan Weber,[a] Gary Lee,[c] Helena Mertlíková-
Kaiserová,[a] John Ziebuhr,[b] Gabriel Birkus[c] and Evzen Boura[a]
[a] Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
v.v.i, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic
[b] Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, D-35392
Giessen, Germany
[c] Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
* nencka@uochb.cas.cz
Phospatidylinositol 4-kinases (PI4Ks) are enzymes responsible for phosphorylation of

phosphatidylinositols, common constituents of the plasmatic membranes inside of cells. Numerous
positive-sense single stranded RNA (+ssRNA) viruses hijack phosphatidylinositol 4-kinase IIIβ
(PI4KB), one of four different isoforms of PI4K present in human cells, in order to alter plasmatic
membranes and set up bases for a functional replication machinery. Among others, important human
pathogens such as hepatitis C virus (HCV) from Flaviviridae family or human rhinovirus (HRV) and
coxsackie B3 (CVB3), both from Picornaviridae family, utilize PI4KB to rapidly invade host cells and
start the replication process. Therefore, selective inhibition of PI4KB leads to arrest of viral
replication.[1] We have recently performed an extensive study of novel selective PI4KB inhibitors.
Their rational design was based on the comparison of crystal structures with a selective inhibitor
MI14 [2] and non-selective derivative PIK93 [3] (Figure). The resulting hybrid structures, e.g. MI247,
exerted significantly elevated inhibitory potency and retained selectivity towards PI4KB in
comparison with other cellular lipid and protein kinases as well as outstanding antiviral activities
against HCV, HRV and CVB3.[4]
Figure: Structures of MI14, PIK93 and MI247 (left) and docking of MI247 (right).
Acknowledgments: The work was supported by Czech Science Foundation (No. 15-09310S) and
Gilead Sciences, Inc.
[1]
E. Boura, R. Nencka, Exp. Cell. Res., 2015, 337, 136.
[2]
I. Mejdrová, D. Chalupská, et al, J. Med. Chem., 2015, 58, 3767.
[3]
J.E. Burke, A.J. Inglis, et al, Science, 2014, 344, 1035.
[4]
I. Mejdrová, D. Chalupská, et al, J. Med. Chem., 2017, 60, 100.
47
KL-5
DESIGN AND SYNTHESIS OF NOVEL MODULATORS OF TOLL-LIKE

RECEPTORS AND INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE
Matej Sova,[a],* Urban Švajger,[b] Kaja Rožman,[a] Damijan Knez,[a] Samo Lešnik,[c] Janez
Konc[c] and Stanislav Gobec[a]
[a] Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
[b] Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia
[c] National Institute of Chemistry, Hajdrihova 19, SI-1000, Ljubljana, Slovenia
* matej.sova@ffa.uni-lj.si
Two targets, namely Toll-like receptors (TLRs) and indoleamine 2,3-dioxygenase (IDO), have been
of high interest for the design of small-molecule agents for autoimmune, inflammatory or infectious
diseases and cancer. TLRs as the key component of human innate immune system recognize
specific structurally diverse molecular patterns, such as molecular components of microorganisms
or endogenous molecules resulting from tissue damage.[1]-[2] Among 13 different mammalian TLRs,
we focused our attention on TLR4 and TLR7. On the other hand, high IDO1 expression found in
tumor cells triggers the escape from immune system and has been associated with poor prognosis
in several cancer types.[3] Therefore, our aim was to design and develop novel TLR modulators and
IDO1 inhibitors as potential anti-inflammatory and anticancer agents.
The compounds of interest were designed by advanced in silico drug design approaches. Structure-
and ligand-based virtual screening was performed on the basis of crystallographic structural data for
selected target. Targeting the TLR4–MD-2 interface enabled the discovery of three hit compounds
with promising TLR4 antagonist activity.[4] The most potent hit 1-(4-fluorophenyl)-2-(5-(2-hydroxy-5-
methoxybenzoyl)pyrimidin-2-yl)guanidine also suppressed cytokine secretion by human PBMC. In a
follow-up study, three-step synthetic route was designed and optimized to obtain a series of N-aryl-
N’-(5-(2-hydroxybenzoyl)pyrimidin-2-yl)guanidine derivatives as TLR4 antagonists with EC50 values
in the low micromolar range.[5] Furthermore, 3D similarity-based virtual screening using ROCS
software lead to the discovery of 1-isobutylchromeno[3,4-d]imidazol-4(1H)-one.[6] Additionally,
sixteen novel chromeno[3,4-d]imidazol-4(1H)-one derivatives were synthesized in the optimized
straightforward synthetic pathway and evaluated for TLR7 modulatory activity in a HEK-Blue™ TLR7
reporter assay. The most promising compound exhibited potent TLR7 agonist activity (IC50 of 1.8
µM) which was in the same range as a marketed drug imiquimod.
Recently, the ligand-based virtual screening using IDO1 inhibitor epacadostat as a query was
performed with our software LiSiCA.[7] Moreover, application of structure-based screening protocol
on the human form of IDO1 enzyme using our newly developed ProBiS plugin software [8] enabled
the discovery of structurally diverse hits which were further evaluated for IDO1 inhibitory activity in
an optimized highly sensitive fluorescence-based end-point assay.
Altogether, we obtained useful information about SAR of chromeno[3,4-d]imidazol-4(1H)-one TLR7
agonists, which represent an important starting point for further studies of small-molecule agents
targeting TLRs. Furthermore, novel IDO1 inhibitors were also discovered.
[1]
Y. Kumagai, O. Takeuchi, S. Akira. J. Infect. Chemother., 2008, 14, 86.
[2]
X. Wang, C. Smith, H. Yin, Chem Soc Rev., 2013, 42, 4859.
[3]
U.F. Röhrig et al. J. Med. Chem., 2015, 58(24), 9421.
[4]
U. Švajger et al. Eur. J. Med. Chem., 2013, 70, 393.
[5]
M. Sova et al. Med. Chem., 2016, 12(8), 742.
[6]
U. Švajger et al. Med. Chem. Res., 2015, 24(1), 362.
[7]
S. Lešnik et al. J. Chem. Inf. Model., 2015, 55(8), 1521.
[8]
T. Štular et al. J. Med. Chem., 2016, 59(24), 11069.
48
KL-6
NEW DRUG CONJUGATES BASED ON AZASTEROIDS OR PEPTIDES

FOR TARGETED DRUG DELIVERY IN CANCER THERAPY
Vasiliki Sarli
Department of Chemistry, Aristotle University of Thessaloniki, Greece
sarli@chem.auth.gr
Targeted drug delivery systems (TDDS) offer an attractive strategy to minimize systemic toxicity and
achieve the best therapeutic effect with a lower dose. Peptides (e.g. Arg-Gly-Asp (RGD) peptides,
poly-Arg peptides, octreotide, bombesin) and steroids, have been widely applied to selectively direct
drugs to cancer cells with upregulated receptors. The synthesis and evaluation of peptide-drug
conjugates that target integrin receptors will be thoroughly discussed. One derivative is designed to
carry together with the cytotoxic drug a luminescent probe for either in vivo or in vitro imaging in
order to ensure efficient monitoring of drug delivery. Classical chemotherapeutic drugs for instance
nitrogen mustards, platinum complexes and 5- fluorouracil are linked to the peptide by different
linkers.
In addition, the synthesis of conjugates combining a cytotoxic compound and azasteroidal lactams
will be analyzed. These conjugates improve the physicochemical properties (lipophilicity and
solubility) of known classical alkylators, such as POPAM ((bis(2-chloroethyl)amino)phenoxy)
propanoic acid). The synthesized homo-azasteroidal alkylators showed relatively lower acute
toxicity, very promising and prominent antileukemic activity both in vitro and in vivo.
49
KL-7
A "LIBRARY-ON-LIBRARY" SCREENING APPROACH TO IDENTIFY

SMALL-MOLECULE LIGANDS OF METHYL-LYSINE READER PROTEINS
Gianluca Sbardella
Dipartimento di Farmacia, Epigenetic Med Chem Lab, Università degli Studi di Salerno, Via Giovanni Paolo II
132, I-84084 Fisciano (SA), Italy.
gsbardella@unisa.it
The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the
“druggability” of epigenetic effector molecules. Using a library of biotin-tagged analogs we screened
a protein domain microarray of methyl-lysine effector molecules to rapidly detect compounds with
novel binding profiles - either improved or loosened specificity. Using this approach, we identified
compounds that acquired novel interactions with Tudor domain-and MBT domain-containing
proteins.
50
KL-8
APPLICATION OF UGI MULTICOMPONENT REACTION IN SYNTHESIS

OF NOVEL 2,6-DIKETOPIPERAZINE DERIVATIVES WITH HIGH AND
BROAD ACTIVITY IN ANIMAL MODELS OF EPILEPSY
Maciej Dawidowski
Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw,
Banacha 1, 02-097 Warsaw, Poland
maciej.dawidowski@wum.edu.pl
Our research group is interested in developing new broad-spectrum anticonvulsants. Initially, we

have found some active agents among 2,6-diketopiperazine (2,6-DKP) derivatives in a ligand-based
approach.[1] Some compounds proved efficient in many of the primary and secondary animal models
used by the Epilepsy Therapy Screening Program of NIH (eg., MES, 6Hz, scMET, CKM, mTLE). To
increase the in vivo potency of 2,6-DKPs and to achieve adequate SAR information, we next sought
a robust synthetic method that would give access to a variety of derivatives with multiple
diversification points.
We turned our attention to multicomponent reactions (MCRs), in which three or more starting
materials react to form a single product, usually in a technically simple, one-pot procedure and in an
atom-efficient manner. Among the variety of MRCs, Ugi reaction has been known as a rich source
of precursors for heterocyclic ‘drug-like’ scaffolds.[2]
In this lecture development of an Ugi → amide N-de-tertbutylation → intramolecular
cyclocondensation synthetic strategy is presented, that leads to anticonvulsant 2,6-DKPs. The SAR
information obtained through in vivo studies in animal models of epilepsy is discussed.
[1]
M. Dawidowski, F. Herold, A. Chodkowski, J. Kleps, P. Szulczyk, M. Wilczek, Eur. J. Med.Chem., 2011, 46,
4859.
[2]
A. Dömling, W. Wang, K. Wang, Chem. Rev., 2012, 112, 3083.
51
KL-9
HYBRID COMPOUNDS IN THE SEARCH FOR THE NEW HIGHLY

EFFECTIVE ANTICONVULSANTS
Krzysztof Kamiński
Department of Medicinal Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688
Kraków, Poland
k.kaminski@uj.edu.pl
The multifunctional ligands approach is one of the modern strategies in drug discovery especially in
relation to diseases with complex pathomechanism, such as Alzheimer’s disease, cancer, or
epilepsy. This strategy assumes that a single chemical entity is capable of modulating biological
targets simultaneously and overcoming problems related to the use of “multicomponent drugs” such
as different bioavailability or pharmacokinetics, as well as poor compliance in case of “drug
cocktails.” According to this method two (or more) molecules, each with different molecular target or
with specific biological properties, are combined in a single chemical entity to provide complex and
broad activity.[1]
Bearing in mind the assumptions of aforementioned strategy, and with the aim of obtaining more
efficacious antiepileptic drugs (AEDs) that will suppress different types of human seizures, the new
hybrid anticonvulsants based on the pyrrolidine-2,5-dione scaffold have been obtained.[2-4] These
hybrid molecules join on the one chemical template the structural fragments of clinically relevant
AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result, the hybridization process
yielded substances effective in three the most important animal seizure models, namely the maximal
electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and notably the six-
Hertz (6 Hz) model of pharmacoresistant limbic seizures in mice. These substances displayed wider
spectrum of protection, more potent efficacy or/and better safety profile than respective AEDs
creating hybrid structure (ethosuximide, levetiracetam, and lacosamide). Additionally, several
compounds diminished the pain responses in the formalin model of tonic pain and notably in the
neurogenic pain models (capsaicin-induced nociception and oxaliplatin-induced neuropathy) in mice.
Acknowledgements: The studies were supported by the Polish National Science Centre grant
2015/18/E/NZ7/00509.
[1]
R. Morphy, Z. Rankovic, J. Med. Chem,. 2005, 48, 6523.
[2]
K. Kamiński, M. Zagaja, J.J. Łuszczki, A. Rapacz, M. Andres-Mach, G. Latacz, K. Kieć-Kononowicz, J.
Med. Chem., 2015, 58, 5274.
[3]
K. Kamiński, M. Zagaja, A. Rapacz, J.J. Łuszczki, M. Andres-Mach, M. Abram, J. Obniska, Bioorg. Med.
Chem., 2016, 15, 606.
[4]
K. Kamiński, Curr. Top. Med. Chem., 2017, 17, 858.
52
KL-10
CAN MULTIVARIETE STATISTICS AID TO THE REVEAL OF BIOACTIVE

COMPOUNDS? AN NMR AND HPTLC APPROACH
V. I. Boka,[a] K. Stathopoulou,[a] D. Benaki,[b] E. Gikas,[b]

E. Mikros[b] and N. Aligiannis[a],*
[a] Department of Pharmacognosy & Natural Products Chemistry, Faculty of Pharmacy,
University of Athens, Zografou, 15771, Greece;
[b] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens,
Panepistimiopolis Zografou, Athens, Greece
* aligiannis@pharm.uoa.gr
Greece has an exceptionally rich flora which forms, geographically and historically, a link between
the plant-life of Europe and that of Asia.[1] It is characterized by high biodiversity, consisting of 6300
species of which 950 are endemic and thus could be an ideal source for the discovery of bioactive
compounds.[2] The aim of this project is to discover natural compounds with skin whitening properties
via the establishment of a high-throughput platform relying on FCPC, HPTLC and NMR, for their
direct detection and identification prior to any isolation.
600 plants existing in a unique plant-library comprising around 32% of the Greek flora were selected
and the plant extracts were produced by ASE. The extracts were in vitro investigated for their
tyrosinase inhibition activity and nine among the most promising were selected for further
elaboration. More specifically, the extracts were fractionated by FCPC utilizing a gradient step-wise
solvent system consisted of Heptane/Ethyl acetate/Butanol/Methanol/Water providing 45 fractions
per extract. The resulted fractions were assayed for tyrosinase inhibition potential and further
analyzed by HPTLC and NMR.
An integrated HPTLC-based procedure for the tracing of compounds that contributed to tyrosinase
inhibitory effect in active fractions was established with the use of multivariate data analysis.
Additionally, NMR spectral data were correlated with the activity towards tyrosinase resulting in the
identification of bioactive compounds through the combination of the Heterocovariance approach
(HetCA) and the statistical total correlation spectroscopy (STOCSY).
The combined data deriving from NMR and HPTLC correlated to the results of the biological activity
by the statistically driven approach, revealed flavans, flavonols, phenolic compounds and stilbenoids
as the most promising whitening agents, providing a major reduction in workload by direct use of
routine information.
[1]
Kokkini S., Karagiannakidou V., Hanlidou E., Vokou D.: Phyton (Austria), 1988, 28, 215.
[2]
Dimopoulos P., Raust T., Bergmeier E., et al., Berlin 2013.
53
KL-11
ENDOCANNABINOID SYSTEM MODULATION:

THERAPEUTIC IMPLICATIONS AND FUTURE PERSPECTIVES
Marco Macchia
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
marco.macchia@unipi.it
The endocannabinoid system (ECS) consists of two G protein-coupled receptors (CB1R and CB2R),
their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes
involved in the biosynthesis and degradation of endocannabinoids, such as fatty acid amide
hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS is involved in several
physiological and pathological conditions, including cancer and neurodegenerative diseases. The
CB2R has gained a great interest as a therapeutic target in drug discovery. Recent in vitro and in
vivo studies highlight that activation of the CB2R induces apoptosis and inhibits tumour growth and
neo-angiogenesis. It has been also demonstrated that potent and selective CB2R agonists produce
beneficial actions in the brain and in the periphery, with the additional advantage of being devoid of
CB1R-mediated psychotropic side effects. On the other hand, the enhancement of the levels of AEA
and 2-AG, by inhibiting MAGL/FAAH, could preserve the beneficial effects derived from the direct
activation of CBRs. Recent investigations hypothesize an important role for MAGL in cancer cells,
regulating a set of pro-tumorigenic signaling molecules and promoting migration, survival, and in vivo
tumor growth. Hence, overexpression of this enzyme results in increased pathogenicity of cancer
cells, whereas its inhibition reduces cancer growth, indicating that it might constitute a promising
antitumor target. Furthermore, the current comprehension of the complexity of the ECS seems to
indicate a need of multi-target drugs, which exert their pro-cannabinoid activities by means of more
than one mechanism of action. These molecules could offer the advantage of modulating the ECS
in a safer and more therapeutically efficacious way. The development of these multi-target tools
could provide a foothold to investigate the polypharmacology of the ECS in different pathologies.
In our research program aimed at obtaining modulators of the ECS, we focused our attention on
compounds of general structure A, B and C as selective CB2R agonists, selective MAGL inhibitors
and multi-target ECS modulators, respectively.
R3 O O O
R4 Cl R3
NHR2 N NHR2
X N O R1 R3 R4 N O
R1 O R2 R1 C
A B
54
KL-12
COMPUTATIONAL INSIGHT INTO THE CATALYTIC ACTIVITY OF

MONOAMINE OXIDASE FOR TARGETING NEUROLOGICAL DISEASES
Robert Vianello
Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Zagreb, Croatia
robert.vianello@irb.hr
Monoamine oxidase (MAO) is an FAD-dependent flavoenzyme responsible for metabolizing a very

broad range of biogenic and dietary amines including many neurotransmitters in the brain, such as
dopamine and serotonin, whose imbalance is extensively linked with the development and
progression of many neurological disorders. That is why MAO has been a central pharmacological
target in treating neurodegeneration for over 60 years.[1] Still, despite decades of extensive research,
neither its catalytic nor inhibition mechanisms have yet been clearly determined, which is of
paramount importance in designing novel and effective MAO inhibitors as transition state analogues,
particularly since current drugs show serious adverse effects and tend to address only the symptoms
rather than the cause of the dysfunction.
On the basis of QM calculations and EVB QM/MM simulations, we have proposed a new two-step
hydride mechanism for the MAO catalysis (Figure 1),[2] which is gaining some affirmation in the
literature,[3] and is fully corroborated by a very recent 13C kinetic isotope effect measurements.[3c]
Calculations of the pKa values of three tyrosine residues[4] (Figure 2) revealed that MAO active site
is hydrophilic, but turns hydrophobic upon the substrate entrance that binds in the monocationic
form. MAO selectivity has been investigated in the case of histamine,[5] which is not a physiological
MAO substrate, yet is efficiently metabolized by MAO upon the N-methylation of the imidazole ring.
Our results rationalized the MAO specificity with two substrates, histamine and N-methylhistamine,
differing only in a single methyl group distant from the reactive centre. The insight gained through all
these results led us to propose several promising strategies for preventing neurodegeneration.[6]
Figure 1: Free energy profiles for the MAO B catalyzed Figure 2: MAO B active site with
degradation of histamine and N-methylhistamine. dopamine bound as the substrate.
[1]
a) R.R. Ramsay, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2016, 69, 81.; b) S. Chajkowski-Scarry,
J.M. Rimoldi, Future Med. Chem., 2014, 6, 697.; c) R.R. Ramsay, Curr. Top. Med. Chem. 2012, 12, 2189.
[2]
a) R. Vianello, M. Repič, J. Mavri, Eur. J. Org. Chem., 2012, 7057.; b) M. Poberžnik, M. Purg, M. Repič, J.
Mavri, R. Vianello, J. Phys. Chem. B, 2016, 120, 11419.
[3]
a) V.E. Atalay, S.S. Erdem, Comp. Biol. Chem., 2013, 47, 181.; b) G. Zapata-Torres et al., J. Chem. Inf.
Model., 2015, 55, 1349.; c) J.R. Tormos et al., Arch. Biochem. Biophys., 2016, 612, 115.
[4]
R. Borštnar, M. Repič, S.C.L. Kamerlin, R. Vianello, J. Mavri, J. Chem. Theory Comput., 2012, 8, 3864.
[5]
A. Maršavelski, R. Vianello, Chem. Eur. J., 2017, 23, 2915.
[6]
M. Pavlin, M. Repič, R. Vianello, J. Mavri, Mol. Neurobiol., 2016, 53, 3400.
55
KL-13
LIGAND-BASED DRUG DESIGN OF NOVEL ALDOSE REDUCTASE

INHIBITORS FROM DATABASES OF INDOLE-1-ACETIC ACIDS
Magdaléna Májeková,* Jana Ballekova, Marta Soltesova Prnova and Milan Stefek
Department of Biochemical Pharmacology, Institute of Experimental Pharmacology and Toxicology
Slovak Academy of Sciences, Dubravska cesta 9, 541 04 Bratislava, Slovakia
* magdalena.majekova@savba.sk
Aldose reductase (ALR2) is a frequent therapeutic target in searching for efficient treatment of long-
term diabetic complications and other chronic diseases. Compounds with indole-1-acetic acid moiety
are known as promising leads for design of aldose reductase inhibitors (ARIs). Ligand-based
strategy was used in searching for novel ARIs in databases of purchasable compounds. Among the
compounds studied, 2-(2-(ethoxycarbonyl)-8-methoxy-3,4-dihydro-1H-pyrido[4,3-b]indole-5(2H)-yl)
acetic acid (Figure) was identified as the most promising inhibitor of aldose reductase (ALR2), with
IC50 in nanomolar region and selectivity factor relative to aldehyde reductase (ALR1) around 750.[1]
Profitable inhibition properties were also confirmed for isolated rat lens red blood cells. In vivo
experiment of streptozotocin induced diabetes on rats revealed an early ability of DPI-1 to inhibit
sorbitol accumulation in sciatic nerve and blood.
O
O
N
H3CO
N OH
Figure: Structure of DPI-1.
Concurrently, we started to build up the systematic database of compounds with indole scaffold,
whose properties have been studied by a virtual screening method to find optimal pharmacokinetic
and pharmacodynamics properties. The compounds proposed by this study are to be synthesized
and tested for their activities as aldose reductase inhibitors and the modulators of other proteins
occurring in the development of chronic diseases together with aldose reductase.
Acknowledgements: This work was supported by VEGA 2/0041/15 and VEGA 2/0033/14. We also
thank the Slovak Research and Development Agency under the contract No. APVV-15-0455 and
SAS – TÜBİTAK Joint Project No. JRP 2015/7 for funding.
[1]
M. Stefek, J. Ballekova, M. Soltesova Prnova and M. Majekova. Use of 5-carboxymethyl-1,2,3,4-
tetrahydro-1H-pyrido[4,3-b]indoles and pharmaceutical preparation containig them: Patent Application PP
50049-2016, Industrial Property Office of the Slovak Republic, 2016.
56
KL-14
PRETARGETED PRODRUG ACTIVATION THROUGH BIOORTHOGONAL

ELIMINATION
Hannes Mikula
Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Getreidemarkt
9/163, 1060 Vienna, Austria
hannes.mikula@tuwien.ac.at
The field of bioorthogonal chemistry has been growing steadily and fascinating scientists worldwide
for more than 15 years with the challenge of engineering chemical transformations that can proceed
within the molecularly complex environment of living systems. In spite of tremendous progress in
recent years, when compared to classic reaction methodology, bioorthogonal chemistry remains in
its infancy. Considering the vast range of organic reactions available to synthetic chemists (additions,
eliminations, substitution, oxidations, reductions, etc.), bioorthogonal chemistry has until recently
been restricted to just one reaction type—bioorthogonal addition—limiting its full potential.
In recent years, bioorthogonal bond cleavage (or bioorthogonal elimination) reactions have emerged
as a thriving area of chemical research, with examples such as the palladium-mediated cleavage of
allyl and propargyl carbamates [1-3] or the elimination of a carbamate-functionalized trans-
cyclooctene (release-TCO, rTCO) upon reaction with a 1,2,4,5-tetrazine (Tz).[4] The latter reaction
has recently led to novel therapeutic concepts, and applications in chemical biology.[4-6]
We have designed and prepared several prodrugs using carbamates and rTCO as protective triggers
also in combination with self-immolative linkers. In general, we have observed that these prodrugs
are significantly less toxic to tumor cells than the respective parent drugs, but can be activated by
co-treatment with a palladium catalyst or tetrazines, respectively. For example, a Tz-moiety was
attached to a highly selective covalent inhibitor affording a bioorthogonal probe that was successfully
applied for pretargeted activation of rTCO-modified prodrugs.
In this talk, an overview will be given of these studies and our recent activities regarding prodrug
activation through bioorthogonal elimination.
[1]
R.M. Yusop, A. Unciti-Broceta, E. M. V. Johansson, R. M. Sánchez-Martín, M. Bradley, Nat. Chem., 2011,
3, 239.
[2]
J. Li, J. Yu, J. Zhao, J. Wang, S. Zheng, S. Lin, L. Chen, M. Yang, S. Jia, X. Zhang, P. R. Chen, Nat. Chem.,
2014, 6, 352.
[3]
J. Li, P. R. Chen, Nat. Chem. Biol., 2016, 12, 129.
[4]
R.M. Versteegen, R. Rossin, W. ten Hoeve, H. M. Janssen, M. S. Robillard, Angew. Chem. Int. Ed., 2013,
52, 14112.
[5]
J. Li, S. Jia, P. R. Chen, Nat. Chem. Biol., 2014, 10, 1003.
[6]
G. Zhang, J. Li, R. Xie, X. Fan, Y. Liu, S. Zheng, Y. Ge, P. R. Chen, ACS Cent. Sci., 2016, 2, 325.
57
KL-15
PATIENT DERIVED TESTING SYSTEMS – REACHING BEYOND TARGED

BASED DRUG DISCOVERY
Vesna Eraković Haber

Translational Research and Alliances, Fidelta Ltd., Zagreb, Croatia
vesna.erakovichaber@glpg.com
Great advances in modern science have provided a clear rational and powerful tools for target based
drug discovery. Combinatorial chemistry and parallel synthetic methods have increased significantly
number of molecules synthetized by chemists. Nevertheless, number of new drugs approved per
billion US dollar spent on R&D has halved approximately every 9 years since 1950s.[1] At least
partially, the cause of that could be found in reductionist approach to biological systems and human
disease.
Current efforts aimed at setting up disease relevant ex vivo system, as well as their use for better
understanding of human disease and testing of novel pharmacological interventions, will be
presented. Donated patient derived material, hand in hand with state of the art micro technologies,
rises a hope of better translation between preclinical and clinical research. Illustrations from several
disease areas will be given, with special focus on inflammation.
[1]
J.W. Scannell, A. Blanckley, H. Boldon, B. Warrington, Nat. Rev. Drug Discov., 2012, 11, 191.
58
ORAL PRESENTATIONS
59
OP-1
ANTI-HELICOBACTER PYLORI ACTIVITY OF A NOVEL DERIVATIVE OF

INTERVENOLIN
Manabu Kawada,[a,b],* Tomokazu Ohishi,[b] Hikaru Abe,[c] Chigusa Hayashi,[d]

Chiharu Sakashita,[c] Shun-ichi Ohba,[b] Hiroyuki Inoue,[b] Masayuki Igarashi,[d] Takumi
Watanabe[c] and Masakatsu Shibasaki[c],*
[a] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, 3-14-23 Kamiosaki,
Shinagawaku, Tokyo 141-0021, Japan
[b] Institute of Microbial Chemistry (BIKAKEN), Numazu, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-
0301, Japan
[c] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Synthetic Organic Chemistry, 3-14-23
Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
[d] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, 3-14-23 Kamiosaki,
Shinagawa-ku, Tokyo 141-0021, Japan
* kawadam@bikaken.or.jp
Helicobacter pylori (H. pylori) infection plays a critical role on pathogenesis of gastric ulcer and
gastric cancer. Thus, the eradication of H. pylori could prevent the onset of these diseases. At
present the standard therapy against H. pylori infection is a combination therapy of a proton pump
inhibitor and two antibiotics such as clarithromycin and amoxicillin. However, there exist H. pylori
strains that show resistance against these antibiotics. Furthermore, adverse effect of these
antibiotics against intestinal bacteria is unavoidable. We previously discovered a novel compound,
intervenolin, from the culture broth of Nocardia sp. ML96-86F2.[1] [2] Intervenolin is a very unique
compound having both antitumor and anti-H. pylori activities. To create a potent anti-H. pylori
compound, we synthesized various derivatives of intervenolin.[3] Among them we identified
compounds that show selective anti-H. pylori activity in vitro without effect on other bacteria including
intestinal bacteria. Oral monotherapy of the derivative exerts significant eradicative effect against H.
pylori-infected mice more than the standard combination therapy. Taken together, we have
successfully created a potent new anti-H. pylori compound.
[1]
M. Kawada, et al, J. Antibiot., 2013, 66, 543.
[2]
H. Abe, et al, Org. Lett., 2013, 15, 2124.
[3]
H. Abe, et al, Tetrahedron, 2013, 69, 7608.
60
OP-2
IN VITRO PHOTODYNAMIC ACTIVITY OF A NEW TRI-CATIONIC

AMPHIPHILIC PORPHYRIN AGAINST HERPES SIMPLEX VIRUS 1,
BACTERIA AND CANCER CELLS
Nela Malatesti,[a],* Maja Cokarić Brdovčak,[a] Lara Djaković,[a] Igor Jurak,[a]

Anđelo Šuvak,[a] Ivana Gobin,[b] Anja Harej[a] and Sandra Kraljević Pavelić[a]
[a] Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia
[b] Department of Microbiology and Parasitology, Faculty of Medicine, Braće Branchetta 20, 51000
Rĳeka, Croatia
* nela.malatesti@biotech.uniri.hr
Photodynamic therapy (PDT) is a type of phototherapy that uses harmless red light for the activation
of a photosensitiser (PS) and consequential, localised formation of the cytotoxic singlet oxygen or
other reactive oxygen species.1 Even though PDT was first discovered on a microorganism, it has
been primarily developed to treat cancer, and is only recently getting more attention as an
antimicrobial therapy.2
We have synthesized 5-(4-octadecanamidophenyl)-10,15,20-tris(N-methylpyridinium-3-yl)porphyrin
trichloride (C18PyP3) in order to investigate the effect of the lipophilic moiety on PDT activity of this
amphiphilic porphyrin, in comparison to the hydrophilic analogue, 5-(4-acetamidophenyl)-10,15,20-
tris(N-methylpyridinium-3-yl)porphyrin trichloride (C2PyP3). Both porphyrins have very similar
optical properties and PDT activity in relation to both drug-dose and light-dose, but significantly
higher activity of the amphiphilic porphyrin was demonstrated as the obtained IC50 value for
C18PyP3 was 37 times lower than for C2PyP3, after PS activation with low dose of red light (1.8 J
cm-2, 643 nm) on HeLa cells in vitro.3
Cationic tetraarylporphyrins have been previously used to destroy both Gram positive and Gram
negative bacteria,4 and are also interesting as possible antiviral agents.5 To test the antibacterial
activity of C18PyP3, the minimum inhibitory (MIC) and minimum bactericidal (MBC) concentration
was determined, with the dilution method, on several Gram (+) and Gram (-) bacteria. After 30
minutes incubation with C18PyP3 and further 1 hour of irradiation (overall dose 7.2 J cm-2), there
was no difference between MIC and MBC values, and the lowest values were obtained on Gram (+)
bacteria, namely, Staphylococcus aureus (6.25 µM), including methicillin-resistant strain (MRSA),
Enterococcus faecalis (12.5 µM) and Listeria monocytogenes (12.5 µM).
Finally, to test antiviral activity of C18PyP3, we infected Vero cells treated with different
concentrations of the compound with herpes simplex virus 1 (HSV-1) and measured virus yield.
Replication of the virus was greatly reduced in cells that were treated and irradiated (1.8 J cm-2)
compared to untreated or treated but not irradiated cells. Moreover, the inhibition of replication was
drug-dose dependent. These results strongly indicate that C18PyP3 activated by light exerts antiviral
properties. Furthermore, our preliminary results show that it affects HSV-1 replication by inhibiting
virus gene expression and by limiting the infectivity of HSV-1 virions. Important to note, the
concentrations of C18PyP3 used in these experiments did not show a significant toxicity in Vero
cells.
[1]
R.R. Allison, K. Moghissi, Clin. Endosc., 2013, 46, 24.
[2]
S.K. Sharma, P. Mroz, T. Dai, Y-Y. Huang, T.G. St. Denis, M.R. Hamblin, Isr. J. Chem., 2012, 52, 691.
[3]
N. Malatesti, A. Harej, S. Kraljević Pavelić, M. Lončarić, H. Zorc, K. Wittine, U. Andjelkovic, D. Josic,
Photodiagnosis Photodyn. Ther., 2016, 15, 115.
[4]
E. Alves, L. Costa, C.M. Carvalho, J.P. Tomé, M.A. Faustino, M.G. Neves, A.C. Tomé, J.A. Cavaleiro, A.
Cunha, A. Almeida, BMC Microbiol., 2009, 9, 70.
[5]
L. Costa, M.A.F. Faustino, M.G.P.M.S. Neves, A. Cunha, A. Almeida, Viruses, 2012, 4, 1034.
61
OP-3
DISCOVERY OF NEW, POTENTIAL ANTI-INFECTIVE

COMPOUNDS BASED ON CARBONIC ANHYDRASE
INHIBITORS BY RATIONAL TARGET-FOCUS
REPURPOSING APPROACH
G. Annunziato,[b] A. Angeli,[c] F. D’Alba,[a] A. Bruno,[a],* M. Pieroni,[a] D. Vullo,[d]

V. De Luca,[e] C. Capasso,[e] C. T. Supuran[c,d],* and G. Costantino[a]
[a] Dipartimento di Scienze degli Alimenti e del Farmaco, P4T group, University of Parma; Parco Area
delle Scienze, 27/A, 43124, Parma (Italy)
[b] CIM-Centro Interdipartimentale Misure “Giuseppe Casnati”, University of Parma, Parco Area delle
Scienze 23/A, 43124, Parma (Italy)
[c] Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, University of Florence,
Via U. Schiff 6, 50019 Sesto Fiorentino, Florence (Italy)
[d] Polo Scientifico, Laboratorio di Chimica Bioinorganica, University of Florence, Via della Lastruccia
3, 50019 Sesto Fiorentino, Florence (Italy)
[e] Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli (Italy)
* agostino.bruno@unipr.it; claudiu.supuran@unifi.it
Drug-repurposing or repositioning (DR) denotes an ensemble of tasks aimed to the identification of

new drug indications for existing drugs, and is an alternative strategy in drug discovery program,
both in pharma and academia. In academia, DR can be also translated into compound-recycling
(CR) that is the repurposing of compound library collections already available in-house. Indeed, small
molecules already synthesized, that resulted inactive against a target of interest, can be tested on
other targets, leading to a new-purpose for an old molecule.[1] We embarked in a project aimed at
the repurposing of the compound libraries available in-house, looking for a new potential applications
for our compounds. In this scenario a rational target-based drug repurposing approach was
applied.[2] The analysis of the data available in literature, for similar classes of chemical structures,
allowed us to identify the Carbonic Anhydrase (CA, EC 4.2.1.1) metalloenzyme family as potential
target of some of our compound series. A thoroughly validated docking screenings protocol was
combined with chemical synthesis and in vitro assays to disclose new potential CA inhibitors which
are characterized by a low μM affinity for microbial CA and unprecedented selectivity profile for this
class of molecules (Figure). Even if, the activity profile of the compounds needs to be improved, the
identified molecules can represent excellent hits to be further optimized in hits-to-lead campaigns.
Figure: Compound 18 docked into the SspCA active site, and its corresponding Ki on other relevant CA
families and human isoforms.
[1]
M. Mori, Y. Cau, G. Vignaroli, I. Laurenzana, A. Caivano, D. Vullo, C. T. Supuran, M. Botta, ACS Chem.
Biol., 2015, 10, 1964.
[2]
J. Langedijk, A. K. Mantel-Teeuwisse, D. S. Slijkerman, M.-H. D. B. Schutjens, Drug Discov. Today, 2015,
20, 1027.
62
OP-4
DISCOVERY OF NOVEL GYRASE B INHIBITORS AND GYRASE

B/TOPOISOMERASE IV (ParE) DUAL INHIBITORS WITH IN VITRO
ANTIBACTERIAL ACTIVITY
Michaela Barančoková,[a] Janez Ilaš,[a] Tihomir Tomašič,[a] Nace Zidar,[a]

Andraž Lamut,[a] Davide Benedetto Tiz,[a] Päivi Tammela,[b] Antonio Felici,[c]
Vanesa Garrido[c] and Danijel Kikelj[a],*
[a] Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
[b] Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland
[c] Aptuit Verona S.r.l. - Centre of Drug Discovery and Development, Via A. Fleming 4, 37135 Verona,
Italy
* danijel.kikelj@ffa.uni-lj.si
With increasing threat of bacterial resistance, topoisomerases became attractive targets for
antibacterial drug discovery. Currently there is no ATP-competitive inhibitor in clinical use, since
novobiocin as representative of aminocoumarines was withdrawn from the market in 1960s due to
eukaryotic toxicity.[1] Topoisomerases are essential enzymes changing topological state of DNA by
binding and cleaving DNA strand at GyrA/ParC subunit. Energy required for this process is obtained
by ATP hydrolysis on GyrB or ParE subunit containing ATP-binding site.[2]
Based on studies of solved crystal structure of E. coli GyrB with ligand (PDB code 5L3J) recently
published by our group,[3] we replaced dibromopyrrole-/dichloropyrrolecarboxamide moiety attached
to position 2 or 6, respectively, of benzo[d]thiazole-2,6-diamine scaffold with 3,4-dichloro-5-
methylpyrrole-2-carboxamide group to complete structure-activity relationship in the series. We
obtained improved analogues with increased inhibitory activity against both gyrase B and
topoisomerase IV. Scaffold hopping approach was used to prepare compounds with
benzo[d]imidazole-2,6-diamine core with improved physico-chemical properties and increased in
vitro antibacterial activity. Introducing different acyl moieties such as imidazolidinones or acyl groups
optionally containing basic moieties such as piperazin ring is another example of our efforts to
improve antibacterial activity.
O R1
NH O O
R2 H H
N X n R1 O N X
n NH
NH
O X = S, N O O N R2
N
n = 0; 1 O N
H
R1 = Me; Et; H
R2 = 4,5-dibromo; 3,4-dichloro-5-methyl
Figure: General structures of series of compounds with benzo[d]thiazole- or benzo[d]imidazole-2,6-diamine
scaffold.
[1]
G.S.Bisacchi, J.I. Manchester, ACS Infect. Dis., 2015, 1, 4.
[2]
J.J. Champoux, Annu. Rev. Biochem., 2001, 70, 369.
[3]
M. Gjorgjieva, T. Tomasic, M. Barancokova, S. Katsamakas, J. Ilas, P. Tammela, L.P. Masic,D. Kikelj, J.
Med. Chem., 2016, 59 (19), 8941.
63
OP-5
FIGHTING ANTIMICROBIAL RESISTANCE BY BREAKING RESISTANCE

MECHANISMS
Tommaso Felicetti,* Rolando Cannalire, Giuseppe Manfroni, Maria Letizia Barreca,

Sabatini Stefano, and Violetta Cecchetti
Department of Pharmaceutical Science, University of Perugia, via del Liceo, 1 - 06123 Perugia, Italy
* tommaso.felicetti90@gmail.com
Antimicrobial resistance is an increasingly risk for global public health and it threatens an ever-
increasing range of infections caused by bacteria, viruses, fungi, and parasites.[1] It is therefore of
crucial importance to find, as soon as possible, a way to fight antimicrobial resistance.
In this scenario, the development of molecules able to inhibit the efflux of the antimicrobial agents
from the bacterial cells shows a huge potential in order to address the global threat of antimicrobial
resistance.
S. aureus overexpresses several efflux pumps; among them NorA is the most expressed and
responsible for the extrusion of different substrates such as fluoroquinolones (i.e. ciprofloxacin –
CPX) and dyes (i.e. ethidium bromide – EtBr) out of the bacterial cells.[2] Thus, taking into account
the strong inhibitory activity on NorA efflux pump displayed from our previously reported 2-
phenylquinoline derivatives,[3,4] in this work we have explored the effects of the introduction of a
methoxy group, a substituent frequently recurrent in both natural and synthetic NorA efflux pump
inhibitors, in different positions of the quinoline core. The O-alkylamino chains at the C-4 position
were selected on the basis of the structure-activity relationship previously delineated.
All the synthesized compounds were preliminary tested in order to evaluate their ability to inhibit EtBr
efflux in S. aureus strain overexpressing norA gene. Then, compounds with EtBr efflux inhibition
higher than 80% were assayed to assess their capability to restore CPX MIC in different S. aureus
resistant strains. Results of this study will be presented.
[1]
LJ. Piddock, Lancet Infect. Dis. 2012, 12, 249.
[2]
D. Patel, C. Kosmidis, S.M. Seo, and G.W. Kaatz, Antimicrob. Agents Chemother., 2010, 54, 5070.
[3]
S. Sabatini, F. Gosetto, G. Manfroni, O. Tabarrini, G.W. Kaatz, D. Patel, and V. Cecchetti, J. Med. Chem.,
2011, 54, 5722.
[4]
S. Sabatini, F. Gosetto, N. Iraci, M.L. Barreca, S. Massari, L. Sancineto, G. Manfroni, O. Tabarrini, M.
Dimovska, G.W. Kaatz, and V. Cecchetti, J. Med. Chem., 2013, 56, 4975.
64
OP-6
α-ENAMINONES: NEW BUILDING BLOCKS FOR DIRECT SYNTHESIS OF

BIOLOGICALLY ACTIVE ALKALOIDS
David Lankri, Ghassan Albarghouti and Dmitry Tsvelikhovsky*

The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of
Jerusalem, Jerusalem 91120, Israel
* dmitryt@ekmd.huji.ac.il
We disclose novel reactivity of α,β-unsaturated enaminones driven by their "dual electronic attitude".
We introduce unexplored, stable α-enaminone synthones, radically different from the β-counterparts
by their chemical behavior, and unlock unusual, and never before observed functionalities of these
building blocks. The feasibility of new concept and its potential general applicability is demonstrated
in direct metal- or radical-free functionalization of enaminone precursors such as: amination, 1,2-
1,3- or 1,4-addition, alkylation, C-O bond formation, and many others. We designed general and
collective synthesis of several important classes of heterocycles via controlled cyclizations of easily
accessible collective precursor.[1-3] The rapid composition of novel key α-enaminone synthones
yields an assembly of Oxazines, Azaspirones, Quinolinones, Quinolinoles, Azepines, Oxazepines
and many other bi- and polycyclic systems in a regio- and chemoselective fashion via controlled
intramolecular cyclizations of a single molecular unit. To the best of our knowledge, a general and
collective approach toward the construction of all the above-mentioned scaffolds has yet to be
reported. We unite these families under a common synthetic strategy and devise a simple means for
building these heterocyclic motives in a rapid and efficient manner. Oxazines, Azaspirones,
Quinolinones, Quinolinoles, Azepines, Oxazepine structures are frequently observed as scaffold
segments of various biochemical compounds, natural products and pharmaceuticals. These
architectures have been identified as building blocks of numerous alkaloids, as well as other families
of diverse, and often remotely related metabolites. Unfortunately, access to a large number of these
target molecules and their structural analogues is either unknown or hindered by their multistep
syntheses. An in-depth analysis of the introduced cores reveals that α-enaminones have the
potential to serve as operational, collective key precursors for their construction, via controlled
intramolecular cyclizations. This is the first attempt to link simple and single enaminone core with
such a diverse, heterocyclic architectures. With this in mind, our current interest is to develop a
streamlined, synthetic methodology allowing for rapid, collective composition of multiple targets,
using a single, common precursor.
[1]
Y. Mostinski, V. Valerio, D. Lankri, D. Tsvelikhovsky‚ J. Org. Chem., 2015, 80, 10464.
[2]
V. Valerio, Y. Mostinski, R. Kotikalapudi, D. Tsvelikhovsky‚ Chem. Eur. J., 2016, 22, 2640.
[3]
G. Elbarghouti, R. Kotikalapudi, D. Lankri, D. Tsvelikhovsky‚ Chem. Commun., 2016, 52, 3095.
65
OP-7
NOVEL BENZO[B]FURAN DERIVATIVES – BIOLOGICAL ACTIVITY AND

PROTEIN TARGET IDENTIFICATION IN LEUKEMIC CELLS
Marcin J. Cieślak,[a],* Karolina Królewska,[a] Julia Kaźmierczak-Barańska,[a]

Milena Sobczak,[a] Bożena Kuran,[b] Mariola Napiórkowska,[c] Jerzy Kossakowski,[b] Iwona
Wybrańska[d,e] and Barbara Nawrot[a]
[a] Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of
Bioorganic Chemistry, 112 Sienkiewicza Str., 90-363 Lodz, Poland
[b] Chair and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097
Warsaw, Poland
[c] Department of Medical Chemistry, Medical University of Warsaw, 3 Oczki Str., 02-007 Warsaw,
Poland
[d] Department of Genetic Diagnostics and Nutrigenomics, Chair of Clinical Biochemistry, The
Jagiellonian University, Medical College, 15 Kopernika Str., 31-501 Krakow, Poland
[e] Department for Genetic Research and Nutrigenomics, The Malopolska Centre of Biotechnology
Jagiellonian University, 7 Gronostajowa Str., 30-387 Krakow, Poland
* marcin@cbmm.lodz.pl
Novel derivatives of benzo[b]furan were found to be selectively toxic towards human chronic
myelogenous (K562), acute myelogenous (HL-60) and acute lymphoblastic (MOLT-4) leukemia cells
and much less toxic to primary human endothelial cells. The cytotoxicity of novel benzofurans
(expressed as IC50 values) in K562 and HL-60 cells was similar or higher compared to registered
drugs, such as cytarabine, sorafenib or CPT-11. The caspase 3/7 activity assay and annexin V-
FITC/PI flow cytometry analysis have shown that benzofurans induce apoptosis in K562 and MOLT-
4 cells. Both, receptor and mitochondrial apoptotic pathways were activated in leukemic cells in the
presence of test compounds, what was evidenced by increased activity of caspase 8 and 9. To
explain the mechanism of apoptosis induced by novel benzo[b]furans, the profiling of apoptosis-
associated genes expression was performed in leukemia K562 cells. Benzofuran derivatives
increased the expression of several proapoptotic genes involved in both receptor (e.g. TNFRSF 10A,
TNFRSF 10B, CASP8) and mitochondrial (e.g. BAX, BID, NOXA, APAF1) pathways of apoptosis.
To identify cellular proteins targeted by test benzofurans, the biotinylated derivative has been
synthesized and used in pull-down experiments in K562 leukemic cells. The proteomic analysis
revealed that tubulin is a target for biotinylated probe. Moreover, incubation of K562 cells with test
benzofurans resulted in depolymerization of microtubules. Biological activity of novel derivatives of
benzo[b]furans makes them potential candidates as lead compounds for synthesis and evaluation
of new anticancer drugs.
Acknowledgments: The financial support from Polish Ministry of Science, project NCN OPUS
UMO-2014/15/B/NZ7/00966 is acknowledged.
66
OP-8
DEVELOPMENT OF NOVEL DRUG CANDIDATE AGAINST PROSTATE

CANCER
Moran Shubely,[a],* Dhanoop Manikoth Ayyathan,[b] Michael Shokhen,[a]

Michael Blank[b] and Arie Gruzman[a]
[a] Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel
[b] Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel
* Moran.sobely@live.biu.ac.il
Prostate cancer is the third highest cause of death from cancer in men of all ages. Despite progress
in early diagnostics and treatment, prostate cancer still is one of the most devastating human
diseases. Thus, the development of anti-prostate cancer drugs remains urgent.
Smurf2 (Smad ubiquitin regulatory factor 2) is an E3 ubiquitin ligase that plays an important role in
the regulation of protein homeostasis. Previous studies[1] demonstrated that the distribution of
Smurf2 is different in normal and cancer tissues: Nuclear Smurf2 is a negative regulator of RNF20
that causes modifications in the epigenetic landscape, in particularly in monoubiquitination of histone
H2B. The H2B histone packs and orders the DNA and plays an important role in gene expression
regulation and DNA damage response. On the other hand, cytosolic Smurf2 has been reported to
reduce the steady-state of Axin and GSK3β (two negative regulator of Wnt/β-catenin signaling). The
activation of this signaling pathway leads to uncontrolled cell growth.
Smurf2 is a member of HECT-type family of E3s. This family is characterized by a common modular
organization: an N-terminal C2 domain, two to four WW domains, and a C-terminal HECT domain.
The HECT domain is responsible for the attachment of ubiquitin moieties to target proteins. We
hypothesized that targeting of Smurf2 for inactivation might affect the ability of cancer cells to
proliferate and/or withstand anticancer treatments. Based on the computer modeling several Smurf2
HECT domain specific binders (activators and inhibitors) were designed[2] and synthetized. Then, in
vitro evaluation in prostate cancer models showed that two novel peptidomimetic compounds were
active in an nM concentration range.
This novel approach for the possible treatment of prostate cancer which based on the modulation of
Smurf2 function is not reported yet.
[1]
M.Blank et al., Nat. Med., 2012, 18, 227.
[2]
M.Shokhen et al., ChemBioChem, 2011, 12, 1023.
67
OP-9
EVALUATION OF HALOGEN BONDING HOT SPOTS BY VIRTUAL

SCREENING OF COMMERCIAL DATABASES – A CASE STUDY OF 5-
HT7R
Rafał Kurczab,* Grzegorz Satała and Andrzej J. Bojarski

Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12 Smętna
Street, 31-343 Krakow, Poland
* kurczab@if-pan.krakow.pl
A halogen bond (XB) is a non-covalent interaction defined as a directional bond between a covalently
bound halogen atom (acting as a donor) and a Lewis base as an acceptor.[1-3] The XB strength is
comparable to weak or moderate hydrogen bonds and increases in the order of Cl < Br < I. XB has
been indicated to play an essential role in supramolecular systems, liquid crystal engineering,
nanomaterials, nanowire formation, catalysis, and also recently, in drug design and lead optimization
processes.[4,5]
The main aim of early stages of rational drug design is to rank drug candidates to select the ones
with a significant probability of becoming a drug. Virtual screening is generally used with large
databases of compounds which are purchasable or easy to synthesize.
Herein, the recently developed and used systematic molecular modeling approach to search of XB
amino acids hot spots among all crystallized GPCRs A was applied to one of the not yet crystallized
family member, i.e. 5-HT7R. The sets containing the halogenated and unsubstituted derivatives were
extracted from purchasable collection of Mcule database (https://mcule.com/), which contains more
than 35M compounds (access: 14.12.2016). Next, the resultant sets were filtered by CNS MPO (>4),
3D pharmacophore models, and finally docked to a set of 5-HT7R homology models using previously
tested QM/MM-GBSA procedure.[7] The sets in which halogenated derivative showed increase of the
free binding energy upon formation of halogen bonding with any of the predicted hot spots were
purchased and tested in 5-HT7R radioligand binding assay. The results revealed that for the majority
of sets the halogenated derivatives exhibited higher affinity for 5-HT7R than their unsubstituted
analogue. The studies provide evidence that only specific amino acids (XB hot spots) are able to
create halogen bonding in the binding site and, hence, can be used in rational optimization and
design of new drug candidates.
Acknowledgments: The study was supported by the National Science Center, Poland, Grant No
2014/15/D/NZ7/01782.
[1]
P. Politzer, J.S. Murray, T. Clark, Phys. Chem. Chem. Phys., 2010, 12, 7748.
[2]
P. Auffinger, F. Hays, E. Westhof, P.S. Ho, Proc. Natl. Acad. Sci., 2004, 101, 16789.
[3]
T. Clark, M. Hennemann, J.S. Murray, P. Politzer, J. Mol. Model., 2007, 13, 291.
[4]
G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi, G. Resnati, et al., Chem. Rev., 2016, 116, 2478.
[5]
R. Wilcken, M.O. Zimmermann, A. Lange, A.C. Joerger, F.M. Boeckler, J. Med. Chem., 2013, 56, 1363.
[6]
T.T. Wager, X. Hou, P.R. Verhoest, A. Villalobos, ACS Chem. Neurosci., 2010, 1, 435.
[7]
R. Kurczab, Acta Cryst. B, 2017, manuscript accepted.
68
OP-10
BIG DATA: AVOGADRO STOICHIOMETRY EXPLAINS HYPERBOLIC

LIGAND EFFICIENCY TREND
Jaroslaw Polanski,* Urszula Kucia, Aleksandra Tkocz, Roksana Duszkiewicz and Anna
Pedrys
Institute of Chemistry, University of Silesia, 9 Szkolna Street, 40-006 Katowice, Poland
* polanski@us.edu.pl
The relationship between a structure and property is an essential concept in chemistry and this
method is an important decision-making guide in drug design. Eventually however it is the market
that decides on the fate of a drug. As recently big data got an importance in the analysis of economic
effects, e.g., the potential use of big data in US health care could reduce costs by $300 billion a
year,[1] this should also appear in medicinal chemistry. Unexpectedly however, this strategy is not
widespread here, even despite, common belief of a data flood in drug design. It is social science,
psychology or economy where big data are commonly generated. The explanation comes with a
comparison of 120 mln chemical compounds that have been registered to human society having 7
bln individuals. Therefore, human interactions, e.g. (pharmaco)economics generate bigger data,
e.g., we have recently analyzed market price of a large library of 2.5 mln chemical compounds.[2]
During the lecture we will discuss big data structure and applications in drug design and
(pharmaco)economics. Below we discuss an example how important big data can be for the
understanding of the substantial chemical effects in these areas.
Figure: Hyperbolic plots of LE [kcal/g] (BindingDB, left) and market price PE [$/g] big data (center) vs MW
(left) or atom counts (center). MW vs atom count forms a linear plot (right).
In Figure we compared the prices of the large 2.5 mln chemical compound library[2] charged in [$/g]
with the ligand efficiency LE, i.e. binding data per heavy atom count, or per MW [binding data/g] with
typical hyperbolic plots. Below we are solving hyperbolic LE trend, an unexplained puzzle of
medicinal chemistry.[3] Replicated molecules can be normalized by a fixed number (usually an
Avogadro number NA) of molecules. Alternatively, we can use a fixed weight metric, e.g., one gram
of a substance, which is commonly used while measuring biological activity in lab. Then this is
recalculated into the molar metric. We will show that one gram of a substance contains 1/MW
molecules. In turn, LE is a direct measure of binding efficiency measured in a fixed weight metric.
However, unlike in a molar metric of a fixed NA number of molecules, a number of molecules will
change here according to a 1/MW factor; therefore; decreasing hyperbolically with the increasing
MW. Accordingly, a lower number of molecules will be available for ligand-receptor interaction for
high MW. It is interesting that LE that was designed as molecular descriptor, appears in fact a direct
property measure.[4] This brings a need for critical evaluation of previous LE models reported.
[1]
N. Szlezák, M. Evers, J. Wang, L. Pérez, Clin. Pharmacol. Ther., 2014, 95, 492.
[2]
J. Polanski, U. Kucia, R. Duszkiewicz, A. Kurczyk, T. Magdziarz, J. Gasteiger, J. Sci. Rep., 2016, 23;6:28521.
[3]
A.L. Hopkins, G.M. Keseru, P.D. Leeson, D.C. Rees, C.H. Reynolds, Nat.Rev.Drug Disc., 2014, 13, 105.
[4]
J. Polanski, J. Gasteiger, in: Leszczynski ed. Handbook of Computational Chemistry, Springer, 2016.
69
OP-11
FROM PUBLIC DOMAIN COMPOUND COLLECTIONS TO CELL-ACTIVE

EPIGENETIC MODULATORS. THE CASE OF THE NCI REPOSITORY.
Vassilios Myrianthopoulos,[a] Nadine Martinet,[b] Christian Bronner,[c] Jessica Ann Downs,[d]

Susanne Müller,[e-g] Stefan Knapp[e-g] and Emmanuel Mikros[a],*
[a] Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens,
Greece
[b] CNRS UMR 7272, Institut de Chimie, Universite de Nice-Sophia Antipolis, Nice, France
[c] Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS, INSERM, Universite de
Strasbourg, France
[d] Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton
BN1 9RQ, U.K
[e] Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford,
Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K
[f] Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford,
Roosevelt Drive, Oxford OX37BN, U.K
[g] Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang
Goethe-University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
* mikros@pharm.uoa.gr
A continuously increasing number of epigenetic proteins are identified as potential drug targets of
high importance for numerous therapeutic fields. To efficaciously validate those targets and enable
dissection of their possible roles in a therapeutic perspective, small-molecule cell-active and highly
selective modulators of their biological activity are needed. Utilization of in-silico screening
methodologies coupled with high-throughput biophysical techniques can advance efficient
exploration of the chemodiversity available within academic or commercial compound collections,
thus maximizing the anticipated success rate by guiding the whole procedure towards the most
favored chemical space. In this study, the results of a tandem virtual screening campaign undertaken
for evaluating the public domain NCI Repository collection towards epigenetic modules of emerging
interest are presented. The epigenetic proteins targeted were readers involved in recognition of
either acetyl-lysine marks (Bromodomains related to SWI/SNF chromatin remodeling complexes,
PB1) or hemi-methylated DNA (Ubiquitin-like protein that contains PHD and RING finger 1, UHRF1).
Screening was based on a consensus approach combining various ligand-based and structure-
based search techniques of significant orthogonality, such as docking-scoring calculations, two-
dimensional fingerprint analysis or three-dimensional shape similarity screening. Top-ranked
compounds were evaluated experimentally using DSF, ITC, MS and X-ray crystallography and a
number of primary hits were identified, showing high affinity for their respective targets, marked
selectivity and, most interestingly, measurable activity in cell-based assays based on the FRAP and
P-LISA settings. Those hits comprise highly promising starting points for sustaining hit-to-lead
optimization studies.
70
OP-12
MASS SPECTROMETRIC IMAGING AS A PRECLINICAL TOOL FOR

MEDICINAL CHEMISTS
Thavendran Govender
Catalysis and Peptide Research Unit, University of KwaZulu Natal, South Africa
govenderthav@ukzn.ac.za
Mass spectrometry imaging (MSI) allows for the label-free detection and mapping of a broad range
of molecules from complex surfaces, and it has become a fascinating molecular histology tool in
pharmaceutical and medical research. The fundamental contributions of this method are rapid
provision of molecular weight-specific maps or images at high resolution and sensitivity, offering a
new powerful medical tool for pathology,[1] chemotherapeutics,[2] and discovery of disease
biomarkers.[3] Over the past decade this technique has been adopted for the investigation of TB, HIV
and many other diseases. Our group is currently involved in understanding the neuroprotective
potential of current and pipeline anti TB drugs.[4-7]
[1]
P. Chaurand, M.E. Sanders, R.A. Jensen, R.M. Caprioli, Am. J. Pathol., 2004, 165(4),1057.
[2]
G. Marko-Varga, T.E. Fehniger, M. Rezeli, B. Döme, T. Laurel, Á. Végvári, J. Proteomics, 2011, 74(7),982.
[3]
M.L. Reyzer, R.M. Caprioli, J. Proteome Res., 2005, 4(4),1138.
[4]
A. Shobo, D. Bratkowska, S. Baijnath, S. Naiker, L.A. Bester, S. Singh, G.E.M. Maguire, H.G. Kruger, T.
Govender, Assay Drug Dev. Techn., 2015, 13, 277.
[5]
S. Baijnath, S. Naiker, A. Shobo, C. Moodley, J. Adamson, B. Ngcobo, L.A. Bester, S. Singh, H.G. Kruger,
T. Naicker, T. Govender, J. Mol. Histol., 2015, 46, 439.
[6]
A. Shobo, S. Baijnath, D. Bratkowska, S. Naiker, A.M. Somboro, L.A. Bester, S. Singh, T. Naicker, H.G.
Kruger, T. Govender, Drug Test Anal., 2016, 8, 832.
[7]
C.F. Munyeza, A. Shobo, S. Baijnath, D. Bratkowska, S. Naiker, L.A. Bester, S. Singh, G.E.M. Maguire, H.G.
Kruger, T. Naicker, T. Govender, Xenobiotica, 2016, 46, 385.
71
OP-13
PYRAZOLOQUINOLINONES, REVISITED GABAA RECEPTOR TOOL

COMPOUNDS
David Chan Bodin Siebert,[a] Xenia Simeone,[b] Konstantina Bampali,[b]

Marko Mihovilovic,[a] Michael Schnürch[a] and Margot Ernst[b],*
[a] TU Wien, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
[b] Medical University of Vienna, Department of Molecular Neurosciences, Spitalgasse 4, 1090 Vienna,
Austria
* margot.ernst@meduniwien.ac.at
γ – Aminobutyric acid (GABA) is a wide-spread transmitter which

binds to two pharmacologically diverging GABA receptors, GABAA
and GABAB. GABAA receptors (GABAARs) are transmembrane
pentameric ligand-gated chloride ion channels and represent an
important target of many clinically relevant drugs (e.g.
benzodiazepines, barbiturates, etc.). These receptors consist of
different subunits (e.g. α,β,γ, etc.), which are drawn from nineteen
subunit isoforms that are grouped into classes (e.g. α1-α6, β1- β3,
etc.).[1-4] The pyrazoloquinolinone (PQ) ligands bind at the
benzodiazepine (BZ) binding site (α+/γ- interface) and at the newly
described α+/β- interface.[5] This compound class has proven to be
a valuable tool to investigate the GABAAR function.
Figure 1: Homology model of an
α1β2γ2 GABAA receptor (top view)
indicating different extracellular binding
sites (α+/β- interface: red arrow).
Here, a small set of pyrazoloquinolinones were synthesized which show

the following properties: high affinity to the BZ binding site and low-
potency modulation at the α+/β- interface. In addition we report the first
β - subtype selective compounds that even distinguish between all three
beta isoforms. These findings provide more insights into the subtype-
selective modulation of GABAARs. Further investigation could not only
Figure 2: Pyrazoloquinolinone result in beneficial pharmacological tools, but also in selective ligands for
scaffold containing different receptor pools that cannot be targeted with existing compounds.
residues Rx.
[1]
W Sieghart, Pharmacol. Rev.,1995, 47, 181.
[2]
E Siegl, Curr. Top. Med. Chem., 2002, 2, 833.
[3]
M. Ernst el at., Neuroscience, 2003, 119, 933.
[4]
Olsen RW and Sieghart W, Pharmacol. Rev., 2008, 6, 243.
[5]
Ramerstorfer J et al., J. Neurosci., 2011, 31, 870.
72
OP-14
SYNTHESIS OF TISSUE-SPECIFIC CONJUGATES FOR TARGETED

DRUG DELIVERY INTO HEPATIC CELLS
S. Yu. Maklakova,[a],* V. V. Hapko,[a] R. A. Petrov,[a] T. S. Zatsepin,[a,b,c]

T. O. Abakumova,[a] O. V. Sergeeva,[c] E. K. Beloglazkina,[a]
N. V. Zyk,[a] V. E. Koteliansky[a,c] and A. G. Majouga[a,d]
[a] Lomonosov Moscow State University, Chemistry department, Leninskie Gory, 1/3, Moscow,
119991, Russia
[b] Central Research Institute of Epidemiology, Novogireevskaya, 3a, Moscow 111123, Russia
[c] Skolkovo Institute of Science and Technology, Novaya St., 100, Skolkovo, 143025, Russia
[d] National University of Science and Technology MISiS, Leninskiy pr, 4, Moscow, 119049, Russia
* maklakova.svetlana91@gmail.com
Targeted delivery is a promising approach of medicinal chemistry that allows to improve efficiency
of a drug and to diminish its toxicity. Particularly there is a desperate need for delivery systems of
oligonucleotides and anticancer drugs due to abovementioned drawbacks.[1]
The asialoglycoprotein receptor (ASGP-R) appears to be an appropriate target for the delivery into
hepatic cells, in view of its abundant presence on parenchymal liver cells, selective binding to
terminal D-galactose and N-acetylgalactosamine residues and ability to transport molecules through
cell membrane. It was shown [2] that the best binding to the receptor could be achieved in case of
using branched ligands containing three aforementioned carbohydrate moieties.
AHA1 mRNA levels relative to ACTB mRNA for groups

treated with anti-AHA1 siRNA versus anti-Luciferase
siRNA GalNAc conjugates (in vivo studies on mice)
We investigated synthetic approaches to conjugates of ligands for the ASGP-R with oligo-
nucleotides,[3] anticancer therapeutics and fluorescent dyes. Biological testing of obtained
compounds was conducted on human hepatocellular cell lines HepG2 and HuH7 with induced by
biotin ASGP-R. In vivo studies were performed on C57BL/6 mice.
This work was supported by RSF, grant №17-14-01316.

[1]
T. Zatsepin, Y. Kotelevtsev, V. Koteliansky, Int. J. Nanomedicine, 2016, 11, 3077.
[2]
X. Huang, J.-C. Leroux, B. Castanger, Bioconjugate Chem., 2017, 28, 283.
[3]
S.Yu. Maklakova, F.A. Kucherov, V.V. Gopko, G.A. Shipulin, T.S. Zatsepin, E.K. Beloglazkina, N.V. Zyk,
A.G. Majouga, V.E. Koteliansky Russ. Chem. Bull., Int. Ed., 2015, 64, 1655.
73
OP-15
NOVEL POLYCYCLIC N-ACYLPYRROLIDINES AS 11β-HSD1

INHIBITORS
Rosana Leiva,[a],* Constantí Seira,[b] Andrew McBride,[c] Margaret Binnie,[c]

Axel Bidon-Chanal,[b] F. Javier Luque,[b] Scott P. Webster[c] and Santiago Vázquez[a]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and IBUB,
Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, Spain.
[b] Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and IBUB, University
of Barcelona, Av. Prat de la Riba, 171, 08921 Santa Coloma de Gramenet, Spain.
[c] Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical
Research Institute, EH16 4TJ, United Kingdom.
* rosana.leiva@ub.edu
Glucocorticoids (GCs) are hormones that play a major role in the modulation of inflammatory and
immune responses, metabolism regulation, cardiovascular homeostasis and our body response to
stress.[1] It is now well accepted that the GC concentration in peripheral tissues where they perform
their activity, not only depends on the adrenal secretion but also on the intracellular metabolism in
these peripheral tissues. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the
cortisol regeneration from its inactive form cortisone.[2] During the last years, both academia and
industry have made great efforts to determine the role of this enzyme in several diseases and to
develop potent inhibitors as potential drug candidates.[3]
A polycyclic substituent optimization process from N-(2-adamantyl)amide 1[4] led us to identify the
pyrrolidine-based amide 2 as a potent 11β-HSD1 inhibitor. However, 2 presented low microsomal
stability and suboptimal selectivity.
Herein, we report the exploration of different substituents in the right-hand side (RHS) of the
molecule maintaining the pyrrolidine-based polycycle in order to address the abovementioned
issues. Our endeavor started integrating different aromatic, heteroaromatic, heterocycloalkyl and
branched alkyl substituents in order to generate diversity to build some structure-activity relationship
(SAR) information. From this work we obtained again potent nanomolar inhibitors but still without the
needed selectivity and stability properties. In light of these results, we focused our efforts on a
rational design of new substitution patterns of the RHS group in order to establish additional
interactions in the binding site that would deliver more potent and selective inhibitors.
[1]
R. M. Sapolsky, L. M. Romero, A. U. Munck, Endocr. Rev., 2000, 21, 55.
[2]
J. R. Seckl, B. R. Walker, Endocrinology, 2001, 142, 1371.
[3]
M. Wamil, J. R. Seckl, Drug Discov. Today, 2007, 12, 504.
[4]
R. Leiva, C. Seira, A. McBride, M. Binnie, A. Bidon-Chanal, F. J. Luque, S. P. Webster, S. Vázquez,
Bioorg. Med. Chem. Lett., 2015, 25, 4250.
[5]
R. Leiva, C. Griñan-Ferré, C. Seira, E. Valverde, A. McBride, M. Binnie, B. Pérez, F. J. Luque, M. Pallàs,
A. Bidon-Chanal, S. P. Webster, S. Vázquez, manuscript in preparation.
74
OP-16
ENANTIOSPECIFIC MODULATION OF A2B ADENOSINE RECEPTOR
Maria Majellaro,[a,b] Jhonny Azuaje,[a] Carlos Carbajales,[a] Abel Crespo,[a]

Angela Stefanachi,[b] Cosimo Altomare,[b] Saverio Cellamare,[b] María I. Loza,[c]
José Brea,[c] María I. Cadavid,[c] Hugo Gutiérrez de Terán[d] and Eddy Sotelo[a],*
[a] Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS),
University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
[b] Department of Pharmacy and Drug Sciences, University of Bari “A. Moro”, Via Orabona 4, 70125
Bari, Italy
[c] Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS),
University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
[d] Department of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, Sweden
* e.sotelo@usc.es
A set of specific receptors, classified as A1, A2A, A2B and A3 adenosine receptors (ARs), mediate the
plethora of physiological processes regulated by the purine nucleoside adenosine.[1] Accordingly,
since their discovery ARs have been considered to be attractive targets in drug discovery.[1] Selective
A2B antagonists have been claimed as anti-inflammatory agents or analgesics as well as to treat
asthma.[1] We herein document the identification of novel, potent and selective non-xanthine ligands
that enantiospecifically modulate the A2BAR. The reported ligands were assembled using a Biginelli-
based multicomponent approach and its antagonistic behavior was confirmed through functional
experiments. The optimization was assisted by a receptor-driven molecular modeling study and
allowed valuable SARs to be established for this series. The scaffold documented herein contains a
chiral center at the heterocyclic core. Accordingly, some representative ligands of the series were
resolved into its two enantiomers by chiral HPLC and the absolute configuration of the enantiomers
was established by circular dichroism. The biological evaluation of both enantiomers demonstrated
enantiospecific recognition at A2BAR. This constitutes the first example of antagonistic
enantioselective recognition at the A2B adenosine receptor and it opens new possibilities in the ligand
design.
1200
N Spectr um M ax Plot
sy1ja1675-2AB
40
O 1000
O
800 (±) 16b O
K i hA 2B = 15.1 nM
NH2 20 O
m AU
O 600
+ 400 H % hA 1 (10 mM) = 2%

CD
O Me 200 0 N O
O H N
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 -20 N N Me
% hA2A (10 mM) = 4%
Minutes (S)-16b
1500 Sp ectrum Max Plot
sy1ja1675-2A (R)-16b H % hA3 (10 mM) = 4%
-40
(R)-16b
1250
O
1000
250 300 350 400 (S)-16b
nm
m AU
O 750
500
H
N O 250
O
N 0 O % hA2B (10 mM) = 23%
N N Me 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Sp ectrum Max Plot
sy1ja1675-2B
Minutes
H % hA 1 (10 mM =18%
H 1250
N O
(±)-16b 1000 (S)-16b N
% hA 2A (10 mM) = 10%
750 N N Me
m AU
K i hA 2B = 24.30 nM 500
H % hA3 (10 mM) = 1%
% hA 1 (10 mM) = 21% 250
% hA 2A (10 mM) = 19 %, 0
(R)-16b
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
% hA 3 (10 mM) = 4% Minutes
[1]
B.B. Fredholm, A. Ijzerman, K.A. Jacobson, J. Linden, C. Muller, Pharmacol. Rev., 2011, 63, 1.
[2]
A. Crespo, A. El Maatougui, P. Biagini, J. Azuaje, A. Coelho, J. Brea, M.I. Loza, M. I. Cadavid, X. García-
Mera, H. Gutiérrez-de-Terán, E. Sotelo, ACS Med. Chem. Lett., 2013, 4, 1031.; A. El Maatougui, J. Azuaje,
M. González-Gómez, G. Miguez, A. Crespo, C. Carbajales, L. Escalante, H. Gutiérrez de Terán, E. Sotelo, J.
Med. Chem., 2016, 59, 1967.
75
POSTER PRESENTATIONS
76
P-1
FREE RADICAL SCAVENGING POTENCY OF DIHYDROCAFFEIC ACID:

THERMODYNAMICS OF 2H+/2e PROCESSES
Ana Amić,[a] Zoran Marković,[b] Jasmina Dimitrić Marković,[c] Bono Lučić[d] and
Dragan Amić[e],*
[a] Department of Biology, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
[b] Department of Chemical-Technological Sciences, State University of Novi Pazar, Novi Pazar,
Serbia
[c] Faculty of Physical Chemistry, University of Belgrade, Belgrade, Serbia
[d] Ruđer Bošković Institute, Zagreb, Croatia
[e] Faculty of Agriculture, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
* damic@pfos.hr
Thermodynamics of 2H+/2e free radical scavenging mechanisms of dihydrocaffeic acid (3-(3’,4’-

dihydroxyphenyl)propionic acid), an abundant colon catabolite of complex dietary (poly)phenols,[1]
was studied by DFT method using the Gaussian 09 program package.[2] Geometry optimizations and
frequency calculations were carried out using the M06-2X/6-311++G(d,p) level of theory, in
conjunction with the SMD continuum solvation model.
The role of catechol moiety (reaction path a) and carboxyl moiety (reaction path b) in free radical
scavenging processes was investigated by considering double hydrogen atom transfer (dHAT),
double electron transfer-proton transfer (dET-PT) and double sequential proton loss electron transfer
(dSPLET) mechanisms.[3]
O O
O
H H
O O O
 2H+/2e  2H+/2e
a H b
O O
O
O O
H H O
o-quinone dihydrocaffeic acid dienone lactone
The Gibbs free energies of reactions (rG) indicate that dihydrocaffeic acid possesses potential for
inactivating free radicals of different nature (HO•, HOO•, CH3O•, CH3OO•, CH2=CH–OO•, PhO• etc.)
via dHAT and dSPLET mechanisms. 3’-Methylated, 3’-glucuronidated and 3’-sulfated conjugates of
dihydrocaffeic acid may retain their appreciable activity via reaction path b.
Because dihydrocaffeic acid is produced in colon in high concentrations (up to 90 mM),[1] and could
be much more abundant in the circulation than its precursor molecules, it has potential to contribute
to health benefits associated with regular intake of polyphenol-rich diet by direct scavenging of
reactive oxygen species.
Acknowledgments: This work has been supported by The Foundation of the Croatian Academy of
Sciences and Arts, under the project No. 10-102/244-1-2016. - “Investigations of the antioxidant
mechanisms of polyphenols and their metabolites.”
[1]
B. Halliwell, J. Rafter, A. Jenner, Am. J. Clin. Nutr., 2005, 81, 268S.
[2]
M. J. Frisch, G. W. Trucks et al., Gaussian 09. Revision A.02, Gaussian, Inc., Wallingford CT, 2009.
[3]
A. Amić, B. Lučić, V. Stepanić, Z. Marković, S. Marković, J. M. Dimitrić Marković, D. Amić, Food Chem.,
2017, 218, 144.
77
P-2
RADICAL SCAVENGING AND COX-2 INHIBITION BY COLON

METABOLITES OF POLYPHENOLS: A THEORETICAL APPROACH
Ana Amić,[a],* Zoran Marković,[b] Jasmina M. Dimitrić Marković,[c] Svetlana Jeremić,[b] Bono
Lučić[d] and Dragan Amić[e]
[a] Department of Chemistry, Josip Juraj Strossmayer University, Cara Hadrijana 8A, 31000 Osijek,
Croatia
[b] Department of Chemical-Technological Sciences, State University of Novi Pazar, Vuka Karadžića
bb, 36300 Novi Pazar, Serbia
[c] Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11000, Belgrade,
Serbia
[d] NMR Center, Ruđer Bošković Institute, P.O. Box 180, 10002 Zagreb, Croatia
[e] Faculty of Agriculture, Josip Juraj Strossmayer University, Vladimira Preloga 1, 31000 Osijek,
Croatia
* aamic@kemija.unios.hr
Colon polyphenolic metabolites can reduce activity of enzymes involved in human carcinogenesis,[1]
for instance by inhibition of COX-2.[2] Recent studies have shown the importance of selective
inhibition of COX-2 for the anti-inflammatory and anticancer therapy,[3] indicating COX-2 as a valid
molecular target for cancer prevention and treatment.[4] Theoretical investigations of active site of
COX-2 affirmed some natural phenolic antioxidants as potential inhibitors of this enzyme.[5]
Radical scavenging mechanisms of selected polyphenolic metabolites were studied in water and
pentyl ethanoate as a solvent, by DFT method using Gaussian 09 package.[6] Geometry
optimizations and frequency calculations were carried out using the M06-2X/6-311++G(d,p) level of
theory, in conjunction with the SMD continuum solvation model. Inhibitory potency against COX-2
by colon polyphenolic metabolites and their mono- and di-anionic forms, were theoretically studied.
Free energy of binding and inhibition constant for these ligands at the most favourable binding
positions were estimated.
Hydrogen atom transfer and sequential proton loss electron transfer mechanisms were found to be
thermodynamically probable and competitive processes in both media. The Gibbs free energy
change for reaction of inactivation of radicals indicate selected metabolites as potent scavengers.
Docking analysis with structural forms of selected metabolites indicates dianionic ligands as potent
inhibitors of COX-2. Obtained results indicate that, because polyphenolic metabolites are produced
in high mM concentrations and are usually better absorbed than their precursor molecules, they may
contribute to health benefits associated with regular intake of polyphenol-rich diet.
Acknowledgments: We gratefully acknowledge the financial support to this work from The
Foundation of the Croatian Academy of Sciences and Arts, under the project No. 10-102/244-1-2016.
- “Investigations of the antioxidant mechanisms of polyphenols and their metabolites.”
[1]
C. Miene, A. Weise, M. Glei, Nutr. Cancer, 2011, 63, 653.
[2]
P.C. Karlsson, U. Huss, A. Jenner, B. Halliwell, L. Bohlin, J.J. Rafter, J. Nutr., 2005, 135, 2343.
[3]
G. Dannhardt, W. Kiefer, Eur. J. Med. Chem., 2001, 36, 109.
[4]
R.A. Gupta, R.N. DuBois, Nat. Rev. Cancer, 2001, 1, 11.
[5]
M. Amaravani, N.K. Prasad, V. Ramakrishna, Springerplus, 2012, 1, 58.
[6]
M.J. Frisch, G.W. Trucks, H.B. Schlegel et al., GAUSSIAN 09, Wallingford, CT, 2009.
78
P-3
CYTOTOXICITY OF A KOJIC ACID DERIVATIVE ON A375

HUMAN MALIGNANT MELANOMA AND HGF1 FIBROBLAST CELLS
M. D. Aytemir,[a],* G. Karakaya,[a] A. Ercan[b] and S. Öncül[b]

[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100,
Sıhhiye, Ankara, Turkey.
[b] Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100, Sıhhiye, Ankara,
Turkey.
* mutlud@hacettepe.edu.tr
Malignant melanoma contributes to the majority of skin cancer related to deaths and shows an
increasing incidence every year. It can occur at any age and in any region of the skin. According to
the WHO, the incidence of melanoma is increasing worldwide faster than any other cancer type, with
the exception of nonHodgkin’s lymphoma, lung cancer and testicular cancer, especially where fair-
skinned people receive excessive sun exposure.[1] Despite improved treatment options, patients with
advanced malignant melanoma still have poor prognosis as measured by progression-free and
overall survival.[2,3]
In our laboratory, kojic acid derivatives were synthesized and their extensive bioactivities were
determined including anticonvulsant, antibacterial, antifungal, anti-mycobacterium and antiviral
activities.4-7 In this study, we will present the results of the cytotoxicity activity of the Mannich base
of kojic acid carrying substituted benzyl piperazine moiety. This compound is covered by the Turkish
Patent (23.06.2015-TR2015/07653-WO2016/209180) and International Patent (17.05.2016-
PCT/TR2016/000070). Viability of A375 malign melanoma and HGF1 fibroblast cells exposed to the
compound was assessed by sulforhodamine B (SRB) assay. SRB is an aminoxanthene dye that
binds to the basic amino acid residues of cellular proteins under mild acidic conditions. SRB assay
is a colorimetric method based on measurement of cellular protein content and used for the
determination of cytotoxicity.[8] A375 human malignant melanoma cell line was purchased from
American Type Culture Collection (ATCC-CRL-1619). Vemurafenib, dacarbazine, temozolomide,
lenalidomide and fotemustine currently used in the treatment of malign melanoma were utilized as
control agents. It was found that the cytotoxicity effect of the Compound was higher when compared
to all of the control agents, accept vemurafenib.
Acknowledgments: This research is funded as a project by TÜBİTAK. Project no: SBAG-315S067.

[1]
R.M. MacKie, A. Hauschild, A.M.M. Eggermont, Ann. Oncol., 2009, 20 (Suppl. 6):1.
[2]
T.L. Diepgen, V. Mahler, Brit. J. Dermatol., 2002, 146 (Suppl. 61): 1.
[3]
S.A. Weiss, D. Hanniford, E.Hernando, I. Osman, Cancer, 2015, 121, 4108.
[4]
M.D. Aytemir, Ü. Çalış, M. Özal, Arch. Pharm. Pharm. Med. Chem., 2004, 337, 281.
[5]
M.D. Aytemir, B. Özçelik, Med. Chem. Res., 2011, 20, 443.
[6]
G. Karakaya, M.D. Aytemir, B. Özçelik, Ü. Çalış, J. Enz. Inh. Med. Chem., 2013, 28, 627.
[7]
M.D. Aytemir, B. Özçelik, G. Karakaya, Bioorg. Med. Chem. Lett., 2013, 23, 3646.
[8]
V. Vichai, K. Kirtikara, Nat. Protoc., 2006, 1, 1112.
79
P-4
DESIGN AND SYNTHESIS OF NOVEL TARGETED CHEMICAL

CHAPERONES AS A BASIS FOR AMYOTROPHIC LATERAL SCLEROSIS
(ALS) TREATMENT
Salome Azoulay-Ginsburg,* Tamar Getter, Edward Korshin and Arie Gruzman

Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel
* Salomeazoulay16@gmail.com
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the

selective degeneration of motor neurons in the brain and spinal cord, which leads to progressive
paralysis and death. ALS is mostly acquired spontaneously (sALS), with inherited disease
accounting for only 10-15% of all cases (fALS).[1] One of the most common mutations found in fALS
is a mutation in the gene of SOD1.[1] Recent studies provide compelling evidence that the formation
of the toxic aggregates of SOD1 is the primary cause of this type of fALS and the formation of protein
aggregates in general, is underlie both types of ALS.[2] Chemical chaperones, which include polyols,
trimethyl N-oxide (TMAO), phenylbutyric acid (PBA), and different amino acid derivatives, have been
shown to reverse the mislocalization and aggregation of proteins associated with many human
diseases.[3-4] However, using chemical chaperones as drugs is limited by the very high active
concentrations (mM range) required for their efficacy. We propose to overcome this obstacle by
coupling known chemical chaperones to organelle-targeted moieties, such as lysosomes, ER, Golgi,
and mitochondria, where aggregation takes place. Based on this observation, we hypothesize that
refolding of Superoxide Dismutase 1 (SOD1) by chemical chaperones in lysosomes will allow
lysosome proteolytic enzymes and proteosome systems to cleave the refolded proteins and prevent
SOD1 aggregates and as a result cell death.
We have synthesized several ester- and amide- based TMAO chemical chaperones. The leading
compound, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N dimethyl propan-1-
amine oxide (Figure), has displayed both neuronal and astrocyte-protective effects in vitro in a
micromolar concentration range,[5] and in daily doses of 10 mg/kg has dramatically improved the
neurological functions and has delayed the body weight loss in ALS mice. In addition, the compound
significantly increased the survival rate of Drosophila flies. Now, we have synthesized a series of
novel compounds using FDA-approved chemical chaperone: phenylbutyric acid (PBA) with different
intracellular targeting moieties and linkers. We hope that these new compounds might serve as drug
candidates for ALS disease treatment.
Figure: 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N-dimethyl propan-1-amine oxide.
[1]
Y. Sheng, M. Chattopadhyay, J. Whitelegge, J. Selverstone Valentine, Curr.Topics Med.Chem., 2012, 12,
2560.
[2]
L. I. Bruijn, M. K. Houseweart, S. Kato, K. L. Anderson, S. D. Anderson, E. Ohama, A. G. Reaume, R. W.
Scott, D. W. Cleveland, Science, 1998, 281, 1851.
[3]
R. S Rajan, K. Tsumoto, M. Tokunaga, H. Tokunaga, Y. Kita, T. Arakawa, Curr. Med. Chem., 2011, 18, 1.
[4]
C. Bai, J. Biwersi, A. Verkman, M. A. Matthay, J. Pharm. Toxicol. Methods, 1998, 40, 39.
[5]
T. Getter, I. Zaks, T. Barhum, T. Ben-Zur, S. Böselt, S. Gregoire, O. Viskind, H. Gottlieb, T. Shani, O. Green,
M. Shubely, H. Senderowitz, A. Israelson, I. Kwon, S. Petri, D. Offen, A. Gruzman, ChemMedChem, 2015, 10,
850.
80
P-5
MULTICOMPONENT SYNTHESIS OF NOVEL

ANDROSTANO-PYRIMIDINES AND THEIR PHARMACOLOGICAL
EVALUATION IN VITRO
Ádám Baji,[a],* Éva Frank[a] and Mónika Kiricsi[b]

[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8. H-6720, Szeged, Hungary
[b] Department of Biochemistry and Molecular Biology, University of Szeged, Közép fasor 52, H-6726
Szeged, Hungary
* bajia@chem.u-szeged.hu
Semi-synthesized derivatives of natural sex hormones (e.g. dihydrotestosterone) often display

biological activities other than the parent compounds. Structural modifications may involve the
incorporation of different heterocycles into the sterane skeleton.[1-3]
During our experiments, different ring A-condensed arylpyrimidines (2a, 2d-i and 3a, 3d-i, 5a-i) were
synthesized from 17β-acetoxy-dihydrotestosterone (1) and its 2-hydroxymethylidene derivative (4)
by two kinds of multi-component reactions. The microwave-assisted syntheses were carried out in
closed vessels. The reactions were completed within 10-15 minutes under the applied conditions
and the corresponding products were obtained in moderate to good yields. The structures of the
synthesized arylpyrimidines were determined by NMR spectroscopy.
In vitro viability assays of the heterocyclic derivatives were performed in collaboration. According to
the results compounds 5c and 5f seem to be promising leads for further investigations.
Acknowledgments: The work of Ádám Baji was supported by a PhD Fellowship of the Talentum
Fund of Richter Gedeon Plc.
[1]
R. M. Mohareb, F. Al-Omran, R. A. Azzam, Steroids, 2014, 84, 46.
[2]
É. Frank, Z. Mucsi, I. Zupkó, B. Réthy, G. Falkay, Gy. Schneider, J. Wölfling, J. Am. Chem. Soc., 2009, 131,
3894.
[3]
Á. Baji, A. Gyovai, J. Wölfling, R. Minorics, I. Ocsovszki, I. Zupkó, É. Frank, RSC Adv., 2016, 6, 27501.
81
P-6
A COMPARATIVE MOLECULAR MODELLING STUDY OF

MAO-A, MAO-B AND SSAO INHIBITORS
Balázs Balogh,[a],* Michela Contu,[b] Elias Maccioni[b] and Péter Mátyus[a][c]

[a] Department of Organic Chemistry, Semmelweis University, Hőgyes E. u. 7, H-1092, Budapest,
Hungary
[b] Dipartimento Farmaco Chimico Tecnologico, University of Cagliari, Via Ospedale 72, 09124
Cagliari, Italy
[c] Drug Discovery and Safety Centre, Semmelweis University, Hőgyes E. u. 7, H-1092, Budapest,
Hungary
* balogh.balazs@pharma.semmelweis-univ.hu
Monoamine oxidase enzymes (MAO) exist in two isoforms MAO-A and MAO-B and possess a 70%
amino-acid sequence identity. These flavin adenine dinucleotide (FAD) containing enzymes
metabolize a wide range of endogen amines and xenobiotics and they are involved in the
pathomechanism of various diseases. Semicarbazide-sensitive amine oxidase (SSAO) enzyme also
known as vascular adhesion protein-1 (VAP-1) is another metabolic enzyme of amines with
potentially great medical importance. Unlike MAO-A and B this protein belongs to the family of
copper containing amine oxidases (AOCs) and as the name (semicarbazide sensitive) indicates it
has a partially different inhibitor selectivity.
The aim of our investigation was to study and compare the enzyme-inhibitor interactions within these
enzyme classes on an atomic level via binding site analyses and computational dockings. As a
continuation of our studies in the field,[1] we also aimed to investigate whether docking can
discriminate compounds differing in their activities (based on docking scores) and in enzyme
selectivity.
Over 40 human MAO-B X-ray structures co-crystalized with various inhibitors (both reversible and
covalent) have been published. We narrowed our studies to highly and moderately active reversible
compounds including diphenylbutene (1OJ9), farnesol (2BK3), safinamide (2V5Z), coumarine
analogues (2V60 and 2V61), zonisamide (3PO7), pioglitazone (4A79) and rosiglitazone (4A7A). A
few covalent inhibitors, namely selegiline (aka deprenyl, 2BYB), rasagiline both R- (1S2Q) and S-
forms (1S2Y) and mofegiline (2VZ2) were also involved. A few human MAO-A X-ray structures have
only been published so far. We used in our study the only available harmine (2Z5X, reversible) and
clorgiline (2BXR, covalent) containing structures. Human SSAO/VAP-1 structures were also hardly
available; a covalent inhibitor, 2-hydrazinopyridine (2C11) and some reversible pyridazinone (4BTW,
4BTX and 4BTY) containing X-ray structures were selected for our modeling studies.
Schrödinger’s prime module was used for protein structure modeling and Glide was applied to
docking. In case of irreversible inhibitors, Schrödinger’s covalent docking protocol was utilized. The
procedures were validated via re-dockings, the docking poses were compared with the ligand
conformers of X-ray structures by calculating the RMSD values whereas ranking of docking scores
was compared with that of biological activities. The docking studies were extended to a novel series
of highly active MAO inhibitors of arylalkenylpropargylamines designed and synthesized by our
research group.[2]
In our conclusion, a detailed comparison of structural features required for inhibition of different
classes of amine oxidases will be made.
[1]
R. Meleddu, S. Distinto, R. Cirilli, S. Alcaro, M. Yanez, M. L. Sanna, A. Corona, C. Melis, G. Bianco, P.
Matyus, F. Cottiglia and E. Maccioni, J. Enzyme Inhib. Med. Chem., 2017, 32, 264.
[2]
P. B. Huleatt, M. L. Khoo, Y. Y. Chua, T. W. Tan, R. S. Liew, B. Balogh, R. Deme, F. Goloncser, K. Magyar,
D. P. Sheela, H. K. Ho, B. Sperlagh, P. Matyus, C. L. L. Chai, J. Med. Chem. 2015, 58, 1400.
82
P-7
IDENTIFICATION OF NEW KDM4 INHIBITORS THROUGH A

HTS AND HIT REFINEMENT STRATEGY
A. L. Balzano,[a],* F. Sarno,[b] C. Milite,[a] G. Franci,[b,c] I. Forné,[d] L. Altucci,[b,e]

A. Ihmof,[d] S. Castellano[a,f] and G. Sbardella[a]
[a] Department of Pharmacy, University of Salerno, Fisciano, Italy
[b] Department of Biochemistry, Biophysics and General Pathology, University of Campania “Luigi
Vanvitelli”, Naples, Italy
[c] Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, Naples,
Italy
[d] Adolf-Butenandt-Institute and Center for Integrated Protein Science Munich, Ludwig-Maximilians-
University, Munich, Germany
[e] Istituto di Genetica e Biofisica, IGB “Adriano Buzzati Traverso”, Naples, Italy
[f] Department of Medicine and Surgery, University of Salerno, Fisciano, Italy
* abalzano@unisa.it
JHDMs (JmjC-domain-containing histone demethylases) are the largest class of demethylase

enzymes, contain a Jumonji C (JmjC) domain and catalyze lysine demethylation of histones through
an oxidative reaction that requires Fe(II) ion and α-ketoglutarate (αkG) as cofactors. The
misregulation of these enzymes, in particular JMJD2 subfamily, has being significantly implicated in
cancer initiation and progression.[1] Potent and specific inhibitors of these enzymes have not been
identified yet. Moreover, most of the reported ones show a good affinity to many other Fe(II)/αkG
dependent oxygenases, are non-specific for the different isoforms or are affected by undesirable
characteristics.[2] By means of an high throughput screening (HTS) campaign, we selected a pool of
interesting hit compounds and then, to refine the results, filtered out poor quality scaffolds not
suitable for future optimization. The use of a multiple combined approach of different in vitro
techniques led us to select EML586 as scaffold for further derivatization. From a series of EML586
analogues we were able to derive a pharmacophore hypothesis and structure-activity relationships
(hit-to-lead), and to select 3-hydroxy-2,3-dihydroquinazolinone moiety as starting point for the
development of novel optimized derivatives. The substitution of quinoxaline ring with more aliphatic
portions gave derivatives such as EML678 and EML684, which demonstrate a better activity against
hKDM4A compared to the starting hit compound. Furthermore, they induced a marked reduction in
methylation of lysines H3K9 and H3K27 in a cell-based assay together with an arrest in the S-phase
of cell cycle.
O
OH
N
N
H
O
CF3
EML678
O
OH
N
Cl
N
H
Cl
EML684
Figure: SARs of EML586 and most potent derivatives.
[1]
D. Rotili, A. Mai, Genes & Cancer, 2011, 2, 663.
[2]
U. Leurs, R. P. Clausen, J. L. Kristensen, B. Lohse, Bioorg. Med. Chem. Lett., 2012, 22, 5811.
83
P-8
SYNTHESIS AND ANTIOXIDATIVE ACTIVITY OF SOME QUATERNARY 3-

HYDROXYQUINUCLIDINIUM SALTS
DETERMINED BY DPPH METHOD
Linda Bazina, Matilda Šprung, Barbara Soldo and Renata Odžak*

Department of Chemistry, Faculty of Science, University of Split, R. Boškovića 33, Split, Croatia
* rodzak@pmfst.hr
Antioxidants play an important role as health protecting factors. Scientific evidence suggests that
antioxidants reduce the risk for chronic diseases including cancer and heart disease. Primary
sources of naturally occurring antioxidants are whole grains, fruits and vegetables. Plant sourced
antioxidants like vitamin C, vitamin E, carotenes, phenolic acids etc. have been recognized as agents
having the potential to reduce the risk for disease development. Most antioxidants from a typical diet
are derived from the plant sources and belong to various classes of chemical compounds with a
wide variety of physical and chemical properties.[1] However, recent studies have shown that some
synthetic organic compounds could also exhibit a strong antioxidative potential with a possible
application in food and pharmaceutical industries.[2]
In this study, we have synthesized the quaternary 3-hydroxyquinuclidinium salts (Figure 1) bearing
different long alkyl chains (C8, C10, C12 and C14). All compounds were obtained in very good yields
and characterized.
Figure 1 Figure 2
A rapid, simple and inexpensive method to measure antioxidant capacity involving the free radical,
2, 2-diphenyl-1-picrylhydrazyl (DPPH) was utilized in order to test the ability of the synthesized
compounds to act as free radical scavengers or hydrogen donors and to evaluate their antioxidant
activity. Our preliminary results suggest that the compounds displaying the higher antioxidative
activities are those with the longer alkyl chains. Evaluation of the biological potential including the
DNA protecting ability of the newly synthesized compounds is currently underway (Figure 2).
[1]
T. Sravani, P.M. Paarakh, Indian J. Nat. Products Res,. 2016, 3, 354.
[2]
A. Augustyniak et al., Free Radic. Res., 2010, 44, 1216.
84
P-9
PHYTOCHEMICAL COMPOSITION AND BIOLOGICAL ACTIVITY OF THE

EXTRACTS OF SATUREJA SUBSPICATA VIS. GROWING IN BOSNIA
AND HERZEGOVINA
Mejra Bektašević,[a],* Ivana Carev,[b] Marin Roje,[c] Mladenka Jurin[c] and

Olivera Politeo[b]
[a] Department of Biochemistry, Biotechnical Faculty, Bihać, BiH
[b] Department of Biochemistry, Faculty of Chemistry and Technology, Split, Croatia
[c] Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia
* mejra_b@yahoo.com
Satureja subspicata Vis. (mountain savory) is a rare, endemic species distributed in the eastern
Mediterranean area.[1] In traditional medicine of Bosnia and Herzegovina (BiH) S. subspicata is in
ethnobotany used to treat leukemia and syndromes of lymphatic nodes. In this area preparations of
S. montana and S. subspicata have been used with excellent results for different cardiovascular
disorders, especially arrhythmia, heart fibrillation and the diseases of blood vessels.[2] There are only
a few studies about the chemical composition and biological activity of non-volatile extracts of S.
subspicata growing in Croatia and none report on the extracts from BiH.
In this work we investigated the phytochemical composition of methanolic and hot aqueous extracts
of S. subspicata collected in BiH, total phenols and flavonoids. In addition, the aim of this work was
to determine the antioxidant potential and inhibition of cholinesterases of aqueous extracts.
Chemical composition of extracts was assessed using HPLC/DAD technique. Antioxidant capacity
was determined using DPPH, FRAP methods[3,4] and by determining activity of extracts in linoleic
acid emulsion.[5] Ellman method was used to determine inhibition of acetilcholinesterase and
butyrylcholinesterase.[6]
The major compounds found in methanolic extract where: rosmarinic acid, eriodictyol and
kaempferol, while in hot aqueous extract major compounds where: rosmarinic acid, myricetin and
ferulic acid. Obtained results for content of total phenols and total flavonoids indicate considerable
amount of these compounds. In concentration of 1 g/L in stock solution extracts showed low inhibition
of both cholinesterases and good antioxidant potential.
[1]
Č. Šilić, Endemične biljke, Svjetlost, Sarajevo, 1990.
[2]
S. Redžić, J. Medicinal Plants Res., 2010, 4, 1003.
[3]
I.F. Benzie, J.J. Strain, Anal. Biochem., 1996, 239, 70.
[4]
W. Brand-Williams, M.E. Cuvelier, C. Berset, Food Sci. Technol., 1995, 28, 25.
[5]
G.C. Yen and C.L. Hsieh, J. Agric. Food Chem., 1998, 46, 3952.
[6]
K.D. Ellman, V. Andres, R.M. Featherstone, Biochem. Pharmacology, 1961, 7, 88.
85
P-10
NOVEL ANTICANCER DRUGS DISPIRO-OXINDOLE SERIES BASED ON

VARIOUS TYPES OF HETEROCYCLES: SYNTHESIS AND BIOLOGICAL
TESTING
A. A. Beloglazkina,[a],* A. A.Barashkin,[a] G. A. Kotovskii,[a] M. A. Kunin,[a]

N. A. Karpov,[a] M. E. Kukushkin,[a] E. K. Beloglazkina,[a] N. V. Zyk[a]
D. A. Skvortsov,[a] N. A. Vorobyeva[b] and A. G. Majouga[a,b]
[a] Chemistry Dept, Moscow State University, 119991, Moscow, Leninskie gory, 1/3, Russia
[b] National University of Science and Technology, 119049, Moscow, Leninskiy prospect, 4, Russia
* anastas-beloglaz@mail.ru
Prostate cancer is one of the leading cancer type in the world: for example, in Russia about 14,000
cases are registered per year. Prostate cancer causes almost 10% of cancer deaths in men and it
is one of the main causes of death for older men. In the USA, prostate cancer is the third most
common cause of death from cancer.[1]
MDM2 inhibitors, containing in its structure spiro-oxindole core are relatively new class of biologically
active compounds, it has been reported that these compounds could effectively block the interaction
of MDM2 and p53 protein-protein interaction (PPI).[2] Previously in our group the «hit»-compound
with the promising anticancer activity 2,1 µM was found.[3] For this compound the enantioselective
separation of two diastereoisomers was made and it was shown, that only one isomer had selectivity
and cytotoxic effect for p53. In this work, we describe the synthesis of dispiro-compounds shown
below on the base of different types of heterocyclic compounds as substrates for 1,3-cycloaddition:
The biological activity of synthesized compounds were studied using MTT assay on HCT p53(+, +),
HCT p53(-, -) , LNCap and PC3 cell lines.
Acknowledgments: This work was supported by the Russian Foundation for Basic Research
(grant № 16-33-60166).
[1]
K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. Oiu, S. Shangary, W. Gao, D. Oin, J. Stuckey, K.
Krajewski, P. P. Roller, S. Wang., J. Med. Chem., 2006, 49, 3432.
[2]
Y. Zhao, L. Liu, W. Sun, J. Lu, D. McEachern, X. Li, S. Yu, D. Bernard, P. Ochsenbein, V. Ferey, J. Carry,
D. Sun, S. Wang J. Am. Chem. Soc., 2013, 135, 7223.
[3]
Y. Ivanenkov, S. Vasilevski, E. Beloglazkina, M. Kukushkin, A. Machulkin, M. Veselov, N. Chufarova, A.
Vanzcool, N. Zyk, D. Skvortsov, A. Khutornenko, A. Rusanov, A. Tonevitsky, O. Dontsova, A. Majouga, Med.
Chem. Lett., 2015, 25, 404.
86
P-11
OSTEOBLASTIC CELL BEHAVIOUR ON DIFFERENT TITANIUM

- SURFACE ANALYSIS
M. Lukaszewska-Kuska,[a] R. Majchrowski[b] and B. Dorocka-Bockowska[a],*

[a] Department of Oral Pathology and Medicine, Poznan University of Medical Sciences, Bukowska
70, Poland
[b] Faculty of Chemistry, Institute of Mechanical Technology, Poznan University of Technology,
Piotrowo 3, Poland
* b.dorocka@gmail.com
The surfaces of endoosseous dental implants have been subjected to numerous modifications which
results in changes to the chemical composition and topography of the surfaces.[1,2]
The aim of this study was to evaluate the surface topography and chemistry of various modified
titanium surfaces prior to in vitro evaluation with human osteoblast cells. Five such groups were
investigated: machined surface (MA), alumina-blasted (Al2O3), alumina-blasted and acid-etched
(Al2O3 DE), hydroxyapatite/tricalcium phosphate grit-blasted (HA/TCP) and hydroxyapatite/tricalcium
phosphate grit-blasted and acid-etched (HA/TCP DE).
Materials and methods: Commercially pure titanium class 4b discs measuring 1mm thick and 8 mm
radius were used. Five different surfaces modifications were evaluated. The surfaces were subject
to topographic analysis by SEM, roughness analysis by optical profilometry and chemical
composition evaluation by means of EDS analysis.[3-5]
Results: The SEM surface images of the machined samples revealed regular, linear, parallel grooves
created during machining. Al2O3 and HA/TCP sandblasted samples presented topographies with
numerous irregular cavities, and clearly defined sharp-edged rims. In the case of the HA/TCP blasted
and etched samples, the surfaces seemed to be slightly more irregular than the Al2O3 blasted and
etched samples.
Roughness analysis revealed two types of surfaces: the smoother surface with MA sample
Sa=181,91nm, and the rougher surfaces on the remaining samples with Sa ranging from 507,48nm
(HADE) to 748,45nm (Al2O3 DE). The sample surface chemical composition revealed titanium and
oxygen as the main components present in all samples with minor quantities of aluminium appearing
on the surfaces of the Al2O3 and Al2O3 DE samples while calcium and phosphorus were found on
the surfaces of the HA samples.
Conclusions: Blasted sampled along with blasted and etched samples were isotropic and rough. The
grit-blasting procedure resulted in the incorporation of minor quantities of the grit medium into
titanium surface.
[1]
A. Wennerberg, T. Albrektsson, Clin. Oral Implants. Res., 2009, 20, 172.
[2]
A. Ponche, M. Bigerelle, K. Anselme, Proc. Inst. Mech. Eng. H, 2010, 224, 1471.
[3]
A. Canabarro, C.G. Paiva, H.T. Ferreira, B. Tholt-de-Vasconcellos, G. De-Deus, R. Prioli, A.B. Linhares,
G.G. Alves, J.M. Granjeiro, Scanning, 2012, 34, 378.
[4]
K. Anselme, M. Bigerelle, J. Mater. Sci. Mater. Med., 2006, 17, 471.
[5]
A. Zareidoost, M. Yousefpour, B. Ghaseme, A. Amanzadeh, J. Mater. Sci. Mater. Med., 2012, 23, 1479.
87
P-12
A NOVEL CLASS OF HIGHLY POTENT SMALL MOLECULE INHIBITORS

OF RHINOVIRUS REPLICATION: 6-{[2-(METHYLCARBAMOYL)PYRIDIN-
4-YL]OXY}BENZO[B]THIOPHENE-2-CARBOXYLIC ESTER DERIVATIVES
S. B. Han,* J. W. Kim, U.-K. Jung, J. Y. Lee, C. Kim and Y.-S. Jung

Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology
* sbhan@krict.re.kr
Human rhinovirus (hRVs) is the cause of common colds and infections. The respiratory symptoms
that are associated with these illnesses exacerbate asthma and chronic obstructive pulmonary
diseases (COPD). The large number of serotypes of hRV that exist has complicated the development
of rhinovirus replication inhibitors that can be employed to treat these maladies. In the current
investigation, we developed a novel series of 6-{[2-(methylcarbamoyl)pyridin-4-
yl]oxy}benzo[b]thiophene-2-carboxylic ester derivatives that potently inhibit replication of both hRV-
A and hRV-B strains. One member of this group was observed to inhibit replication of a group of
hRVs, including hRV-B14, hRV-A21 and hRV-A71, with respective EC50 values of 0.053, 0.08 and
0.016 μM. The results of a time-of-addition study revealed that it acts at an entry stage of the viral
replication process. In addition, virus variants that are resistant to the compound were shown to
possess a mutation at L25 of the viral capsid protein VP3. The results of a computational study
suggested that it displays a capsid-binding mode that is similar to that of pleconaril, which involves
a key interaction with the VP3 side chain located nearby the capsid canyon. Finally, the 6-{[2-
(methylcarbamoyl)pyridin-4-yl]oxy}benzo[b]thiophene-2-carboxylic ester derivatives were observed
to also significantly inhibit replication of poliovirus 3 (PV3), implying that these substances might
show potentially general inhibitory activities against other enterovirus species.
[1]
A. Muehlenbachs, J. Bhatnagar, S. R. Zaki, J. Pathol., 2015, 235, 217.
[2]
N. G. Papadopoulos, G. Sanderson, J. Hunter, S. L. Johnston, J. Med. Virol., 1999, 58, 100.
[3]
S. E. Jacobs, D. M. Lamson, K. St. George, J. T. Walsh, Clin. Microbiol. Rev., 2013, 26, 135.
[4]
A. C. Palmenberg, D. Spiro, R. Kuzmickas, S. Wang, A. Djikeng, J. A. Rathe, C. M. Fraser-Liggett, S. B.
Liggett, Science, 2009, 324, 55.
88
P-13
SYNTHESIS, DOCKING AND ANTI-CANDIDA ACTIVITY OF SOME NEW

1,4-PHENYLENE-BISTHIAZOLES AS INHIBITORS OF LANOSTEROL 14α-
DEMETHYLASE
Anca-Maria Borcea,[a],* Ilioara Oniga,[b] Gabriel Marc,[a] Dan C. Vodnar,[c]

Adrian Pîrnău,[d] Laurian Vlase,[e] Andreea Pricopie,[a]
Brîndușa Tiperciuc[a] and Ovidiu Oniga[a]
[a] Department of Pharmaceutical Chemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy,
41 Victor Babeş Street, 400012 Cluj-Napoca, Romania
[b] Department of Pharmacognosy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 41 Victor
Babeş Street, 400012 Cluj-Napoca, Romania
[c] Department of Food Science and Technology, University of Agricultural Sciences and Veterinary
Medicine, 3-5 Mănăştur Street, 400372 Cluj-Napoca, Romania
[d] National Institute for Research and Development of Isotopic and Molecular Technologies, 67-103
Donath Street, 400293 Cluj-Napoca, Romania
[e] Department of Pharmaceutical Technology and Biopharmaceutics, “Iuliu Haţieganu” University of
Medicine and Pharmacy, 41 Victor Babeş Street, 400012 Cluj-Napoca, Romania
* borcea.anca@umfcluj.ro
The incidence of systemic opportunistic infections caused by fungi in immunocompromised patients

(treatment with chemotherapy, corticosteroids, immunosuppresive agents, patients with AIDS) is
increasing. Furthermore, the resistance strains of Candida spp. have become a major cause of
human morbidity and mortality worldwide. In order to reduce the development of resistance
phenomenon it is necessary to discover new bioactive compounds.[1,2]
In the context highlighted above, eighteen new molecules with a 1,4-phenylene-bisthiazole scaffold
were synthesized and evaluated as anti-Candida agents. 1,4-phenylene-bisthiazole derivatives were
obtained in good yields through a Hantzsch condensation reaction between the thioamide
intermediary and various alfa-haloketones or alfa-haloesters. The purity of the newly synthesized
compounds was confirmed by thin layer chromatography. The proposed structure of the compounds
was confirmed by quantitative elemental analysis and spectral data: infrared spectroscopy, mass
spectrometry and 1H-NMR. Compounds were screened in vitro for their ability to inhibit the growth
of the patogenic Candida spp. In order to elucidate the mechanism of action, the synthesized
compounds were docked into the active site of lanosterol 14α-demethylase isolated from
Saccharomyces cerevisiae. The results of the in vitro antifungal evaluation and the molecular
docking study showed that the new compounds have potential anti-Candida activity.
[1]
F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, A. Granese, S. Carradori, M. D'Ascenzio, D. Lilli,
D. Rivanera, Eur. J. Med. Chem., 2011, 46, 378.
[2]
L.T. Maillard, S. Bertout, O. Quinonéro, G. Akalin, G. Turan-Zitouni, P. Fulcrand, F. Demirci, J. Martinez, N.
Masurier. Bioorg. Med. Chem. Lett., 2013, 23, 1803.
89
P-14
SCREENING OF BIOLOGICAL ACTIVITY OF CENTAUREA SPECIES

AQUEOUS EXTRACTS
Ivana Carev,[a],* Anja Golemac,[b] Sanda Raić,[b] Jelena Žarković,[a] Ana Kelavić,[a] Maria
Šarić,[a] François-Xavier Pellay[b] and Olivera Politeo[a]
[a] Faculty of Chemistry and Technology, Split, Croatia
[b] NAOS group/Jean-Noël Thorel, 13855 Aix-en-Provence, France & MedILS, Split Croatia
* ivana.carev@ktf-split.hr
Centaurea species are used as medical plants or as a food in eastern Mediterranean area.[1-3] The
aim of our study was to make a screening of biological activity of twelve different aqueous extracts
from seven Croatian Centaurea species: toxicity, antioxidant potential and inhibition of
cholinesterases. The antioxidant and toxic properties of plant extracts and their constituents may be
used in pharmaceutical, cosmetic and food industry. The inhibition of both cholinesterases by plant
extracts may lead to a discovery of a potential chemical compound used in Alzheimer disease
treatment.[4] Antioxidant capacity of extracts was determined using DPPH and FRAP methods.[5,6]
Inhibition of both acetilcholinesterase and butyrylcholinesterase was determined using Ellman
method.[7] Toxicity of Centaurea extracts was measured on primary fibroblasts through the MTT
assay.[8] Aqueous extracts (AE) were prepared from wild growing Centaurea ragusina, C. scabiosa,
C. solstitialis, C. rupestris, C. alba, C. jacea and C. salonitana. Among the tested aqueous extracts
highest acetilcholinesterase inhibition exhibited C. solstitialis already known having chemical
compounds responsible for fatal neurological disease in horses.[9] All of the tested Centaurea species
aqueous extracts did not show inhibition on butyrylcholinesterase. Centaurea species show low to
moderate antioxidant activity of AE. All of 3 AE of C. ragusina presented a higher toxicity than any
other species with survival ranging from 10 to 50% at 0.5 g/L. Both AE of C. salonitana showed a
slightly less toxic profile with 20 to 30% survival at 1 g/L of extracts. Every other AE showed low
toxicity and C. scabiosa, wild edible species, showed no toxicity even at 1g/L of extract. Future
investigation of chemical composition should highlight the main compounds in these extracts
responsible for those biological activities. As far as previous research showed it is expected that
some of the main groups of compounds could be sesquiterpene lactones, phenolic compounds and
organic acids. Phenolics in plant extracts are usually responsible for a good in vitro antioxidant
potential.[10] Sesquiterpene lactones are usually connected with a toxic properties of Centaurea
extracts.[11]
[1]
B. Ozcelik, I. Gurbuz, T. Karaoglu, E Yesilada, Microbiology Res., 2009, 165, 545.
[2]
L. Luczaj, K. Dolina, N. Fressel, S. Perković, Ethnobotany and Biocultural Diversities in the Balkans:
Perspectives on Sustainable Rural Development and Reconciliation. 2014.
[3]
F. Bakkali, S. Averbeck, D. Averbeck, M. Idaomar, Food Chem. Toxicol., 2008, 46, 446.
[4]
P.J. Houghton, Y. Ren, M.J. Howes, Nat. Prod. Rep., 2006, 23,181.
[5]
I.F. Benzie, J.J. Strain, Anal. Biochem., 1996, 239, 70.
[6]
W. Brand-Williams, M.E. Cuvelier, C. Berset. Food Sci. Technol., 1995, 28, 25.
[7]
K.D. Ellman, V. Andres, R.M. Featherstone, Biochem. Pharmacol., 1961, 7, 88.
[8]
D. Gerlier, N. Thomasset, J. Immun. Meth., 1986, 94, 1.
[9]
H.T. Chang, W.K. Rumbeiha, J.S. Patterson, B. Puschner, A.P. Knight, Veterinary Pathology, 2012.
[10]
O. Kenny, T.J. Smyth, D. Walsh, C. T. Kelleher, C. M. Hewage, N. P. Brunton, Food Chem., 2014, 161, 79.
[11]
J. Y. Cho, A. R. Kim, J. H. Jung, T. Chun, M. H. Rhee, E. S. Yoo, Eur. J. Pharmacol., 2004, 492, 85.
90
P-15
ANTIOXIDANT ACTIVITY AND LIPOPHILICITY EVALUATION OF SOME

NEW THIAZOLYL-TRIAZOLE SCHIFF BASES
Cezar Login,[a] Daniela Benedec,[b] Ioana Ionuţ,[c] Cristina Nastasă,[c] Anca Stana,[c] Ovidiu
Oniga[c] and Brîndușa Tiperciuc[c],*
[a] Physiology Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41 Victor Babeş
Street, 400012 Cluj-Napoca, Romania
[b] Pharmacognosie Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41 Victor
[c] Pharmaceutical Chemistry Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41
Victor Babeş Street, 400012 Cluj-Napoca, Romania
* brandu32@yahoo.com
Schiff bases have also been shown to exhibit a broad range of biological activities, including
antifungal, antibacterial, antiproliferative, anti-inflammatory, antioxidant and antipyretic properties.[1-
5]
Thiazoles, triazoles and their derivatives play an important part in heterocyclic chemistry due to
their biological activity.[6] The ample evidence reported in the literature on the biological potential of
Schiff bases containing thiazolo-triazole moieties in their structure led us to the synthesis,
characterization and biological activity evaluation of 15 new Schiff bases of 4-amino-5-(4-methyl-2-
phenylthiazol-5-yl)-4H-1,2,4-triazole-3-thiol, that combine the bioactive potential of the two
heterocycles or bring new biological properties. These compounds were previously reported for their
anti-Candida activity.[7] The lipophilicity study has been done in order to establish how the chemical
structure and the hydrophobicity of these compounds influence their biological activity.[8]
The antioxidant activity of the Schiff bases was evaluated using several assays: the DPPH,
autooxidation rate of hemoglobin method, hemoglobin ascorbate peroxidase activity inhibition
(HAPX) and ABTS assay. In the DPPH assay all the compounds shown antioxidant activities similar
or superieur to Trolox used as reference.The ABTS based assay demonstrated the ability of all
compounds to quench the ABTS•+ radical. The ascorbate peroxidase activity of hemoglobin was
slowly affected by the presence of these compounds, the positive values obtained in suggesting an
antioxidant effect.
The lipophilicity has been determined by using PCA based on reversed-phase thin layer
chromatography data. Data analysis showed that halogen-substituted-thiazolyl-triazoles Schiff
bases were the most lipophilic, proving thus the importance of halogen atoms for the modulation of
the lipophilic character of a certain molecule
[1]
Y. Li, C.P. Zhao, H.P. Ma, M.Y. Zhao, Y.R. Xue, X.M. Wang, Bioorg. Med. Chem., 2013, 21, 3120.
[2]
E.L. Chazin, P.S. Sanches, E.B. Lindgren, W.T. Vellasco, et all, Molecules, 2015, 2, 1968.
[3]
A. Pandey, D. Dewangan, S. Verma, A. Mishra, R.D. Dubey, Int. J. ChemTech Res., 2011, 3, 178.
[4]
P. Przybylski, A. Huczynski, K. Pyta, B. Brzezinski, F. Bartl, Curr. Org. Chem., 2009, 13, 124
[5]
S. Arulmurugan, P.H. Kavitha, R.P. Venkatraman, Rasayan. J. Chem., 2010, 3, 385.
[6]
M. Hanif, Z.H. Chohan, Spectrochim. Acta Part A, Mol. Biomol. Spectros., 2013, 104, 468.
[7]
A. Stana, A. Enache, D.Vodnar, C.Nastasă, D.Benedec, I.Ionuț, C.Login, G.Marc, O.Oniga, B.Tiperciuc,
Molecules, 2016, 21, 1595.
[8]
R.Tamaian, A Moţ, R. Silaghi-Dumitrescu, I. Ionuţ, A. Stana, O. Oniga, C. Nastasă, D. Benedec, B.Tiperciuc,
Molecules, 2015, 20, 22188.
91
P-16
NOVEL 2,4-DIAMINOPYRIMIDINE BEARING FUSED TRICYCLIC RING

MOIETY FOR ANAPLASTIC LYMPHOMA KINASE (ALK) INHIBITOR
Chang-Soo Yun,[a] Chong Ock Lee,[b] Hyoung Rae Kim,[b] Chi Hoon Park,[b]
Pilho Kim[b] and Jong Yeon Hwang[b],*
[a] Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical
Technology, Daejeon 34114, Republic of Korea
[b] Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114,
Republic of Korea
* jyhwang@krict.re.kr
Anaplastic lymphoma kinase (ALK) is one of the receptor tyrosine kinases and has been implicated
in a variety of tumors including anaplastic large-cell lymphoma (ALCL), diffuse large B-cell lymphoma
(DLBCL), inflammatory myofibroblastic tumors (IMT), and solid tumors.[1,2] Since ALK gene is fused
with various partner genes, such as NMP, EML4, and KIF5 genes, the resulting fusion protein is
constitutively activated, leading to a state of oncogenic addition. The constitutive kinase activity
associated with ALK fusions seems to play an essential role in the growth and survival of cancer
cells. Several drugs targeting ALK, such as crizotinib, ceritinib, and alectinib have been approved for
the treatment of ALK-driven non-small cell lung cancer (NSCLC) patients. Brigatinib and lorlantinib
are currently undergoing evaluation in clinical trials.
In our previous efforts to discover potent ALK inhibitors,[3,4] we synthesized LDK378 and CEP-37440
with hybridized structures, thereby leading to a novel structure, which is a 2,4-diaminopyrimidine
bearing tetrahydronaphthalenyl moiety.[5] Several compounds showed promising pharmacological
results in in vivo, ex vivo, and pharmacokinetic studies. Also, in vivo efficacy study demonstrated
highly potent inhibitory activity in H3122 tumor xenograft model in mice. In this study, a series of
novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor.[6]
The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at
the 2-position of pyrimidine in ceritinib. A few compounds showed promising activities in both
enzymatic-and cell-based assays. Also, an in vivo efficacy study against H3122 tumor xenograft
model in mice demonstrated highly potent inhibitory activity without body changes, similar to ceritinib,
suggesting that it might be used for a novel ALK inhibitor development.
[1]
A.V. Galkin, J.B. Melnick, S. Kim et al, Proc. Natl. Acad. Sci. USA, 2007, 104, 270.
[2]
T. Sasaki, S.J. Rodig, L.R. Chirieac et al. Eur. J. Cancer, 2010, 46, 1773.
[3]
C.H. Park, H. Choe, I.Y. Jang, S.Y. Kwon et al, Bioorg. Med. Chem. Lett., 2013, 23, 6192.
[4]
J.I. Yun, E.H. Yang, M. Latif, H.J. Lee et al, Arch. Pharm. Res, 2014, 37, 873.
[5]
D. Song, M. Lee, C.H. Park, S. Ahn et al, Bioorg. Med. Chem. Lett., 2016, 26, 1720.
[6]
R. Achary, G.R. Mathi, D.H. Lee, C.S. Yun et al, Bioorg. Med. Chem. Lett., 2017, in press.
92
P-17
TARGETED DELIVERY OF CYTOTOXIC AGENTS VIA cRGD PEPTIDE IN

CANCER THERAPY AND THERANOSTICS
Theodora Chatzisideri,[a] Savvas Thysiadis,[a] Sotirios Katsamakas,[b]

Theodore Lazarides[a] and Vasiliki Sarli[a],*
[a] Department of Chemistry, Aristotle University of Thessaloniki
[b] School of Pharmacy, Aristotle University of Thessaloniki
* sarli@chem.auth.gr
In the fight against cancer the traditionally employed therapeutic approach is chemotherapy.
However, as with any other non-selective delivery method of cytotoxic drugs, chemotherapy cannot
differentiate between healthy and cancer cells, destroying both. Highly potent anti-cancer drugs
suffer of poor bioavailability due to off-target toxicity and lack tumour specificity, requiring higher
doses of the chemotherapeutic agent, resulting in severe side-effects.[1] Targeted delivery systems
offer a more sophisticated and efficient approach, minimising side effects during the course of the
treatment.
In this work, targeted delivery systems are presented, which takes advantage of the synergistic effect
of cycloRGD (Arg-Gly-Asp) peptide, which selectively recognizes integrins overexpressed at tumour
sites,[2] with a cytotoxic drug, which destroys cancer cells. Natural products and known
chemotherapeutic agents were employed as cytotoxic agents.
Another important advantage of these flexible conjugated systems is that they can be combined with
various dyes, in order to control and simultaneously detect the drug in tumor cells.[3] Thus, treatment
and diagnosis can be combine, hence the name of the general approach, theragnostics.
Release of the parent drug is also very important for efficacy and toxicity of the conjugate. The
cytotoxic agent is coupled with the peptide via a linker. The ideal linker should be stable in the blood
stream and labile at the cancer site to allow release of the cytotoxic drug. Amide linkers, are non-
cleavable linkers, which were found to have improved stability in the bloodstream. In this case,
release of the cytotoxic agent depends solely on the process of lysosomal degradation. On the other
hand, disulphide linkers, which are cleavable linkers, take advantage of the reducing environment
within cancer cells due to the elevated concentration of thiol molecules (e.g. glutathione).[4]
Conjugates containing both amide and disulphide linkers have been synthesised. The mode of action
of each one will be investigated in biological studies.
Due to the significant difference of the acidity between the normal tissues (pH≈7.4) and the
intracellular organelles such as lysosome and endosome (pH≈5.6), stability of the conjugates under
these conditions are examined.
The stability of the conjugate, as well as that of the linker, under physiological or slightly acidic
conditions, along with their biological activity against various cell lines, will be discussed and be
taken under consideration, for the selection of the most potent conjugate.
[1]
C. Landen, T. Kim, Neoplasia, 2008, 10, 1259.
[2]
J. Desgrosellier, D. Cheresh, Nat. Rev. Cancer, 2010, 10, 9.
[3]
M. Lee,J. Kim, J. Am. Chem. Soc., 2012, 134, 12668.
[4]
C. Peters, S. Brown, Biosci. Rep, 2015, 35, e00225.
93
P-18
METHODS OF SYNTHESIS OF BIOLOGICALLY ACTIVE ANALOGUES

AND HOMOLOGUES AMINOPHOSPHONATES AND
AMINOBISHOSPHONATES
Ewa Chmielewska,[a],* Joanna Wietrzyk[b] and Paweł Kafarski[a]

[a] Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and
Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
[b] Laboratory of Experimental Anticancer Therapy, Institute of Immunology and Experimental
Therapy, ul. Rudolfa Weigla 12, 53-114 Wroclaw, Poland
* ewa.chmielewska@pwr.edu.pl
Bisphosphonates are class of drug molecules, used to treat osteoporosis, Paget’s disease, and
hypercalcemia due to malignancy because they are powerful inhibitors of bone resorption.[1] They
act by inhibiting the enzyme farnesyl diphosphate synthase (FPPS).[2] Bisphosphonates have been
found to have antibacterial[3] and anticancer[4] properties and to stimulate γ, δ,T cells of immune
drawing interest in cancer immunotherapy.[5]
The aim of our studies is synthesis the aminomethylenebisphosphonic acids, analogs of
cycloheptylaminomethylenebisphosphonate (commercialized as incadronate, the latest generation
of antiosteoporotic drugs) as potential antiosteoporosis drugs. The simplest procedure for
preparation of aminomethylenebisphosphonates relays on three-component reaction between
amine, triethyl orthoformate and diethyl phosphite, followed by acid hydrolysis (Figure 1).[6]
H
H2O/HCl N PO3H2
R-NH2 + HC(OEt)3 + 2 HP(O)(OEt)2 R
PO3H2
Figure 1: Synthesis of aminomethylenebisphosphonates
There is substantial evidence that aminobisphosphonates have a direct effect on osteoclasts by

mechanisms that may lead to osteoclast cell death by apoptosis. They inhibit proliferation and cause
cell death in macrophages in vitro. We present the studies of the preselection in vitro in the model
mouse macrophage-like cell line J774E to choose potent compounds[6] and also influence of
proliferation of two cancer cell lines: of human breast cancer MCF-7 and of prostate cancer PC-3.
Heteroaromatic phosphonic acids have been scarcely studied and only selected examples of
potentially useful compounds have been described so far. We synthesized aminophosphonates in a
single-step procedure Kabachnik–Fields. It involves the condensation of three components: a
primary or secondary amine, aldehyde (or ketone) and dialkyl phosphite (Figure 2). The influence of
proliferation of two cancer cell lines: of human breast cancer MCF-7 and of prostate cancer PC-3
has been determinated for selected phosphonates.
O RO O RO O
NH + C + P - H2O P N
RO H RO C
Figure 2: The synthesis of aminophosphonates in Kabachnik – Fields reaction
[1]
R. G. G Russell, Ann. N. Y. Acad. Sci., 2006, 1068, 367.
[2]
J. Sanders, A. O. Gomez, J. Mao, G. A. Meints, E. M. Van Brussel, A. Burzynska, P. Kafarski, D. Gonzalez-
Pacanowska, E. Oldfield, J. Med. Chem., 2004, 46, 5171.
[3]
A. Leon, L. Liu, Y. Yang, C. T. Morita, E. Oldfield, J. Med. Chem.,. 2006, 49, 7331.
[4]
A. J. Roelofs, F. H. Ebetino. R. G. G. Russell C. M. Shipman, Int. J. Cancer, 2006, 119,1254.
[5].
J. M. Sanders, A. Burzynska, P. Kafarski, E. Oldfield, J. Med. Chem., 2004, 47, 375.
[6]
E. Chmielewska, K. Kempińska, J. Wietrzyk, A. Piątek, J. J. Kuryszko, Z. Kiełbowicz, P. Kafarski, P. Novel
bisphosphonates and their use. Int Pat Appl WO2015159153 (A1) ― 2015-10-22.
94
P-19
MOLECULAR MODELING AND DYNAMICS STUDIES OF LIGAND-

DEPENDENT CONFORMATIONAL MACROSTATES OF A2A ADENOSINE
RECEPTOR
Yoonji Lee,[a] Changbong Hyeon[b] and Sun Choi[a],*

[a] College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University,
Seoul 03760, Korea
[b] School of Computational Sciences, Korea Institute for Advanced Study, Seoul 02455, Korea
* sunchoi@ewha.ac.kr
G-protein coupled receptor (GPCR) is a class of membrane protein that mediates the extracellular
stimuli to the downstream signaling. Dynamics and functions of GPCRs are finely regulated
depending on the type of bound ligands. While it is well understood that the binding of an agonist
activates GPCR by reorganizing the transmembrane helices and recruiting a G-protein, the
underlying mechanism of such allosteric signaling in presence of the agonist still remain elusive.
To explore the allosteric mechanism of GPCRs, we generated each of 1 microsec molecular
dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist-
bound forms. We investigated GPCR dynamics in terms of 10 on-off switch states defined by the
micro-switches, which are highly conserved in class A GPCRs. Statistical analysis of the 10 binary
switches, we clearly showed that the apo, antagonist-bound, and agonist-bound forms retain distinct
dynamic properties. The antagonist- and agonist-bound forms explore quite different conformational
space, and the apo form lies between them. Also, the correlation map among the 10 binary switches
suggested that the direct sensing of the agonist by W246 residue derives the rest of intra-molecular
signaling. The conformational features captured in our statistical representation of 10 binary switches
confirmed the existing knowledge on the receptor and also made the specific predictions amenable
to a further experimental study.
95
P-20
NEW DICARBOXIMIDE DERIVATIVES – ANTICANCER ACTIVITY AND

MECHANISM OF ACTION
Julia Kaźmierczak-Barańska,[a] Karolina Królewska,[a] Marcin J. Cieślak,[a]

Milena Sobczak,[a] Bożena Kuran,[b] Mariola Napiórkowska,[c]
Jerzy Kossakowski[b] and Barbara Nawrot[a]
[a] Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of
Bioorganic Chemistry, 112 Sienkiewicza Str., 90-363 Lodz, Poland
[b] Chair and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097
Warsaw, Poland
[c] Department of Medical Chemistry, Medical University of Warsaw, 3 Oczki Str., 02-007 Warsaw,
Poland
There is a permanent need for new anticancer drugs with improved pharmacological profiles. We
have screened new derivatives of dicarboximides developed and synthesized in Department of
Medical Chemistry of Warsaw Medical University. Among them, several entities exhibited interesting
cytotoxic properties, i.e. displayed toxicity towards human leukemia cells (K562, HL-60, MOLT-4)
and were non-toxic to adherent cancer cells (HeLa, CFPAC) neither to normal endothelial cells
(HUVEC). We have shown that in leukemia cells these compounds induce programmed cell death
(apoptosis) via receptor and mitochondrial pathways. This is evidenced by increase in activity of
caspases 3, 7, 8 and 9 and enhanced annexin V staining. Based on the structural similarity between
test dicarboximides and thalidomide, a known immunomodulatory drug (IMiD),[1,2] we hypothesized
that their mechanism of action could be analogous. We tested whether incubation of leukemia cells
with dicarboximides resulted in changes the level of transcription factors Ikaros (IKZF1) and Aiolos
(IKZF3). K562 and MOLT4 cells treated with dicarboximides expressed lower levels of Ikaros and
Aiolos.
PASS (Prediction of Activity Spectra for biologically active Substances) suggested that
dicarboximides might inhibit the activity of proteasomal ATPase. Therefore, we studied the activity
of proteasome in leukemia cells treated with dicarboximides and found that one derivative of
dicarboximides inhibits proteasomal activity in MOLT4 cells.
Acknowledgments: The financial support from Polish Ministry of Science, project NCN OPUS
UMO-2014/15/B/NZ7/00966 is acknowledged.
[1]
T. Ito, Science, 2010, 327, 1345.
[2]
K. Stewart, Science, 2014, 343, 256.
96
P-21
ANTIPROLIFERATIVE ACTIVITY OF QUINONE METHIDES WITH BODIPY

CHROMOPHORE
Matej Cindrić,[a],* Nikola Basarić,[a] Irena Martin Kleiner,[b] Lidija Uzelac[b] and
Marijeta Kralj[b]
[a] Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54,
10000 Zagreb, Croatia
[b] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb,
Croatia
* cindric@irb.hr
BODIPY is a trade name for the well known fluorescent dyes comprising different 4,4-difluoro-4-
bora-3a,4a-diaza-s-indacene derivatives.[1] These chromophores absorb in the visible region of
spectrum and have excellent photophysical and spectral properties characterized by sharp
fluorescence peaks with high fluorescence quantum yields.2 Small modifications of molecular
structure lead to fine-tuning of their spectroscopic and photophysical properties.3 Therefore, a large
number of different BODIPY derivatives has been synthesized and their spectroscopic properties
have been investigated.
We have become interested in the photochemistry of appropriately substituted phenols that undergo
photodehydration and deliver quinone methides (QMs).[4] The interest in the chemistry of QMs has
been initiated due to their biological properties. It has been demonstrated that QMs react with amino
acids, proteins, nucleotides and DNA. Moreover, ability of QMs to cross-link DNA has been
associated to biological action of some anticancer antibiotics such as Mitomycin C. Consequently,
QMs represent potential new class of anticancer drugs. However, QMs are reactive intermediates
that cannot be stored, they have to be generated in situ. The best method for the generation of QMs
is photodehydration of phenol derivatives. To have molecules applicable as drugs in human medicine
it is of pivotal importance to make QM precursors on the chromophoric system absorbing in the
visible part of the spectrum (at > 600 nm) to assure penetration of light through tissue.
Herein we present synthesis of QM precursors that bear BODIPY chromophore, investigation of their
photochemical reactivity and aptitude to deliver QMs, as well as antiproliferative activity of
photogenerated QMs. To test the effect of irradiation, the antiproliferative activity is tested on human
cancer cell lines that are treated with compounds and kept in dark or irradiated with visible light.
[1]
https://www.thermofisher.com/hr/en/home/brands/molecular-probes.html
[2]
A. Loudet, K. Burgess, Chem. Rev., 2007, 107, 4891.
3]
N. Boens, V. Leen, Chem. Soc. Rev., 2012, 41, 1130.
4
N. Basarić, K. Mlinarić-Majerski, M. Kralj, Curr. Org. Chem., 2014, 18, 3.
97
P-22
MEPHEDRONE METABOLITES AND DERIVATIVES
Daniela Cintulova,[a] Laurin Wimmer,[a] Harald H. Sitte[b] and Marko D. Mihovilovic[a],*

[a] Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC,
1060, Vienna, Austria
[b] Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology,
Währingerstrasse 13A, 1090 Vienna, Austria
* marko.mihovilovic@tuwien.ac.at
The endogenous monoamines dopamine, serotonin and norepinephrine are essential

neurotransmitters in the mammalian system. They have been the focus of considerable research
because their interaction at monoamine transporters has profound effects upon many
pharmacological outcomes,[1] One diverse class of chemical compounds - the amphetamines, acts
as inhibitors of monoamine transporter system and thus elicits strong psychostimulant effect which
renders them liable for recreational abuse.[2]
Mephedrone
One frequently occurring recreational drug of this group is mephedrone - a derivative of naturally
occurring alkaloids - cathinones. Mephedrone has been linked to a number of fatalities and seizure
incidents across Europe.
Despite its short time in blood plasma this compound has a long lasting effect in humans.[3]
Within this contribution we present the enantioselective synthesis of Phase I mephedrone
metabolites to better understand the mode of action of mephedrone itself and to investigate the
activity of single enantiomers of its metabolites.
REDUCT
ION
OXIDATI DEMETHYL
ON ATION
[1]
P. C. Meltzer, D.Butler, J. R. Deschamps, B. K. Madras, J. Med. Chem., 2006, 49, 1420.
[2]
H. H. Sitte, M. Freissmuth, Trends iPharmacol. Sci., 2015, 36, 41.
[3]
A. J. Pedersen, L. A. Reotzel, S. S. Johansen, K. Linnet, Drug Test. Analysis, 2012, 5, 313.
98
P-23
NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2-

OXAADAMANTANE MOIETY I: PIPERIDINE DERIVATIVES
Sandra Codony,[a],* Javier Pizarro,[b] Elena Valverde,[a] Eugènia Pujol,[a] M. Isabel Loza,[c][d]
J. Manuel Brea,[c][d] Elena Sáez,[e] Julen Oyarzábal,[e] Belén Pérez,[f]
Rosana Leiva,[a] Manuel Vázquez-Carrera[b] and Santiago Vázquez[a]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), and [b]Laboratori de
Farmacologia, Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de
Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31,
08028, Barcelona
[c] Drug Screening Platform/Biofarma Research Group. CIMUS Research Center. University of
Santiago de Compostela (USC)
[d] Health Research Institute of Santiago de Compostela (IDIS)
[e] Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical
Research (CIMA), University of Navarra, Avenida Pio XII 55, E-31008 Pamplona, Spain
[f] Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona,
08193 Bellaterra, Barcelona, Spain
* sandra.codony@gmail.com
Soluble epoxide hydrolase (sEH) converts epoxyeicosatrienoic acids (EETs), endogenous chemical
mediators derived from arachidonic acid (AA), to their corresponding dihydroxyeicosatrienoic acids
(DHETs). Taking into account that EETs show anti-inflammatory, antihypertensive, analgesic,
angiogenic, and antiatherosclerotic effects, it has been proposed that inhibition of sEH may have
therapeutic effects in various inflammatory diseases.[1] A number of very potent sEH inhibitors (sEHI)
have been developed, several of them featuring an adamantane moiety, that may account for the
low solubility and poor pharmacokinetic profile that have hampered their progress into clinics.[2]
Recently, we have found that the replacement of a methylene unit in the adamantane moiety of
known AR9281 by an oxygen atom leads to a more soluble compound with retention of the inhibitory
activity (analog 1). In this work, we report the synthesis and evaluation of several analogs of 1,
featuring different substituent on the piperidine ring, in order to improve their potency and
pharmacokinetic profiles.
[1]
C. Morisseau, B. D. Hammock, Annu. Rev. Pharmacol. Toxicol., 2013, 53, 37.
[2]
H. C. Shen, B. D. Hammock, J. Med. Chem., 2012, 55, 1789.
99
P-24
NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2-

OXAADAMANTANE MOIETY II: AROMATIC DERIVATIVES
Eugènia Pujol,[a],* Javier Pizarro,[b] Elena Valverde,[a] Sandra Codony,[a]

Tiziana Ginex,[c] M. Isabel Loza,[d,e] J. Manuel Brea,[d,e] Belén Pérez,[f]
Elena Sáez,[g] Julen Oyarzábal,[g] F. Javier Luque,[c] Rosana Leiva,[a]
Manuel Vázquez-Carrera[b] and Santiago Vázquez [a]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC)
[b] Laboratori de Farmacologia, Departament de Farmacologia, Toxicologia i Química Terapèutica,
Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII,
27-31, 08028, Barcelona, Spain
[c] Departament de Nutrició, Ciències de l’Alimentació i Gastronomia, Facultat de Farmàcia, and
Institute of Biomedicine (IBUB), Universitat de Barcelona, Avda. Prat de la Riba 171, 08921 Santa
Coloma de Gramenet
[d] Drug Screening Platform/BioFarma Research Group. CIMUS Research Center, University of
Santiago de Compostela (USC)
[e] Health Research Institute of Santiago de Compostela (IDIS)
[f] Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona,
08193 Bellaterra, Barcelona, Spain
[g] Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical
Research (CIMA), University of Navarra, Av. Pío XII 55, 31008 Pamplona, Spain.
* epujol@ub.edu
The soluble epoxide hydrolase (sEH) is an enzyme implicated in the metabolism of

epoxyeicosatrienoic acids (EETs), endogenous lipid mediators involved in the regulation of
inflammation.[1] Therefore, sEH appears to be a potential therapeutic target for the treatment of
diverse diseases with an important inflammatory component.[2] Although several compounds
targeting sEH have been developed, yet none has reached the market, mainly because of poor drug-
like physicochemical properties.
In this regard, our research group has developed new 2-oxaadamantylureas as sEH inhibitors
(sEHI), displaying not only high potency but also improved physicochemical properties. Herein we
report structure-activity relationship studies around the replacement of the trifluorophenyl group of
our recently discovered lead sEHI 1 by a variety of aromatic and heteroaromatic rings.
[1]
C. Morisseau, B.D. Hammock, Annu. Rev. Pharmacol. Toxicol., 2013, 53, 37.
[2]
J. He, C. Wang, Y. Zhu, D. Ai, J. Diabetes, 2016, 8, 305.
100
P-25
BIOLOGICAL ACTIVITIES OF EXTRACTS FROM THYME (THYMUS

VULGARIS) LEAVES
Biljana Damjanović-Vratnica,[a],* Slađana Krivokapić,[b] Snežana Pantović[c] and Svetlana

Perović[b]
[a] Faculty of Metallurgy and Technology, University of Montenegro, Dz. Vasingtona bb, Podgorica,
Montenegro
[b] Department of Biology, Faculty of Natural Science and Mathematics, Dz. Vasingtona bb,
Podgorica, Montenegro
[c] Faculty of Medicine, University of Montenegro, Krusevac bb, Podgorica, Montenegro
* biljanad@ac.me
The genus Thymus, member of the Lamiaceae family, contains about 400 species of perennial
aromatic, evergreen or semi-evergreen herbaceous plants with many subspecies, varieties,
subvarieties and forms.[1] Thymus species are commonly used as herbal tea, flavoring agents
(condiments and spices) and for medicinal purposes. In the Mediterranean environment, there are
several ecotypes of wild-growing thyme, which differ in morphological characteristics, distinguished
by a strong and penetrating odor and sometimes a very evident balsamic and spicy flavor.[2] Thyme
(T. vulgaris) is used mainly as a food seasoning, but also as a source of essential oils that are used
in perfumery and as a worming and bactericidal agent in medicine.[3]
The aim of this study is to determine biological activities of extracts from Thymus vulgaris leaves
from Montenegro.
Fresh leaves of cultivated T. vulgaris were collected manually from the cultivation site (near
Danilovgrad) in June 2016. Dried herb material was milled and extracted with different polarity
solvents (hexane, acetone, methyl-alcohol and ethyl-alcohol).
For antimicrobial activity of extracts of Thymus vulgaris from Montenegro microdilution method was
used and minimal inhibitory concentration (MIC) was determined.
Ability of the extracts to scavenge the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH• ) was
determined. Ascorbic acid solution was used as a reference standard. The absorbance of samples
was compared to that of ascorbic acid standards and the results were expressed as the number of
equivalents of ascorbic acid.
The results revealed that thyme extracts exhibited antimicrobial activity against Gram (+) and Gram
(-) bacteria.
All examined extracts of thyme leaves cultivated in Montenegro showed rather good antioxidant
capacity. Obtained results revealed that highest antioxidative potential has thyme ethanolic extract.
Acknowledgements: Financial support of this work to Montenegrian Ministry of Science (Project

E!9906) is gratefully acknowledged.
[1]
L. De Martino, M. Bruno, C. Formisano, V. De Feo, F. Napolitano, S. Rosselli, F. Senatore, Molecules, 2009,
14, 4614.
[2]
A. De Lisi, L. Tedone, V. Montesano, G. Sarli, D. Negro, Food Chem., 2011, 125, 1284.
[3]
AI. Dawidowicz, E. Rado, D. Wianowska, M. Mardarowicz, J. Gawdzik, Talanta, 2008, 76, 878.
101
P-26
SYNTHESIS, ANTICANCER ACTIVITY AND DOCKING STUDIES

OF NEW PHENYLAMINOPYRIMIDINE DERIVATIVES
Aslı Demirci,[a] İrem Durmaz,[b] Rengül Çetin Atalay[b] and İlkay Küçükgüzel[a],*
[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668
İstanbul, Turkey
[b] Graduate School of Informatics, Cancer Systems Biology Laboratory, Middle East Technical
University, 06800 Ankara, Turkey
* ikucukguzel@marmara.edu.tr
Cancer chemotherapy has showed a major progress for the last few decades. Since the launch of
imatinib in 2001, kinase inhibitors in drug discovery remains to be one of the hot topics regarding
cancer treatment in academia and in pharmaceutical industry.[1] The clinical success of imatinib has
led to one or more new ‘tinib’ analogue small molecule kinase inhibitor has been discovered almost
every year so that great majority of them have entered to the clinic. The number of kinase inhibitor
drugs approved by FDA is currently over 30.[2]
Kinases are established as important modulators of cells. Small molecule kinase inhibitor discovery
remains to be one of the crucial interests of medicinal chemistry. Imatinib is the pioneering kinase
inhibitor drug which has phenylaminopyrimidine core structure. In literature, there are various data
indicating that phenylaminopyrimidine derivatives are straight candidates for anticancer drug
discovery.[3,4]
For this purpose, a series of novel phenylaminopyrimidine derivatives were designed and
synthesized. Purity of the synthesized compounds was checked with TLC and HPLC. The structures
of the final compounds were confirmed by FTIR, 1H-NMR, 13C-NMR and mass spectral data besides
elemental analysis. Cytotoxic bioactivity of synthesized compounds was evaluated in vitro against
breast (MCF-7), liver (Huh-7) and colon (HCT-116) cancer cell lines.
Molecular modeling studies have been performed to simulate potential inhibition of different kinases
by synthesized compounds. ABL2, SRC, VEGFR and AXL kinase proteins were rationally selected
in accordance with biological studies. Docking studies on ABL2 and SRC kinases were run with
inactive states of proteins; while docking studies on VEGFR kinase were run with both active and
inactive state. In addition, docking studies on AXL kinase were run with its active form.
Possible binding conformations of each ligand were evaluated. Interactions with hinge region and
interactions with DFG motif of the kinase proteins which are both crucial for kinase inhibition were
visualized after docking processes. Binding energies and conformations were re-evaluated in the
light of biological study results.
Further in silico and in vitro studies associated with synthesized compounds are in progress and the
results will be discussed in detail.
[1]
P. Wu, Drug Discov. Today, 2016, 21, 1.
[2]
P. Fisher, Med. Res. Rev., 2016, 0, 0, 1.
[3]
I. M. El-Deeb, S. H. Lee, Bioorg. Med. Chem., 2010, 18, 11.
[4]
J. Dietrich, C. Hulme, Bioorg. Med. Chem., 2010, 18, 15.
102
P-27
RADIOLABELED 1,2,4,5-TETRAZINES AS BIOORTHOGONAL

IMAGING TOOLS
Christoph Denk,[a],* Martin Wilkovitsch,[a] Thomas Wanek,[b]

Claudia Kuntner-Hannes,[b] Dennis Svatunek[a] and Hannes Mikula[a]
[a] Vienna University of Technology, Institute of Applied Synthetic Chemistry, Vienna, Austria
[b] Austrian Institute of Technology, Biomedical Systems, Austria
* christoph.denk@tuwien.ac.at
Labeled antibodies are highly specific imaging probes that are incompatible with short-lived
radionuclides due to their slow accumulation. This dilemma can be circumvented by pretargeting
using bioorthogonal reactions (Figure).[1,2] These fast and biocompatible “click” type ligations are
capable of forming a covalent linkage between a pre-administered marker compound and a labeled
pull down reagent (PDR) in vivo.[2] Due to particularly high ligation rates the inverse electron demand
Diels-Alder reaction (IEDDA) of strained dienophiles with 1,2,4,5-tetrazines (Tz) is especially suited
for in vivo application.[1-3]
Figure: Comparison of “traditional” immuno-imaging vs a bioorthogonal approach.
In addition to fast ligation rates PDRs must exhibit homogenous biodistribution, good in vivo stability
and fast excretion. Within this contribution the development and application of several radiolabeled
tetrazines, serving as small molecule imaging agents, will be presented. 1,2,4,5-Tetrazines labeled
with the positron emitter fluorine-18 were thought to be inaccessible due to reported degradation
during radiolabeling.[4] In 2014 our group was able to prepare the first 18F-tetrazine by trading
increased stability for reduced IEDDA reactivity.[5] This initial development our 18F-tetrazines were
constantly improved. The newest developments include 18F-Tz derivatives with ~200-fold elevated
ligation rate that still possess excellent in vivo stability, thus showing great promise as secondary
imaging agent. Tetrazines for therapeutic application bearing radionuclides of iodine or the α-emitter
astatine-211 were furthermore synthesized and evaluated.
We are convinced that radiolabeled tetrazines can overcome problems associated with slow-
accumulating vectors (such as antibodies and other nanomedicines), and should allow for many
applications in the field of medicine, medicinal chemistry and drug development.
[1]
R. Rossin et. al., J. Nucl. Med., 2013, 54, 1989.
[2]
B.M.Zeglis et. al., J. Nucl. Med., 2013, 54, 1389.
[3]
J.P. Meyer et. al., Bioconjugate Chem., 2016, 27, 2791.
[4]
Z. Li et. al., Chem. Comm., 2010, 46, 8043.
[5]
C. Denk et. al., Angw. Chem. Int. Ed., 2014, 53, 9655.
103
P-28
IDENTIFICATION OF EXPANDED CAG REPEATS LIGANDS

TO COUNTERACT HUNTINGTON’S DISEASE
Jenny Desantis,[a],* Kenji Schorp,[b] Serena Massari,[a] Anna Bochicchio,[c] Frank Matthes,[d]
Judith Schilling,[d] Stephanie Weber,[d] Nina Offermann,[d] Paolo Carloni,[c] Kamyar
Hadian,[b] Giulia Rossetti,[c] Oriana Tabarrini[a] and Sybille Krauss[d]
[a] Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy
[b] Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology,
Helmholtz Zentrum München für Gesundheit und Umwelt, Ingolstädter Landstr. 1, 85764,
Neuherberg, Germany
[c] Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience
and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany
[d] German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn,
Germany
* jenny.desantis@hotmail.it
Huntington’s disease (HD) is a fatal, devastating, and inherited neurodegenerative genetic disorder,
for which there is currently no cure.[1] The disease is caused by an autosomal dominant mutation at
the huntingtin (HTT) gene encoding for the ubiquitously expressed Huntingtin protein (Htt), which is
essential for brain development.[2,3]
Growing evidences emerged that HTT mRNA transcripts with expanded CAG repeats (n > 36) (i)
contribute to the pathogenesis of HD;[4] (ii) aberrantly regulate several cellular mechanisms;[5] (iii)
bind to proteins in repeat size-dependent manner to form pathological complexes.[6-9] In particular,
the interaction between mRNA transcripts of pathogenic length and the Midline-1 protein (MID1) is
involved in the overproduction of aberrant Htt protein.[10]
Hence, the design of ligands with high affinity for expanded CAG mRNA transcripts able to inhibit
the formation of pathological mRNA/proteins complexes represents a promising, although
challenging, strategy to interfere with the neuronal derangement associated with HD. Until now, a
few small molecules able to bind CAG repeats in RNA in vitro have been identified, but unfortunately
none of them resulted to be selective for the pathogenic CAG repeats in HTT, when assayed in
vivo.[11]
Here, we are currently selecting small molecules that might bind to mutant HTT RNA in vitro and in
turn could inhibit the MID1/HTT RNA complex formation.
[1]
C.A. Ross, S.J. Tabrizi, Lancet Neurol., 2011, 10, 83.
[2]
M.E. MacDonald, C.M. Ambrose, M.P. Duyao, R.H. Myers, C. Lin, G. Barnes, S.A. Taylor, M. James, N.
Groot, H. MacFarlane, B. Jenkins, M.A. Anderson, N.S. Wexler, J.F. Gusella, Cell, 1993, 72, 971.
[3]
A. Reiner, I. Dragatsis, S. Zeitlin, D. Goldowitz, Mol. Neurobiol., 2003, 28, 259.
[4]
M. Wojciechowska, W.J. Krzyzosiak, RNA Biol., 2011, 8, 565.
[5]
R. Nalavad, N. Griesche, D.P. Ryan, S. Hildebrand, S. Krauß, Cell Death Dis,. 2013, 4, e752.
[6]
A. Kiliszek, R. Kierzek, W.J. Krzyzosiak, W. Rypniewski, Nucleic Acids Res., 2010, 38, 8370.
[7]
M. de Mezer, M. Wojciechowska, M. Napierala, K. Sobczak, W.J. Krzyzosiak, Nucleic Acids Res., 2011, 39,
3852.
[8]
L.P. Ranum, T.A. Cooper, Annu. Rev. Neurosci., 2006, 29, 259.
[9]
A. Fiszer, W.J. Krzyzosiak, J. Mol. Med. (Berl.), 2013, 91, 683.
[10]
S. Krauss, N. Griesche, E. Jastrzebska, C. Chen, D. Rutschow, C. Achmüller, S. Dorn, S.M. Boesch, M.
Lalowski, E. Wanker, R. Schneider, S. Schweiger, Nat. Commun., 2013, 4, 1511.
[11]
A. Kumar, R. Parkesh, L.J. Sznajder, J.L. Childs-Disney, K. Sobczak, M.D. Disney, ACS Chem. Biol., 2012,
7, 496.
104
P-29
SYNTHESIS OF SOME NEW BENZOTHIAZOLONE DERIVATIVES AND

INVESTIGATION OF THEIR CHOLINESTERASE INHIBITOR ACTIVITIES
Deniz S. Doğruer,* Merve Erdoğan and Burcu Kılıç

Department of Pharmaceutical Chemistry, Gazi University Faculty of Pharmacy, 06330 Ankara, Turkey
* denizdogruer2002@yahoo.com
Alzheimer's disease (AD) was first identified by Dr. Alois Alzheimer in 1906. Since then, the average
life expectancy has been significantly extended, AD has become an important health problem all
over the world especially in developed countries. Since the cause of disease are not fully elucidated,
available treatments are insufficient. Pathophysiological changes of AD cover lack in cholinergic
neurotransmission, faulty amyloid-β (Aβ) protein metabolism, formation of intracellular neurofibrillary
tangles and the participation of inflammatory, oxidative and hormonal pathways. Based on these
markers, several hypotheses have been proposed to explain the mechanism of AD, which are
cholinergic, amyloid and tau hypotheses.[1] According to the cholinergic hypothesis, since the
symptoms of Alzheimer’s disease (AD) was linked to a deficiency in the brain neurotransmitter
acetylcholine (ACh) that mediates memory and learning functions, current treatment of AD focuses
on increasing acetylcholine levels by inhibiting cholinesterase, the enzymes responsible for ACh
hydrolysis. Because AChE is the main enzyme involved in the breakdown of ACh in the normal brain,
cholinergic therapy for AD initially focused on AChE inhibition. Recently research shows that the
enzyme has also non-cholinergic function in addition to catalytic activity of AChE.[2] On the other
hand, as the disease progresses, AChE levels decrease while the levels of BuChE increase.[3]
Therefore, concurrent inhibition of both enzymes should provide additional benefits in the treatment
of AD.
In the present study, we designed and synthesized eight new benzothiazolone derivatives in order
to investigate their acetylcholinesterase/butyrylcholinesterase inhibitory activities. The chemical
structures of synthesized compounds were confirmed by 1H-NMR, 13C-NMR, HRMS and elemental
analysis.
[1]
M. Singh, M. Kaur, H. Kukreja, R. Chugh, O. Silakari, D. Singh, Eur. J. Med. Chem., 2013, 70, 165.
[2]
G. Johnson, S.W. Moore, Current Pharmaceutical Design., 2006, 12, 217.
[3]
X. Sai-Sai, W. Xiao-Bing, L. Jiang-Yan, Y. Lei, K. Ling-Yi, Eur. J. Med. Chem., 2013, 64, 540.
105
P-30
LONG-CHAIN DERIVATIVES OF
(TRIFLUOROMETHYLPHENYL)PIPERAZINES – SYNTHESIS AND
EVALUATION OF THE ACTIVITY TOWARDS 5-HT RECEPTORS
Anna Drabczyk,[a] Jolanta Jaśkowska,[a],* Damian Kułaga,[a] Grzegorz Satała[b] and

Magdalena Malinowska[a]
[a] Cracow University of Technology, Department of Chemical Engineering and Technology, Institute
of Organic Chemistry and Technology, 24 Warszawska St., 31-155 Cracow, Poland
[b] Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12
Smetna St., 31-343 Cracow, Poland
* jaskowskaj@chemia.pk.edu.pl
Smart drugs (designer drugs) is common term for the single substances, the group of substances or
mixtures thereof, which have psychoactive effects. This group include the arylpiperazines that are
bioactive compunds, having affinity towards serotonin 5-HT receptors. Among the arylpiperazine
derivatives (1-(3-trifluoromethyl)phenyl)piperazine (TFMPP) can be found – a substance that is a
non-selective agonist of serotonin receptors 5-HT1B, 5-HT2A, 5-HT2C. TFMPP and other
arylpiperazine derivatives can be obtained by synthesis of substituted aniline with bis(2-
chloroethyl)amine hydrochloride in the presence of base. However, the disadvantage of this method
is low yield of obtaining the products and a very long reaction time lasting several hours.[1,2]
An interesting aspect is the aryl-piperazine modifications leading to the formation of long chain
derivatives of these compounds (LCAPs - Long Chain Aryl Piperazines), that have an amide or imide
in the terminal part. Compared to the arylpiperazines affecting only on the 5-HT receptors, LCAPs
have a wider activity - not only towards serotonin receptors, but also towards dopamine receptors.
The literature data show high bioactivity of popular substances belonging to the group of LCAPs,
such as Buspirone or NAN-190, as well as derivatives of mentioned TFMPP with
bromobutylphthalimide e.g. 4-[4-(2-phthalimido)butyl]-1-(3 -trifluoromethylphenyl) piperazine.[3]
These ligands can be prepared in lasting many hours and requiring the use of large amounts of toxic
solvents synthesis. Furthermore, the resulting products requires purification by using column
chromatography.[4,5]
The research began by performing the synthesis of (trifluoromethylphenyl)piperazine derivatives via
method which fulfills the principle of "Green Chemistry". The impact of the proposed reaction
conditions on the yield and purity of obtaining the desired product was tested. In the next stage of
the study, received derivatives of (trifluoromethylphenyl)piperazine were used for the synthesis of a
series of LCAPs, which contained alkyl chain terminated with imide or amide moiety. The syntheses
were carried out under microwave irradiation in a new, eco-friendly way that allows the reduction of
solvents used during the reaction. In addition, thus obtained ligands were characterized by high
purity and good physico-chemical properties. The results received after carrying out an in vitro tests
for all of the ligands obtained by this method, have confirmed high biological activity of newly
synthesized compounds.
Acknowledgments: The study was financially supported by the National Centre for Research and
Development, Project LIDER VI (No. LIDER/015/L-6/14/NCBR/2015).
[1]
R. Perrone et al. J. Med. Chem., 1994, 37, 99.
[2]
E. Mishani et al. Tetrahedron Lett., 1996, 37, 319.
[3]
M. Paluchowska et al. Arch. Pharm. Chem. Life Sci., 2006, 339, 498.
[4]
P.Kowalski et al. Arch. Pharm., 2013, 346, 339.
[5]
P. Kowalski et al. Arch. Pharm. Chem. Life Sci., 2012, 345, 81.
106
P-31
SYNTHESIS AND EVALUATION OF THE ACTIVITY TOWARDS 5-HT

RECEPTORS OF NEW LIGANDS FROM THE LCAPS GROUP
Anna Drabczyk,[a] Jolanta Jaśkowska,[a],* Damian Kułaga,[a] Grzegorz Satała[b] and

[b] Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12
Long-chain arylpiperazines (LCAPs) are an interesting group of compounds which have activity
towards the serotonin receptors.[1] These compounds contain in their structure arylpiperazine moiety
which, through the flexible alkyl chain, is linked mostly to imide, amide, or sulfonamide moiety. These
compounds are generally obtained by several hours’ long, multi-step synthesis which requires the
use of large amounts of solvents. This method of carrying out the reactions also requires the removal
of solvents from the reaction mixture and purification of the compounds by using Pressure Liquid
Chromatography Column.[2-4]
One of the best known compounds belonging to the group of LCAPs having activity against the
serotonin 5-HT receptors is NAN-190 – 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine which
has a methoxy substituent in the ortho position in the aromatic ring of arylpiperazine moiety.[5]
Within the framework of the research, basing on the structure of NAN-190, it was decided
to check the influence of lengthening the alkyl chain connecting the arylpiperazine group
with the phthalimide, as well as the impact of the position of methoxy group in the aromatic ring of
arylpiperazine moiety. The group of ligands was obtained by newly developed method of synthesis
which follows the principles of “Green Chemistry”. The reactions were carried out within a few
minutes under microwave irradiation, using small amounts of solvents. The performed reactions
allow obtaining the desired products with high purity in a short time and with a high yield. All obtained
ligands were evaluated in in vitro tests for their affinity with selected serotonin 5-HT receptors. The
results from these studies confirm high biological activity of testing compounds.
[1]
G. Caliendo et al. Curr. Med. Chem., 2005, 12, 763.
[2]
P. Kowalski et al. Archiv der Pharm., 2013, 346, 339.
[3]
P. Kowalski et al. Arch. Pharm. Chem. Life Sci., 2012, 345, 81.
[4]
N. Cesari et al. J. Med. Chem., 2006, 49, 7826.
[5]
A. J. Bojarski et al. Bioorg. Med. Chem. Lett., 2004, 14, 5863.
107
P-32
SYNTHESIS OF PHOTOSWITCHABLE INHIBITORS FOR CNS

APPLICATIONS
D. Dreier,[a] M. Holy,[b] K. Jäntsch,[b] H. H. Sitte[b] and M. D. Mihovilovic[a],*

[a] Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
[b] Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna,
Währinger Straße 13A, 1090 Vienna, Austria
Recent advances in the field of photo pharmacology[1] enabled photo control over a variety of proteins
(e.g. ion channels). Photo switchable molecules can be switched between two isomers by irradiation
with light. Ideally, the biological activity of the two isomers is largely different.
Within this contribution we investigate the feasibility to apply this concept to key proteins of CNS
networks. We present the synthesis of novel photo switchable analogs based on well-studied
ligands. Photo switchable small molecules might alter the functionality of targeted proteins to be light
dependent. These photo-sensitive proteins would allow to study them in greater detail and thereby
provide a deeper understanding of their functionality.
Azobenzene and Hemithioindigo[2] based photo switches (Figure) were utilized as two potential
substance classes to achieve our goals. These two compound classes exhibit a wide range of
thermal half-life times and different activation wavelengths. In addition, we report on preliminary
biological data obtained from cell based assays.
Figure: Application of Azobenzenes and Hemithioindigos in photopharmacology.

[1]
J. Broichhagen, J. A. Frank, D. Trauner, Acc. Chem. Res., 2015, 48, 1947.
[2]
S. Wiedbrauk, H. Dube, Tetrahedron Lett., 2015, 56, 4266.
108
P-33
AER METHOD: A GOOD WAY TO OBTAIN APIs AS IONIC LIQUIDS
E. Alcalde,[a] I. Fallon,[a] F. Roig,[b] J. Esquena,[c] M. J. García-Celma[b,c] and

I. Dinarès[a],*
[a] Unitat de Química Orgànica, Dep. Farmacologia, Toxicologia i Química Terapèutica [§]
[b] Unitat de Tecnologia Farmacèutica, Dep. Farmàcia, Tecnologia Farmacèutica i Fisicoquímica [§]
[c] Institut de Química Avançada de Catalunya (IQAC) [ǂ]
* idinares@ub.edu
Ion-exchange resins are widely used in different processes. Anion exchange resins (AER) have been
employed as an efficient tool to perform the anion exchange and their application has been extended
to a variety of chemical reactions. In recent years, our research group has developed a broad and
efficient method to swap the halide ion in quaternary heteroaromatic and ammonium salts for a
variety of anions using an AER in non-aqueous media.[1] This simple procedure involves the
preparation of AER (A¯ form) with the selected anion (anion loading) and then the halide exchange
(Figure). The choice of the solvents for loading and for exchange is critical to achieve the best results.
Following the AER method halide-free ion pairs with ionic liquid (IL) properties can be obtained.
Figure: AER method applied to arylpropionic derivatives.
Both charged counterparts in ILs can be independently modified, providing tunability in the design of
new functional materials such active pharmaceutical ingredients (APIs) modulating the properties
with novel performance enhancement, bioavailability and delivery options. Poor water solubility of
active pharmaceutical ingredients (API) is a major challenge in drug development impairing
bioavailability and therapeutic benefit. Direct synthesis of ILs from weakly acidic or weakly basic
drugs shows perhaps the most promise for significant alteration of drug properties, such to avoid the
crystallinity or to promote aqueous solubility.
As a part of our ongoing research, AER simple method was applied to the synthesis of several drug
examples of arylpropionic acids (non-steroidal anti-inflamatory drugs) or bisphosphonates
(osteoporosis treatment) with ILs properties. Moreover, toxicity and biocompatibility of cation should
be taken into account. In addition, the study of the release from micro and nanogels as drug delivery
systems was carried out.
Acknowledgments: AGAUR-Generalitat de Catalunya (2014SGR1655), MINECO (CTQ2016-

80645-R), and SCT-UB.
[§]
Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Av. Joan XXIII 27-31, 08028-
Barcelona.
[ǂ]
CSIC i CIBER-BBN, Jordi Girona 18-26, 08034-Barcelona.
[1](a)
I. Dinarès, C. Garcia de Miguel, A. Ibáñez, N. Mesquida, E. Alcalde. Green Chem., 2009, 11, 1507.; (b) E.
Alcalde, I. Dinarès, A. Ibáñez, N. Mesquida Chem. Commun., 2011, 47, 3266.; (c) E. Alcalde, I. Dinarès, A.
Ibáñez, N. Mesquida, Molecules, 2012, 17, 4007.
109
P-34
SYNTHESIS OF SOME NEW BENZOXAZOLONE DERIVATIVES AND

EVALUATION OF THEIR CHOLINESTERASE INHIBITOR ACTIVITIES
Merve Erdoğan,* Burcu Kılıç and Deniz S. Doğruer

Department of Pharmaceutical Chemistry, Gazi University Faculty of Pharmacy, 06330 Ankara, Turkey
* merve1392@gmail.com
According to World Health Organization (WHO), Alzheimer’s disease (AD), most common age-
related neurodegenerative disease, affects more than 30 million people around the world and
number of AD patient expected to increase up 100 million by 2050.[1] AD is characterized by
progressive cognitive impairments, learning problems and decrease language and motor skills.[2]
Although extensive research has focused on pathogenetic mechanism of AD, exact cause is still
uncertain. Several hypothesis has been explained as the cause of AD. One of them is cholinergic
hypothesis, suggested that decreased level of neurotransmitter acetylcholine in some parts of the
brain such as hippocampus related to learning and cognition is the typical pathological hallmarks of
AD.[3] Thus, the acetylcholine level in the brain is enhanced by inhibition of cholinesterase enzymes.
Recent approved cholinesterase inhibitors (ChEIs) donepezil, galantamine and rivastigmine have
been used for this purpose. However, present cholinesterase inhibitor drugs are only effective in mild
and moderate stages of AD, their effectiveness varies individually and they can cause peripheral
side effects.[4] These restrictions motivate researchers to investigate for new alternatives. As a result,
cholinesterase inhibitors keep their values for drug development studies.
In the present study, we designed and synthesized eight new benzoxalone derivatives in order to
investigate their acetylcholinesterase/butyrylcholinesterase inhibitory activities. The chemical
structures of synthesized compounds were confirmed by 1H-NMR, 13C-NMR and HRMS.
[1]
Alzheimer's Disease International, World Alzheimer Report. 2011, p. 1.
[2]
A. Wimo, B. Winblad, L. Jönsson, Alzheimers Dement., 2010, 6, 98.
[3]
N. Guzior, A. Wickowska, D. Panek, B. Malawska. Curr. Med. Chem., 2015, 22, 373.
[4]
H. B. Nygaard, Clin. Ther., 2013, 35, 1480.
110
P-35
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW SERIES

OF DIHYDROXYLATED 2,6-DIPHENYL-4-CHLOROPHENYLPYRIDINES:
DNA NON-INTERCALATIVE CATALYTIC TOPOISOMERASE I & IIα DUAL
INHIBITOR
Eung-Seok Lee,[a],* Ganesh Bist,[a] Til Bahadur Thapa Magar,[a] Aarajana Shrestha,[a]
Pramila Katila[a] and Youngjoo Kwon[b]
[a] College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea

[b] College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
* eslee@yu.ac.kr
A novel series of eighteen dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines were systematically

designed, and investigated for their topoisomerase (topo) I and IIα inhibitory properties and
antiproliferative effect in HCT15, T47D, and HeLa cancer cell lines. Compounds 22-30 which
possess a meta- or para-phenol on 2-, or 6-position of central pyridine ring showed significant dual
topo I and topo IIα inhibitory activities with strong antiproliferative activities against all the tested
human cancer cell lines. However, compounds 13-21 which possess an ortho-phenol on 2-, or 6-
position of central pyridine ring did not show significant topo I and topo IIα inhibitory activities but
displayed moderate antiproliferative activities against all the tested human cancer cell lines. The
structure-activity relationship study revealed that the para position of a hydroxyl group at 2-and 6-
phenyl ring and chlorine atom at the para position of 4-phenyl ring of the central pyridine exhibited
the most significant topo I and topo IIα inhibition, which might indicate introduction of the chlorine
atom at the phenyl ring of 4-pyridine have an important role in topo I & IIα dual inhibition. Compound
30 with the most potent dual topo I and topo IIα inhibition with strong antiproliferative activity in T47D
cell line was selected to perform further study on the mechanism of action and was found to be
functioning as a potent DNA non-intercalative catalytic topo I and IIα dual inhibitor.
111
P-36
SYNTHESIS OF RING A-FUSED PYRAZOLE REGIOISOMERS IN THE

ANDROSTANE SERIES AND AN EVALUATION OF THEIR CELL-
GROWTH INHIBITORY EFFECTS IN VITRO
Éva Frank,[a],* Ádám Baji,[a] Gergő Mótyán[a] and István Zupkó[b]

[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
[b] Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720
Szeged, Hungary
* frank@chem.u-szeged.hu
Pyrazoles represent an important class of five-membered N-containing heterocycles in view of the

broad spectrum of their bioactivity.[1] The incorporation of a pyrazole moiety into the relatively rigid
and planar backbone of natural sex hormones, either connected to[2] or condensed with one of the
core-forming rings,[3] also deserves attention from pharmacological aspects. Some of these
derivatives have been reported to exhibit direct antiproliferative effects on cancer cell lines of diverse
origins in a hormone receptor independent manner.[4]
Herein a rapid and simple synthesis of novel ring A-condensed steroidal pyrazoles from
2-hydroxymethylene-dihydrotestosterone (1) with different arylhydrazines (2a-h) is described. The
Knorr-type transformations led to a 5:4 mixture of two regioisomeric arylpyrazoles (3 and 4) in good
yields within 5 min using pyridine as solvent. However, strong electron-withdrawing groups (CN,
NO2) attached to the phenylhydrazine ring (2g and 2h) were observed to affect the isomeric
distribution ratio favoring the formation of 4 over 3, though the reaction rates were left unchanged.
After separating the related isomers by column chromatography, they were subjected to in vitro
pharmacological studies to explore their antiproliferative activities against three human breast
malignant cell lines (MCF7, T47D, MDA-MB-231).
Overall
Isomeric
Arylhydrazine R yield
ratio (3:4)
(%)
2a H 5:4 89
2b CH3 5:4 82
2c OMe 5:4 82
2d F 4:3 79
2e Cl 4:3 85
2f Br 4:3 84
2g CN 1:2 78
2h NO2 1:2 84
[1]
M.F. Khan, M.M. Alam, G. Verma, W. Akhtar, M. Akhter, M. Shaquiquzzaman, Eur. J. Med. Chem.,
2016,120,170.
[2]
D. Kovács, J. Wölfling, N. Szabó, M. Szécsi, Zs. Schelz, I. Zupkó, É. Frank, Eur. J. Med. Chem., 2016,120,
284.
[3]
D.S. Fischer, G.M. Allan, C. Bubert, N. Vicker, A. Smith, H.J. Tutill, A. Purohit, L. Wood, G. Packham, M.F.
Mahon, M.J. Reed, B.V.L..Potter, J. Med. Chem., 2005, 48, 5749.
[4]
É. Frank, Gy. Schneider, J. Steroid Biochem. Mol. Biol., 2013, 137, 301.
112
P-37
SYNTHESIS, CYTOSTATIC AND ANTIBACTERIAL EVALUATIONS OF N-

4-BENZOYLCYTOSINE–1,2,3-TRIAZOLE AND 7-DEAZAPURINE–1,2,3-
TRIAZOLE HYBRIDES
Maja Stipković Babić,[a] Mande Miošić,[a] Moris Mihovilović,[a] Marijana Jukić,[b]

Ljubica Glavaš-Obrovac,[b] Domagoj Drenjančević,[c,d] Silvana Raić-Malić[a] and Tatjana
Gazivoda Kraljević[a],*
[a] Department of Organic Chemistry, Faculty of Chemical Engeneering and Technology, University of
Zagreb, Marulićev trg 20, 10000 Zagreb, Croatia.
[b] Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine
Osijek, J. J. Strossmayer University of Osijek, Huttlerova 4, HR-31000 Osijek, Croatia.
[c] Department of Microbiology and Parasitology, Faculty of Medicine Osijek, J. J. Strossmayer
University of Osijek, Huttlerova 4, HR-31000 Osijek, Croatia.
[d] Department of Transfusion Medicine, University Hospital Centre Osijek, Huttlerova 4, HR-31000
Osijek, Croatia
* tatjana.gazivoda@fkit.hr
Cytosine and 7-deazapurine (pyrrolo[2,3-d]pyrimidine) derivatives have a great role in medicinal

chemistry and have shown rather marked antitumor, antiviral, antibacterial and antiinflammatory
activities.[1-4] 7-deazapurines are an important class of compounds, structurally and chemically
related to naturally nucleosides. In the last few years, several 7-deazapurine derivatives have been
approved for the treatment of different diseases or are currently in phase I/II clinical trials.[1] As
important pharmacophores, pyrrolo[2,3-d]pyrimidine scaffold is being extensively investigated and
many of such compounds resulted active as kinase inhibitors.[5] Herein we present the synthesis of
novel N-4-benzoylcytosine–1,2,3-triazole and pyrrolo[2,3-d]pyrimidine–1,2,3-triazole hybrides and
their cytostatic and antibacterial evaluations. The novel N-1 propargylated and C-5 alkynylated N-4-
benzoylcytosine derivatives were prepared by N-alkylation of pyrimidine bases and subsequent Pd-
catalysed Sonogashira cross-coupling reaction, while C-6 substituted pyrrolo[2,3-d]pyrimidine
derivatives were afforded by in situ N-heteroannulation of C-5 alkynylated cytosines. Cytosine- and
7-deazapurine–1,2,3-triazole hybrides were obtained by click reaction with corresponding azides in
the pressence of CuI and base. The novel compounds were evaluated against tumor cell lines (HeLa,
CaCo-2, Raji and K562) and on the growth of gram-positive and gram-negative bacterial strains.
[1]
F. Musumeci et al, Eur. J. Med. Chem., 2017, 127, 369.
[2]
L. Wang et al, J. Med. Chem., 2015, 58, 6938.
[3]
V. P. Kumar et al, Bioorg. Med. Chem. Lett., 2013, 23, 5426.
[4]
K. M. H. Hilmy et al, J. Am. Sci., 2011, 7, 308.
[5]
T. Wang et al, Bioorg. Med. Chem. Lett., 2016, 26, 2936.
113
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STERANE-FUSED PYRAZOLES:
AN EFFICIENT MICROWAVE-ASSISTED SYTHESIS ON RING A
Gergő Mótyán,* Réka Kiss-Faludy, János Wölfling and Éva Frank

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
* motyan@chem.u-szeged.hu
Pyrazole derivatives are important class of heterocycles, since they have been found to be a versatile
element in numerous pharmacological and chemically remarkable compounds.[1] Five-membered N-
containing heterocycles are known to have various activities and several compounds have been
proven as, useful intermediates in the deduction of biological targets.[2] The introduction of a pyrazole
moiety condensed to the steroidal skeleton may cause a significant change in the original biological
activities, newly-synthesized derivatives were found to exert pronounced antiproliferative action on
human malignant cell lines.[3,4]
A series of novel A-ring fused pyrazole derivatives containing differently substituted aryl group were
designed and synthesized using efficient and rapid microwave-mediated approach. The newly
gained compounds were subjected to in vitro bioassays and pharmacological investigations against
different human malignant cell lines, further studies ‒ which are in progress ‒ may result in essential
structure-activity relationships and permit the better understanding of the mode of action of the potent
derivatives.
Acknowledgments: This work has been supported by the ÚNKP-ÚNKP-16-3 New National
Excellence Program of the Ministry of Human Capacities.
[1]
É. Frank, Z. Mucsi, I. Zupkó, B. Réthy, G. Falkay, G. Schneider, J. Wölfling, J. Am. Chem. Soc., 2009, 131,
3894.
[2]
A. W. Brown, M. Fisher, G. M. Tozer, C. Kanthouand, J. P. A. Harrity, J. Med. Chem., 2016, 59, 9473.
[3]
G. Mótyán, I. Zupkó, R. Minorics, G. Schneider, J. Wölfling, É. Frank, Mol. Div., 2015, 78, 69.
[4]
G. Mótyán, F. Kovács, J. Wölfling, A. Gyovai, I. Zupkó, É. Frank, Steroids, 2016, 112, 36.
114
P-39
BROADLY EFFECTIVE METAL CHELATORS, AS INFLUENZA PA

ENDONUCLEASE AND HEPATITIS C VIRUS INHIBITORS
Erofili Giannakopoulou,[a] Annelies Stevaert,[b] Efseveia Frakolaki,[c]

Vassilios Myrianthopoulos,[a] Emmanuel Mikros,[a] Ralf Bartenschlager,[d]
Niki Vassilaki,[c] Lieve Naesens[b] and Grigoris Zoidis[a],*
[a] School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National
and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771, Athens, Greece
[b] Rega Institute for Medical Research, KU Leuven – University of Leuven, Herestraat 49, 3000,
Leuven, Belgium
[c] Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521, Athens,
Greece
[d] Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Im Neuenheimer
Feld 345, 69120, Heidelberg, Germany
* zoidis@pharm.uoa.gr
Influenza viruses cause considerable morbidity and mortality whether in the context of seasonal
epidemics or pandemic outbreaks which are associated with huge economic costs. Hepatitis C virus
(HCV) infection is the major cause of chronic liver disease, in approximately 170 million people
worldwide, that often leads to cirrhosis and hepatocellular carcinoma. Since the efficacy of currently
approved antivirals is threatened by emerging viral resistance and their cost remains high, new
antiviral drugs are still required, as they are an indispensable component of the broad approach for
the treatment and prevention of these infections.
By utilizing a structure-based approach, novel substituted indole-flutimide heterocyclic derivatives
were rationally designed, synthesized and evaluated as influenza PA endonuclease and HCV NS5B
polymerase inhibitors.[1] The compounds were also tested for their antiviral effect against HCV and
their cytotoxicity. The source of inspiration for the design of the new analogues was several
compounds that bear a N-hydroxyimidic moiety, a metal chelating group, and especially the
structurally related compound flutimide, the first identified natural product that is found to selectively
inhibit the "cap-snatching" endonuclease reaction of Influenza A and B viruses.[2] All N-
hydroxyimides were potent PA endonuclease inhibitors, while displaying low cytotoxicity. Some of
them also showed additional significant anti-HCV activity and exhibited remarkable selectivity
index.[1] The results of in vitro evaluation contribute in the clarification of the role of several structural
characteristics in the Structure-Activity Relationships of the compounds with the active site of the
enzymes. Our findings suggest that the novel pyrazino[1,2-α]indole-1,3(2H,4H)-dione framework,
that we have developed, offers a promising motif for an ameliorated future design of novel antiviral
agents with optimized properties.
[1]
G. Zoidis, E. Giannakopoulou, A. Stevaert, E. Frakolaki, V. Myrianthopoulos, G. Fytas, P. Mavromara, E.
Mikros, R. Bartenschlager, N. Vassilaki, L. Naesens, MedChemComm, 2016, 7, 447.
[2]
J.E. Tomassini, M.E. Davies, J.C. Hastings, R. Lingham, M. Mojena, S.L. Raghoobar, S.B. Singh, J.S.
Tkacz, M.A. Goetz, Antimicrob. Agents Chemother., 1996, 40, 1189.
115
P-40
ORGANOCATALYSIS MEETS BETA LACTAMS
Thavendran Govender,[a] Tricia Naicker,[a] Hendrik G. Kruger[a] and

Per I. Arvidsson[a,b]
[a] Catalysis and Peptide Research Unit, University of KwaZulu Natal, South Africa
[b] Science for Life Laboratory, Drug Discovery and Development Platform, and Division of
Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska
Institutet,  Stockholm, Sweden  
Compounds containing β-lactams are amongst the most important molecules in clinical use today.[1-
3]
Most notably is their wide utility as antibacterial agents and as related β-lactamase inhibitors;
however, β-lactams are also being explored in other therapeutic areas,[4] including HIV protease
inhibition.[5] Given the global challenge of antibiotic resistance,[6] there is an urgent need for increased
focus on the discovery and development of antibacterial agents. We have exploited the use of
organocatalysis to make realized novel derivatives for medicinal chemistry.[7-10]
Figure: Novel HOMO rising strategies offering a mild and facile route to carbapenam derivatives.
[1]
A. C. Rodloff, E. J. C. Goldstein, A. Torres, J. Antimicrob. Chemother., 2006, 58, 916.
[2]
R. P. Elander, Appl. Microbiol. Biotechnol., 2003, 61, 385.
[3]
F.-R. Schmidt, In Industrial Applications, ed. M. Hofrichter, Springer Berlin Heidelberg 2010; vol 10, pp 101.
[4]
J. M. T. Hamilton-Miller, J. Antimicrob. Chemother., 1999, 44, 729.
[5]
T. Sperka, J. Pitlik, P. Bagossi J. Tozser, Bioorg. Med. Chem. Lett., 2005, 15, 3086.
[6]
F. Rossi, Clin. Infect. Dis., 2011; 52:1138.
[7]
S. A. Pawar, S. Alapour, S. Khanyase, Z. E. D. Cele, S. Chitti, H. G. Kruger, T. Govender, P. I. Arvidsson,
Org. Bio. Chem., 2013, 8294.
[8]
Z. E. D.Cele, S. A. Pawar, T. Naicker, G. E. M. Maguire, P. I. Arvidsson, H. G. Kruger, T. E. Govender, Eur.
J. Org. Chem., 2014, 2253.
[9]
Z. E. D. Cele, P. I. Arvidsson, H. G. Kruger, T. Govender, T. Naicker, Eur. J. Org. Chem., 2015, 638.
[10]
S. Khanyase, T. Naicker, G. E. M. Maguire, H. G. Kruger, P. I. Arvidsson, T. Govender, Tetrahedron
Asymmetry, 2014, 25, 969.
116
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SEARCH FOR 5-HT6 RECEPTOR AGENTS AMONG TRIAZINE

DERIVATIVES OF HYDANTOIN
Jadwiga Handzlik,[a],* Rafał Kurczab,[b] Dorota Łażewska,[a] Małgorzata Więcek,[a] Angelika

Nowakowska,[a] Grzegorz Satała,[b] Andrzej J. Bojarski[b] and
Katarzyna Kieć-Kononowicz[a]
[a] Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College,
ul. Medyczna 9, 30-688 Kraków, Poland
[b] Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences,
Smętna 12, PL 31-343 Kraków, Poland
* j.handzlik@uj.edu.pl
The 5-HT6 receptors are a relatively new subgroup of serotonin receptors that are quite different from
other members. The significant interest in 5-HT6 receptors is related to the therapeutic ability of their
ligands as potential anti-dementia, antipsychotic, antidepressant or anti-obese drugs.[1] Several
families of compounds displaying action on 5-HT6R found previously allowed to postulate
pharmacophore features.[2] Reviewing the library of our compounds, we stumbled on two hydantoin
1,3,5-triazine derivatives that display some features corresponding to those of the pharmacophore
of the 5-HT6R ligand and we decided to evaluate their affinities for 5-HT6R in the radioligand binding
assay.The compounds differed in the co-position of both, triazine and benzyl moieties, in respect to
the hydantoin core. Thus, the compound with 1,3,5-triazine at position 3 of hydantoin and benzyl at
position 1 (1, Figure) had nanomolar 5-HT6R affinity, whereas the compound with triazine at 1 and
the benzyl substitution at position 3 had weak micromolar activity.
Thus, the compound 1 was selected as a lead structure for further modifications to search for new
5-HT6R agents 2-10 (Figure). The new compounds were obtained within 3-step synthesis, including:
(i) an intruduction of ester at position 3, (ii) an alkylation at position 1, and (iii) cyclic condensations
with biguanide to give 1,3,5-triazine moiety. The compounds were examined on their affinities to 5-
HT6R in the radioligand binding assay. Docking to the homology model of 5-HT6R was performed.
The best compounds displayed significant affinities for the serotonin 5-HT6R (Ki < 200 nM). Docking
studies provided new interesting information about poses of the hydantoin-triazines (1-10) within the
ligand binding pocket of this important serotonin receptor.
Acknowledgments: Supported by the Polish National Science Centre (NCN) grant UMO-
2015/17/B/NZ7/02973.
[1]
D. Marazziti, S. Baroni, F. Borsini, M. Picchetti, E. Vatteroni, V. Falaschi, M. Catena-Dell’Osso, Curr. Med.
Chem., 2013, 20, 371.
[2]
B. Benhamú, M. Martín-Fontecha, H. Vázquez-Villa, L. Pardo, M.L. López-Rodríguez, J. Med. Chem.,
2014, 57, 7160.
117
P-42
NOVEL SYNTHESIS OF (+)-DIENOMYCIN C AND ANALOGOUS

COMPOUNDS WITH ANTIBACTERIAL ACTIVITY
Hajime Yokoyama, Yuko Hayashi, Hiromi Ejiri, Masahiro Miyazawa and

Yoshiro Hirai*
Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555,
Japan
* hirai@sci.u-toyama.ac.jp
The piperidine alkaloids (ex 1, 2), many of which have been isolated from the plant kingdom, have
great potential as a source of new drugs. Dienomycin C (1) was isolated from the culture filtrate of
the Streptomyces strain MC67-C1 by Umezawa in 1970.[1] This compound has a characteristic
antibacterial activity against some strains of Mycobacterium tuberculosis.
Hitherto, we have been studying the Pd(II)-catalyzed cyclization of urethane and its application to
the total synthesis of natural products. Here, we describe the application of this cyclization to
asymmetric synthesis of (+)-dienomycin C (1) and analogous compounds.
The key synthetic problem for (+)-dienomycin C (1) is the construction of three consecutive chiral
centers on the piperidine ring. We planned to achieve this by using the combination of Sharpless
asymmetric epoxidation, Pd-catalyzed hydrogenolysis with formic salt and Pd (II)-catalyzed
cyclization of the urethane.
Sharpless asymmetric epoxidation of the allyl alcohol 3 provided the epoxide 4 in 90% yield (78%
ee). After conversion of 4 to the ester 5, hydrogenolysis of 5 gave the alcohol 6 as a single isomer
in 90% yield. Treatment of the allyl alcohol 7, which was easily transformed from 6, with
PdCl2(MeCN)2 in THF at rt gave the cyclized product 8 as a single isomer in 82% yield. Ozonolysis
of 8 followerd by Wittig reaction and deprotection with concd HCl gave (+)-dienomycin C (1). We
also synthesized some analogous compounds of (+)-dienomycin C using Pd(II)-catalyzed
cyclization. Medicinal chemistry based on these compounds are currently under investigation in our
laboratory.
[1]
S. Umezawa, et al. J. Antibiot., 1970, 23, 20; J. Antibiot., 1970, 23, 28.
118
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NOVEL para SUBSTITUTED N-ARYL 3-HYDROXYPYRIDIN-4-ONE

MANNOSIDES: SYNTHESIS, HEMAGGLUTINATION INHIBITORY
PROPERTIES AND MOLECULAR MODELING
V. Petrović Peroković,[a] Ž. Car,[a] K. Meglić,[a] R. Ribić,[a] T. Tandarić,[b]

R. Vianello[b] and S. Tomić[a],*
[a] Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102 a, Zagreb,
Croatia
[b] Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia
* stomic@chem.pmf.hr
Adhesion of pathogenic organisms to host tissues is the initiation of the majority of infectious
diseases. It is often mediated by lectins present on the surface of infectious organisms which then
combine with complementary sugars on the host surface.[1] One of the best characterized bacterial
lectin involved in receptor-ligand interaction is mannose-specific type 1 fimbrial FimH adhesin. For
example, in uropathogenic E. coli (UPEC) mannose-specific adhesion is mediated by this lectin.[2] A
large number of α-D-mannopyranosides with aromatic aglycon moiety were found to bind with high
affinity to FimH and thus prevent agglutination of red blood cells. In our previous work we have
explored the inhibitory potential of α-mannosides with meta and para substituted N-aryl 3-hydroxy-
2-methylpyridin-4-ones as aglycon parts of a molecule.[3,4] The hemagglutination assays revealed
greater preference of FimH towards the para substituted pyridinone mannosides.
In this work we report the synthesis of novel para substituted
N-aryl 3-hydroxypyridin-4-ones without methyl group in
position 2 of the pyridinone ring (Figure). Their inhibitory
properties towards the adhesion of E. coli to quinea pig
erythrocytes will be evaluated using hemagglutination assay.
These results will be compared with inhibitory potencies of
analogous para derivatives of N-aryl 3-hydroxy-2-
methylpyridin-4-ones. Computational analysis complemented
experimental results by elucidating specific interactions within Figure: Structure of N-aryl
the FimH active site responsible for the binding and aided in substituted pyridinone
the interpretation of the observed binding trends. mannosides
Acknowledgements: This research is financially supported by Croatian Science Foundation

(project IP 2014-09-7899).
[1]
N. Sharon, Biochim. Biophys. Acta, 2006, 1760, 527.
[2]
N. Firon, S. Ashkenazi, D. Mirelman, I. Ofek, N.Sharon, Infect. Immun., 1987, 55, 472.
[3]
Ž. Car, T. Hrenar, V. Petrović Peroković, R. Ribić, M. Seničar, S. Tomić, Chem. Biol. Drug Des., 2014, 84,
393.
[4]
V. Petrović Peroković, R. Ribić, Ž. Car, S. Tomić, Croat. Chem. Acta, 2016, 89, 237.
119
P-44
ANTIBACTERIAL AND ANTIPROLIFERATIVE ACTIVITY OF NOVEL 2-

BENZIMIDAZOLYL AND 2-BENZOTHIAZOLYL SUBSTITUED
BENZO[B]THIENO-2-CARBOXAMIDES
Maja Cindrić,[a] Mihaela Perić,[b] Marijeta Kralj,[c] Irena Martin Kleiner,[c]

Hana Čipčić Paljetak,[b] Mario Matijašić,[b] Donatella Verbanac,[b]
Grace Karminski-Zamola[a] and Marijana Hranjec[a],*
[a] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of
Zagreb, Marulićev trg 20, 10000 Zagreb, Croatia
[b] Department for Intercellular Communication, University of Zagreb School of Medicine, Šalata 2,
[c] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb,
Croatia
* mhranjec@fkit.hr
Small heteroaromatic molecules, like nitrogen and sulphur-containing heterocycles play an

extremely important role in medicinal chemistry due to variety of their possible chemical,
pharmacological and industrial applications. These molecules are widely incorporated in the
structure of numerous natural or synthetic medical and biochemical molecules.[1] Benzimidazoles
and benzothiazoles, as one of the privileged sub-structures and an important bioactive heterocyclic
building block in medicinal chemistry, while benzothiophene skeleton is incorporated in the structure
of numerous therapeutic agents.[2]
Herein, we present the synthesis and biological evaluation of novel nitro and amino substituted 2-
benzimidazolyl and 2-benzothiazolyl benzo[b]thieno-2-carboxamides.[3] Antibacterial activity was
assessed against Gram-positive and Gram-negative bacteria and the highest antibacterial activity
was observed for the nitro and amino substituted benzimidazole derivatives with MICs in the range
of 2-8 µg/mL. Additionally, the tested compounds not displaying promising antibacterial activity were
further tested for the antiproliferative activity in vitro against three human cancer cell lines. The most
pronounced and selective antiproliferative activity against MCF-7 cell line was demonstrated by
amino substituted hydrochloride salt of benzothiazole derivative with an IC50 of 0.04 µM.
Cl
O
X
R1 S NH
N R2
5b R1 = NH3+Cl-; R2 = H X = NH antibacterial activity
5d R1 = H; R2 = NH3+Cl- X=S antiproliferative activity
Figure: Lead compounds for further optimization and biological evaluation.

[1]
R. B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Elsevier Academic Press, Second
Edition, 2004.
[2]
a) N. Perin, R. Nhili, M. Cindrić, B. Bertoša, D. Vušak I. Martin-Kleiner, W. Laine, G. Karminski-Zamola, M.
Kralj, M. H. David-Cordonnier, M. Hranjec, Eur. J. Med. Chem., 2016, 122, 530; b) L. Racane, R. Stojkovic, V.
Tralić-Kulenović, H. Cerić, M. Ðakovic, K. Ester, A. Misir Krpan, M. Radic Stojkovic, Eur. J. Med. Chem., 2014,
86, 406.
[3]
M. Aleksić, B. Bertoša, R. Nhili, S. Depauw, I. Martin-Kleiner, M.-H. David-Cordonnier, S. Tomić, M. Kralj,
G. Karminski-Zamola, Eur. J. Med. Chem., 2014, 71, 267.
120
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SYNTHESIS OF DIPEPTIDES CONTAINING PHOTOCHEMICALLY

REACTIVE MODIFIYED TYROSINE AND EVALUATION OF THEIR DNA
BINDING
Antonija Husak,* Josipa Matić, Ivo Piantanida and Nikola Basarić

Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000
Zagreb
* ahusak@irb.hr
Quinone methides (QMs) are recative intermediates with a potential in the development of new leads
for drugs owing to their reactivity with DNA, proteins and enzymes.[1] In particular, some anticancer
antibiotics such as mitomycine base their action on metabolic formation of QMs and subsequent
DNA cross-linking. Therefore, it is important to investigate different classes of simple QMs as
potential anticancer agents. However, QM are reactive intermediates with short inherent lifetimes,
so they have to be prepared in situ in the living cells. An excellent methodology for the generation of
QMs in the biological systems are photochemical reactions of deamination or dehydration.[2]
We have recently demonstrated that tyrosine derivatives can be modified into QM precursors and
imbedded in proteins where they remain photochemically reactive.[3] Furthermore, it is known that
photo-triggered DNA alkylation by QMs can be significantly enhanced by binding QM precursors to
the DNA intercallators.[4]. Here we present synthesis of dipeptides 1 and 2 that contain two unnatural
amino acids, photochemically reactive tyrosine derivative and amino acid bearing DNA intercalators-
phenanthridine[5] or pyrene.[6] Their non-colvalent and photo-triggered covalent DNA binding ability
will be investigated.
NMe2 NMe2
OH OH
O
O H
O H O N
N O O
N N
O O H
H O
O
1 2
[1]
S. E. Rokita, Quinone Methides, Wiley, 2009.
[2]
[3]
A. Husak, B. P. Noichl, T. Šumanovac Ramljak, M. Sohora, Đ. Škalamera, N. Budiša, N. Basarić, Org.
Biomol. Chem., 2016, 14, 10894.
[4]
W. F. Veldhuyzen, P. Pande, S. E. Rokita, J. Am. Chem. Soc., 2003, 125, 14005.
[5]
M. Dukši, D. Baretić, V. Čaplar, I. Piantanida, Eur. J. Med. Chem., 2010, 45, 2671.
[6]
M. Radić Stojković, P. Piotrowski, C. Schmuck, I. Piantanida, Org. Biomol. Chem., 2015, 13, 1629.
121
P-46
TARGETED DEGRADATION OF ANAPLASTIC LYMPHOMA KINASE

(ALK) BY APPLYING THE PROTEOLYSIS TARGETING CHIMERAS
(PROTAC)
Jong Yeon Hwang,* Chi-Hoon Park, Dong Ho Lee, Chung Hyo Kang,
Chong Ock Lee and Jae Du Ha
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600,
Republic of Korea
* jyhwang@krict.re.kr
Recently, a new and powerful technology called “proteolysis targeting chimeras" (PROTAC) has
been actively applied in the field of drug development. Treatment of PROTAC molecule, which
contains a ligand for the targeted protein, a ligand for E3 ubiquitin ligase binding, and a linker for
connection of two ligands, successfully induced targeted protein degradation, thereby inhibiting
cancer growth in in vivo animal model study.[1-3] Anaplastic lymphoma kinase (ALK) gene fused to
various partner genes are observed in 3–7% of non-small cell lung cancer (NSCLC) in humans. The
constitutively activated ALK fusions play an essential role in cancer growth and survival. In this study
we aimed to discover novel ALK target degraders (TDs) by applying PROTAC technology. LDK-378
(ceritinib) as an ALK ligand and VHL or CRBN as an E3 ubiquitin ligase were used. Hydroxyproline
analogs (HP-7) and pomalidomide were used for VHL and CRBN E3 ligase ligands, respectively. All
TDs synthesized in this study were evaluated in enzymatic- and cell-based assays. ALK degradation
by TDs were confirmed by western blotting in SU-DHL-1 cell lines. In vivo antitumor activities were
evaluated in xenograft mouse model with H3122 cell lines.
[1]
D. P. Bondeson, A. Mares, and C. M. Crews, Nat. Chem. Biol., 2015, 11, 611.
[2]
G. E. Winter, D. L. Buckley, J. Paulk, J. M. Roberts, A. Souza, S. Dhe-Paganon, J. E. Bradner, Science,
2015, 348, 1376.
[3]
A. C. Lai, C. M. Crews, Nat. Rev. Drug Discov., 2017, 16, 101.
122
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LIPOPHILICITY EVALUATION AND IN SILICO ADME-TOX STUDIES OF

SOME NOVEL THIOSEMICARBAZONE AND
1,3,4-THIADIAZOLINE DERIVATIVES
Ioana Ionuţ,* Gabriel Marc, Ovidiu Oniga and Brîndușa Tiperciuc

Pharmaceutical Chemistry Department, Iuliu Haţieganu University of Medicine and Pharmacy, 41 Victor
* ionut.ioana@umfcluj.ro
The lipophilic character of a substance is considered as a vital component of drug discovery and
development, because it influences basic steps of a drug pharmacokinetics and pharmacodynamics,
such as absorbtion, distribution, metabolism, excretion and toxicity (ADME-Tox).[1-5]
The lipophilicity of twenty compounds - derivatives of chromenyl-thiosemicarbazone (series 1) and
chromenyl-thiadiazolines (series 2) – has been determined by reversed-phase thin layer
chromatography, using i-propanol-water mixtures as eluents. These compounds were previously
reported for their antiproliferative[6] and antimicrobial activities.[7]
Principal component analysis (PCA) allowed an objective estimation of the retention behavior of the
tested compounds and also afforded to obtain a 2D scatterplot, described by the first two principal
components, which had the effect of separating the compounds from each other the most effectively.
With the use of clustering methods (K-means clustering) based on PCA data, the studied compounds
were finally grouped into two classes. Data analysis showed that, in general, thiosemicarbazones 1a-
j were more lipophilic compared to their corresponding thiadiazolines 2a-j. In both series, the
presence of a -CF3 group substantially increased the lipophilic character.
The compounds were also virtually screened for their ADME-Tox properties. The results obtained
showed good properties and good drug-likeness, all molecules being “accepted” after passing the
ADME-Tox rules.
Further optimization can be performed on these compounds, in order to achieve a better biological
activity and better ADME-Tox properties.
[1]
M. Janicka, M. Sztanke, K. Sztanke, J. Chromatogr. A., 2013, 1318, 92.
[2]
E. Rutkowska, K. Paja̧k, K. Jóźwiak, Acta Pol. Pharm. - Drug Res., 2013, 70, 3.
[3]
A. Toma, D. Hapău, D. Casoni, V. Zaharia, J. Chromatogr. Sci., 2014, 52,1302.
[4]
D. Casoni, A. Kot-Wasik, J. Namieśnik, C. Sârbu, J. Chromatogr. A., 2009, 1216, 2456.
[5]
D. Casoni, C. Sârbu, J. Sep. Sci., 2012, 35, 915.
[6]
I. Ionuţ, C. Nastasǎ, J.T. Ndongo, C. Bruyère, H. Leclercqz, B. Tiperciuc, F. Lefranc, A. Pîrnău, R. Kiss, O.
Oniga, Dig. J. Nanomater. Biostructures., 2013, 8, 1509.
[7]
I.Ionuț, D.C. Vodnar, I. Oniga, O. Oniga, B.Tiperciuc, R. Tamaian, Pakistan J. Pharm. Sci., 2016, 29, 261.
123
P-48
SYNTHESIS OF NOVEL RING STRUCTURES AS GABAA RECEPTOR

LIGANDS WITH FUNCTIONAL SELECTIVITY
Maria Teresa Iorio,[a] Laurin Wimmer,[a] Konstantina Bampali,[b] Margot Ernst[b] and
Marko Mihovilovic[a],*
[a] TU Wien, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060, Vienna, Austria
[b] Medical University of Vienna, Center for Brain Research, Spitalgasse 4, 1090, Vienna, Austria
The GABAA receptors are pentameric channel proteins with an high

subunit diversity. So far 19 subunits were identified: six α subunit, three
β, three γ, one δ, one ε, one θ, one π and three ρ subunits. The different
subunits can be combined in different ways to for the pentamer, but the
most accepted structure presents two α-, two β- and one γ- subunits.[1]
Upon the binding of two molecules of GABA to the receptor, the pore
opens and allows the influx of chloride ions. While the benzodiazepines
act as positive allosteric modulator via a binding site located at the α+γ-
interface in the extracellular domain of GABAA receptors, the 2 GABA
binding sites are located at the two β+α-.[2] Figure 1
The GABAA receptor is the target of many clinically relevant drugs such
as benzodiazepine, barbiturates and steroids for the treatment of anxiety, depression and epilepsy.
Eventhough, benzodiazepines are excellent anxiolytic drugs, they show sedative side effects and
due to their addictive properties they cannot be used in long term treatment. For this reason and in
order to develop tools for further studies of the GABAA receptor new compounds need to be
investigated.
Pyrazoloquinolinones were found to act as positive modulators at the α+β-
interface, maintaining a high affinity for the benzodiazepine binding site of the
receptor.
In order to gain selectivity for the binding site at the α+β- interface some
modifications of this scaffold are required. Therefore, a more stretched structure
needs to be synthesized which may interact better with the β subunit of the
receptor, giving as a result a loss in affinity for the binding site at the α+γ-
interface.[3]
Figure 2
For this purpose a series of indoles derivatives was
synthesized (Figure 3). These compounds might maintain the same binding
mode at the desired interface due to the analogy with the closed structure.
Some preliminary results showed that compounds like these have low affinity
for the benzodiazepine binding site, maintaining the modulation of the GABA
induced current in receptor containing α and β subunits. Due to their interesting
properties these compounds will be further investigated.
Figure 3
[1]
W. Sieghart, G. Sperk. Curr. Top. Med. Chem., 2002, 2, 795.
[2]
Z. Varagic, et al. British J. Pharmacol., 2013, 169, 371.
[3]
K.A. Wafford, B. Ebert, Curr. Opin. Pharm., 2006, 6, 30.
124
P-49
SYNTHESIS AND BIOLOGICAL EVALUATION OF CHALCONE

DERIVATIVES AS NEUROPROTECTIVE AGENTS FOR PARKINSON’S
DISEASE
Bo Ko Jang,[a] Ji Won Choi,[a,b] Jong-Hyun Park,[a] Seul Ki Yeon,[a,b] Si Won Kim,[a,c] Yerim
Lee,[a,d] Su Jeong Shin,[a,b] Hyeon Jeong Kim,[a,b] Hyeon Ji Kim,[a]
Yong Gu Kang,[a] Ae Nim Pae[a,d] and Ki Duk Park[a,c,d],*
[a] Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Institution,
Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu 02792, Seoul,
Republic of Korea
[b] Department of Biotechnology, Yonsei University, 50 Yonsei-ro Seodaemun-gu, Seoul, 03722,
Republic of Korea
[c] KHU-KIST Department of Conversing Science and Technology, Kyung Hee University, 26,
Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
[d] Department of Biological Chemistry, University of Science and Technology, Gajeong-ro,
Yuseonggu, Daejeon, 34113, Republic of Korea
* kdpark@kist.re.kr
Although the etiology of Parkinson’s disease (PD) is unclear, recent reported studies suggest that
oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration.
The Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative
stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing
expression of antioxidant enzyme genes. We have synthesized novel chalcone derivatives to
improve their Nrf2 activity and ADME/Tox profiles. Among the derivatives, compound KIST-389
showed significant efficacy for activating Nrf2 and excellent profiles in ADME/Tox tests. In addition,
compound KIST-389 effectively protected DAergic neurons and attenuated PD-associated
behavioral deficits in the MPTP-induced mouse model.
[1]
L.M. de Lau, M.M. Breteler, Lancet Neurol., 2006, 5, 525.
[2]
J.M. Han, Y.J. Lee, S.Y. Lee, E.M. Kim, Y. Moon, H.W. Kim, O. Hwang, J. Pharmacol. Exp. Ther., 2007,
321, 249.
[3]
J. Segura-Aguilar, I. Paris, P. Munoz, E. Ferrari, L. Zecca, F.A. Zucca, J. Neurochem., 2014, 129, 898.
[4]
S.H. Choi, D.Y. Lee, E.S. Chung, Y.B. Hong, S.U. Kim, B.K. Jin, J. Neurochem., 2005, 95, 1755.
[5]
Z.Q. Jia, H. Zhu, B.R. Misra, Y.B. Li, H.P. Misra, Neurochem. Res., 2008, 33, 2197.
[6]
I.M. Copple, C.E. Goldring, N.R. Kitteringham, B.K. Park, Toxicology, 2008, 246, 24.
[7]
K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, J.D. Engel, M. Yamamoto, Genes Dev., 1999, 13,
76.
125
P-50
SYNTHESIS, STRUCTURE-ACTIVITY RELATIONSHIPS, AND

MOLECULAR MODELING STUDIES OF NEW LONG-CHAIN
CHLOROARYLPIPERAZINES DERIVATIVES AS 5-HT7 AND 5-HT1A
RECEPTOR LIGANDS
Jolanta Jaśkowska,[a],* Paweł Śliwa,[a] Zbigniew Majka,[b] Anna K. Drabczyk,[a] Damian

Kułaga,[a] Magdalena Malinowska[a] and Grzegorz Satała[b]
[b] Adamed Ltd., Pieńkow 149, Czosnów 05-152, Poland
[c] Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12
Diversity in the variety of functions that serotonin plays in the human body is undoubtedly related to
the fact that serotonin receptors have a number of connections with other neurotransmitter systems.
However, the 5-HT1A receptors fulfill the key role because they are crucial in pathogenesis and
treatment of depression and anxiety.[1-3] The research conducted in recent years has proved that the
increased density of 5-HT7 receptors in limbic structure of CNS may be connected with the
occurrence of affective disorders.[4,5] Numerous findings in the literature prove that the active ligands
of 5-HT7 receptors can play a crucial therapeutic role in treating depression and insomnia.[6]
Based on our previous studies of structure activity relationships on N-hexyl-arylpiperazine
derivatives, in this work, we synthesized a new set of long-chain arylpiperazines in order to explain
whether certain structural modifications involving substitution of hydrogen in arylpiperazine by
chlorine may affect the binding affinity for the 5-HT7 receptors and 5-HT1A receptors. It is known that
hexyl-2-chloroarypiperazine shows high affinity for the 5-HT1A receptors 5-HT1A (Ki = 2.67 nM[7]),
therefore we have started the synthesis of ligands from a group containing this moiety. In the terminal
part of these ligands, we tested phtalimide and comparative amide fragment. All ligands were
prepared by a new synthetic reaction in the presence of microwave radiation. Analysis of results
from in vitro studies shows that the most active ligands for the 5-HT1A receptor in the group of hexyl-
phtalimides are ligands which have a substituent 2-chloroarylpiperazine group, and binding
decreases in a series of 2-chloro > 3-chloro > 4-chloro > 2,3-dichloro > 3,5-dichloro arylpiperazines.
However, the most active ligands for the 5-HT7 have 3-chloroarylpiperazine moieties. In the case of
conversion of the phtalimide on salicylamide moiety, we observed several-fold increase in the activity
of both 5-HT1A and 5-HT7. For the most active ligands, we also performed an assessment of the
bioactive conformation in the receptors binding site.
Acknowledgments:The study was financially supported by the National Centre for Research and
[1]
A. P. Front, Neurosci., 2010, 4, 35.
[2]
J. W. Richardson-Jones, Neuron, 2010, 65, 40.
[3]
M. Boldrini, Psychiatr. Res., 2008, 42, 433.
[4]
P.B. Hedlund, Trends Pharmacol. Sci., 2004, 25, 481.
[5]
D.R. Thomas, Curr. Drug Targets CNS Neurol. Disord., 2004, 3, 81.
[6]
A.J. Bojarski, Postępy Polskiej Medycyny i Farmacji 2012, 2, 61.
[7]
K. Tokarski, Postepy Hig. Med. Dosw., 2014, 68, 1104.
[8]
J.L. Mokrosz, J. Med. Chem., 1992, 35, 2369.
126
P-51
NEW METHODS FOR SYNTHESIS OF THE TRAZODONE

ANTIDEPRESSANT
Przemysław Zaręba,[a] Jolanta Jaśkowska[a],* and Zbigniew Majka[b]
[b] Adamed Ltd., Pieńkow 149, Czosnów 05-152, Poland
HN N
N Cl[CH 2 ] 3Br N Cl N
NH N [CH 2 ] 3 Cl N [CH 2 ]3 N N
N N N
Cl
O O O
1 2 3 4 5
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is
a LCAP (Long Chains Arylpiperazine) compound. It acts as an antagonist of serotonin receptors 5-
HT2. In the 1980’s, trazodone was the most frequently applied antidepressant in the United States.[1]
Later, it was superseded by selective serotonin reuptake inhibitors (SSRI). Today we see growing
interest in SARI, including trazodone. It led to search for new, more efficient and faster synthesis
methods.[2]
The aim of the research was to develop the most advantageous method for synthesis of trazodone
(5). 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (1) was the substrate, which was subjected to N-alkylation
of 1-bromo-3-chloropropane (2) in the presence of potassium carbonate and TBAB
(Tetrabutylammonium bromide) as a PTC (Phase Transfer Catalyst). The reaction was carried out
under conventional conditions, in the presence of microwave irradiation (MW) or in the presence of
ultrasound ( ))) ). The influence of different factors was examined: used solvent, its amount, or the
type of glass in which the reactions were carried out, and their impact on the reaction performance.
In the next step, 2-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridine-3(2H)-one (3) was condensed with
1-(3-chlorophenyl)piperazine (4) to give the product (5) under conventional conditions, in the
presence of microwave irradiation (MW), ultrasound ( ))) ) and in tribochemistry variant, with
changing the type and amount of used solvent. The study showed that in both stages of carrying out
the reaction in the presence of MW or ))), they can significantly reduce the reaction time (45 sec in
MW, 40min in )))) ) compared to the synthesis in conventional conditions, where reaction takes a
few hours.[1,3,4] Moreover, these methods reduce the amount of used solvents, which is consistent
with the principles of green chemistry. The described methods were also used for the preparation of
trazodone derivatives with altered chain length and the revised arylpiperazine. The reaction progress
was monitored using TLC (thin layer chromatography). The purity of the resulting products were
analyzed using UPLC-MS and the received calls, and the structure was confirmed using 1H NMR
and IR.
[1]
L. Baiocchi, M. Giannangeli, Boll Chim Farm., 1974, 113, 152.
[2]
M. Jarema, D. Dudek, Psychiatria Polska, 2011, 750, 611.
[3]
T.G. Gant, S. Sarshar, US2009/209550 Auspex Pharmaceuticals Inc., 2009.
[4]
G. Palazzo, B. Silvestrini, US3381009, 1968.
127
P-52
PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS NOVEL POTENT

ANTI-INFLAMMATORY AGENTS
Hui Rak Jeong,[a] Sun Yeung Kim[a] and Jae Yeol Lee[a],*
[a] Department, Institution, Address Research Institute for Basic Sciences and Department of Chemistry,
College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea
* ljy@khu.ac.kr
A novel series of phenylsulfonyl hydrazide derivatives were found to reduce LPS-induced PGE2
levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. Recently,
regioisomeric mixture of phenylsulfonyl hydrazide was formed depending on the reaction conditions.
One regioisomer corresponds to a kinetic product (7a-c) and the other regioisomer corresponds to
a thermodynamic product (8a-c). Among them, the structure of kinetic product 7b was confirmed by
measuring single X-ray crystallography. In vitro PGE2 assay studies showed that the kinetic product
(7a and 7b; IC50 = 0.69 and 0.55 μM against PGE2) is generally more potent than the thermodynamic
product (8a and 8b; IC50 = > 10 and 0.79 μM against PGE2). A molecular docking study also exhibited
that the kinetic product (7a) has a higher MolDock Score (-147.4) than that of 8a (-142.4), which is
consistent with the PGE2 assay results. In vivo test was also carried out in two experimental edema
models of rat, and the results clearly show that 7d has anti-inflammatory effects. A new potent
phenylsulfonyl hydrazide (7d; IC50 = 0.06 μM against PGE2) without affecting COX-1 and COX-2
enzyme activities was identified based on these overall results.
128
P-53
DESIGN, SYNTHESIS AND EVALUATION OF INDOLE DERIVATIVES AS

MULTIFUNCTIONAL AGENTS AGAINST ALZHEIMER’S DISEASE
Jacques Joubert, Ireen Denya and Sarel F. Malan

Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Bellville, South Africa
Alzheimer’s disease (AD) is one of many diseases that can be classified as a neurodegenerative
disorder and is ranked as the leading cause of death among the elderly. The pathology of AD and
other neurodegenerative disorders involves multiple steps leading to neuronal cell death. Current
treatment options include cholinesterase- and monoamine oxidase-B inhibitors, calcium channel
blockers and NMDA receptor antagonists. These treatment options, however, only alleviate the
symptoms of these disorders and are devoid of any neuroprotective and/or neurorestorative
properties that are needed for disease modifying effect. The result is a shift in research towards the
design and discovery of multi-target compounds. This study is thus based on this one-drug-multiple-
target paradigm and aims to produce a new series of indole derivatives with multifunctional activities.
We hypothesize that these compounds will serve as dual cholinesterase and monoamine oxidase
inhibitors and possess superior activity compared to existing anti-Alzheimer’s drugs.
The novel indole derivatives were synthesized by means of nucleophilic substitution reactions.
Structural elucidation was carried out using analytical techniques such as NMR, MS, and IR.
Biological activity on MAO-A and MAO-B, acetyl- and butyrylcholinesterase enzymes were assessed
and IC50 values were calculated.
All compounds were successfully synthesized and confirmed. MAO-A and B inhibitory activities were
tested at various concentrations with clorgyline and rasagiline as reference compounds. All the
compounds showed satisfactory inhibition of both enzymes with some compounds showing low
micromolar inhibitory activities. The compounds also showed promising cholinesterase inhibition
sub-micromolar ranges.
AD poses an enormous socio-economic burden on society and it is critical that research identifies
compounds that are able to slow down or halt the progression of AD. This study identified novel
multifunctional agents with potential neuroprotective properties that may be considered as new lead
compounds/drug candidates against AD.
129
P-54
3,4-DIHYDROQUINAZOLINE DERIVATIVES AS NOVEL AND SELECTIVE

BUTYRYLCHOLINESTERASE INHIBITORS
Da Woon Jung, Jin Han Kim, Hong Bin Yoon and Jae Yeol Lee*
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee
University, Seoul 02447, Republic of Korea
* ljy@khu.ac.kr
A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our

chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their
inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase
(BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak
AChE and strong BuChE inhibitory activities. In particular, compound KYS05080F and KYS05090S
were the most active compounds in the series against BChE with IC50 values of 45 nM and 62 nM,
as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity
of these compounds, molecular docking simulations were performed to get better insights into the
mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound KYS05080F
and KYS05090S bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with
better interaction energy values than AChE, in agreement with our experimental data. Furthermore,
the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding
nature in kinetic studies.
130
P-55
HIGH-THROUGHPUT SCREENING FOR DIPEPTIDYL PEPTIDASE

III-INTERACTING PROTEINS
Snježana Jurić,[a] Katarzyna Kliza,[b] Koraljka Husnjak[b] and Mihaela Matovina[a],*

[a] Ruđer Bošković Institute, Zagreb, Croatia
[b] Goethe University School of Medicine, Institute of Biochemistry II, Frankfurt a/M, Germany
* Mihaela.Matovina@irb.hr
Dipeptidyl peptidase III (DPP III), the ubiquitously expressed member of the M49 family of
metallopeptidases, cleaves dipeptides from the N-termini of 3 to 10 residues long peptides. Over the
last decades, DPP III was primarily investigated at the biochemical and enzymatic levels, while its
physiological roles remained largely unknown. Recent advances in DPP III research showed that
direct binding of DPP III to Keap1 induces translocation of the transcription factor NRF2 from cytosol
into the nucleus, thus initiating the transcription of oxidative stress protective genes. The possibility
that DPP III interacts with other proteins in a similar fashion prompted us to investigate the DPP III
interactome by using two high-throughput screening methods. Yeast two-hybrid screening of the
universal standardized human cDNA library was set up to identify direct interactors of DPP III,
whereas the SILAC-based immunoprecipitation of DPP III coupled to MS analysis was envisioned
to identify the DPP III-containing protein complexes in the cell. We aim to discover the novel DPP III
protein interactors and to confirm these interactions by several complementary approaches, such as
pull-down assays and confocal microscopy techniques. Once confirmed, novel interactors might
open new directions in the investigation of the DPP III physiological roles in the future.
131
P-56
IN VITRO, IN VIVO AND MOLECULAR MODELING STUDIES OF N-(3-{4-

[3-(TRIFLUOROMETHYL)PHENYL]PIPERAZIN-1-YL}PROPYL)-1H-
INDAZOLE-3-CARBOXAMIDE (D2AAK3) AS A POTENTIAL
ANTIPSYCHOTIC
Agnieszka A. Kaczor,[a,b],* Katarzyna M. Targowska-Duda,[c] Marta Kruk-Słomka,[d] Andrea

G. Silva,[e] Peter Kolb,[f] Antti Poso,[b] Grażyna Biała[d] and Marian Castro[e]
[a] Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer
Modeling Lab, Faculty of Pharmacy with Division for Medical Analytics, 4A Chodźki St., PL-20059
Lublin, Poland
[b] School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211
Kuopio, Finland
[c] Department of Biopharmacy, Faculty of Pharmacy with Division of Medical Analytics, Medical
University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland
[d] Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of
Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland
[e] Department of Pharmacology, Universidade de Santiago de Compostela, Center for Research in
Molecular Medicine and Chronic Diseases (CIMUS), Avda de Barcelona, E-15782 Santiago de
Compostela, Spain
[f] Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, DE
35032 Marburg, Germany
* agnieszka.kaczor@umlub.pl
Antipsychotics currently available to treat schizophrenia suffer several limitations: (1) they are
efficient against positive but not negative and cognitive symptoms of the disease; (2) they help only
a half of patients; (3) they have severe side effects including neurological and metabolic side effects.
Thus, novel drugs to treat schizophrenia are highly demanded. We identified a novel dopamine D2
receptor antagonist, D2AAK3, with Ki of 115 nM using structure-based virtual screening. D2AAK3
possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7
receptors, making it an ideal candidate for a multi-target drug. The compound has also some affinity
to M1 and H1 receptors. Here we present homology modeling, molecular docking and molecular
dynamics of D2AAK3 and its molecular targets and animal studies of D2AAK3 as a potential
antipsychotic. The main contact of D2AAK3 and all the receptors studied is the electrostatic
interaction between the protonatable nitrogen atom of the ligand and the conserved Asp(3.32) as
typical for orthosteric ligands of aminergic GPCRs. We confirmed antagonistic/partial
agonistic/agonistic properties of D2AAK3 towards the receptors in in vitro assays and in in silico
studies as the ligand affects the ionic lock interaction. D2AAK3 decreases amphetamine-induced
hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous
locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves
memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3
induces anxiogenic activity 30 minutes after acute treatment, whereas this effect is reversed 60
minutes after administration of the studied compound in mice.
132
P-57
DIRECT PHOSPHONYLATION OF HETEROAROMATIC COMPOUNDS AS

A MEAN TO SYNTHESIZE CYTOTOXIC AGENTS
Ewa Chmielewska,[a] Monika Prokopowicz,[a] Natalia Wojtowicz,[a] Joanna Wietrzyk,[b] Piotr

Młynarz[a] and Paweł Kafarski[a],*
[a] Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and
Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
[b] Laboratory of Experimental Anticancer Therapy, Institute of Immunology and Experimental Therapy,
ul. Rudolfa Weigla 12, 53-114 Wroclaw, Poland
* pawel.kafarski@pwr.edu.pl
The well-documented biological importance of heterocylic phosphonates has stimulated intensive

efforts directed toward methods of their preparation.[1] Numerous studies have indicated that it is a
challenging task, and quite frequently, yields of the applied procedures are moderate or even low.[2]
In most cases the electron rich aromatic heterocycles easily undergo lithation in position 2 when
alkyllithium was used. The formed salts are important intermediates in synthesis of many groups of
organic compounds.[3]
In this paper we describe elaboration of simple and almost one-pot procedure for the synthesis of
heteroaromatic phosphonates by simple phosphonylation of lithium salts of corresponding
heterocycles. A good example is procedure elaborated for lithiation of benzothiophene followed by
diethyl chlorophosphite followed by oxidation of the resulting phosphinate (Figure 1).
Figure 1: Reaction of lithium benzothiophene with diethyl chlorophosphite
This reaction is of a general value and has been applied to a series of aromatic heterocycles.
However, in some cases modification of this general procedure is required. This is well illustrated by
phosphonylation of indole, which require specific protection of its amino moiety (Figure 2).
Unfortunately hydrolysis of this product caused its decomposition.
Figure 2: Phosphonylation of indole
The obtained heteroaromatic phosphonates influence of proliferation of two cancer cell lines: of
human breast cancer MCF-7 and of prostate cancer PC-3.
[1]
K. Moonen, I. Laureyn, C. V. Stevens, Chem. Rev., 2004, 104, 6177.
[2]
S. Van der Jeught, C. Stevens, Chem. Rev., 2009, 109, 2672.
[3]
V. H. Gessner, C. Dächslein, C. Strohman, Chem. Eur. J., 2009, 15, 3320.
133
P-58
EVALUATION OF ANTIMYCOBACTERIAL ACTIVITY FOR A RANGE OF

POLYCYCLIC AMANTADINE AND PENTACYCLOUNDECANE
DERIVATIVES
Erika Kapp,[a] Jacques Joubert,[a] Samantha L. Sampson,[b] Margaretha de Vos[b] and Sarel
F. Malan[a],*
[a] School of Pharmacy, Faculty of Natural Sciences, University of the Western Cape, Cape
Town, South Africa
[b] Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health
Sciences, University of Stellenbosch, Cape Town, South Africa
* sfmalan@uwc.ac.za
Ever-increasing levels of drug resistance in Mycobacterium tuberculosis necessitate novel

approaches in the design of new antimycobacterials as well as the utilization of available treatment
options. As part of a research project to evaluate modulating drug resistance in M. tuberculosis
through strategies to increase intracellular accumulation of antimycobacterials, a range of
compounds were selected from our compound library to be evaluated as possible efflux pump
inhibitors in M. tuberculosis.
The first phase of the research project was to determine the baseline antimycobacterial activity of
the selected polycyclic amantadine and pentacycloundecane derivatives. A number of the
compounds demonstrated significant antimycobacterial activity. This report describes the analysis
of the antimycobacterial activity for the range of compounds with a preliminary investigation into
possible mechanisms of action for the active molecules.
Compounds were primarily selected based on their ability to inhibit voltage gated calcium channels
and N-Methyl-D-Aspartate (NMDA) receptor channels as well as the recurrence of selected
functional groups within the two classes. Consideration of previous data on resistance reversal in
malaria was also factored into the selection. The structures of the selected compounds generally
consisted of a cage moiety (oxa / aza-pentacycloundecane or adamantane) linked to an aromatic
moiety (derivatives of benzyl, nitrobenzyl dansyl, quinoline, aniline and isoindole moieties) via
various linkers.
The 16 selected compounds were initially screened using the attenuated M. tuberculosis H37Rv
leuD panCD strain (SAMMtb). SAMMtb was transformed with the fluorescent marker pCHERRY3
(Addgene). Mycobacterial growth was assessed over the course of 5 days through fluorescence
measurement. Antimycobacterial activity was confirmed employing the same assay method in the
standard laboratory strain, M. tuberculosis H37Rv.
Good correlation was observed between levels of activity measured in SAMMTb and H37Rv. Repeat
analyses were completed for the six most active compounds. Minimum inhibitory concentrations
(MIC99) for all 16 compounds were determined independently and also showed good correlation to
levels of activity observed in fluorescent assays.
Six of the polycyclic compounds screened showed significant antimycobacterial activity (MIC99
ranging from 9.6 µM to 82.2 µM). Interestingly, during MIC determination only one compound, a
benzyl-azapentacycloundecane, showed prominent activity in media where glycerol is the primary
carbon source (Gaste Fe), whereas significant activity for the quinoline derivative was limited to
standard 7H9 glucose rich media. The dansyl, 2,4-dintroaniline and cyanoisoindole structures
showed comparable MIC values in both rich and poor media.
Results confirm that SAMMtb is an appropriate model to identify compounds with possible activity
against M. tuberculosis and point towards different mechanisms of antimycobacterial action, likely
linked to the side chains of the compounds rather than the lipophilic scaffold.
134
P-59
DEVELOPMENT OF A DISINFECTANT PRODUCT CONTAINING THE

ESSENTIAL OIL EXTRACTED FROM ROSMARINUS OFFICINALIS L.
Fetta Kessal,[a],* Amina Dahmoune,[b] Amina Azzam,[c] Boumrar Silia[d] and

Boualem Samia[d]
[a] Laboratory of pharmaceutical industry, University Mouloud Mammeri of Tizi Ouzou, Algeria
[b] Botanical Laboratory, University Mouloud Mammeri of Tizi Ouzou, Algeria
[c] Laboratory of microbiology, University Mouloud Mammeri of Tizi Ouzou, CHU Nedir Mohamed
Algeria
[d] Department of pharmacy, University Mouloud Mammeri of Tizi Ouzou, Algeria.
* kessalfetta@yahoo.fr
Background and aim: Algeria, for its location, offers a rich and diverse vegetation. A big number of
aromatic plants grow spontaneously. To this end, and as part of the valorization of the Algerian flora,
we became interested in Rosemary (Rosmarinus officinalis L.) because of its wide availability at the
University Mouloud Mammeri but especially of the antimicrobial effect of essential oil proved
particularly against germs of mostly hand-transmitted infections. In the present study, an attempt
was made to formulate a gel for hands’ hygiene in hospital, containing Rosmarinus officinalis L.
essential oil and was evaluated for its antimicrobial activity.
Methods: The Rosemary essential oil is extracted by hydrodistillation from its leaves with a yield of
1.45%. In parallel, a pharmaceutical gel was formulated and optimized basing on the results of the
effected controls like pH, density, microbiological quality, skin irritation test and spreadability. The
essential oil was analyzed by GC/MS then introduced into a gel which will be evaluated
microbiologically.
Results: The hydrodistillation gives a yield of 1.45%. GC/MS has shown a chemotype
verbenone/camphor/α-pinene and has identified 65 components representing 97.86% of the
essential oil. The evaluation of its antimicrobial activity has revealed a sensitivity of
Staphylocococcus aureus, Enterococcus faecalis, Escherichia coli, Acinetobacter baumanii and
Candida albicans, while Pseudomonas aeruginosa was resistant to this oil. The CMI (Inhibiting
Microbial Concentration) were between 0.5% (v/v) and 1% (v/v), and the MBC (Microbial Bactericide
Concentration) were ≥ 1% (v/v).
The essential oil was incorporated at a concentration of 2%. The last step of our work will be to
assess in vitro antimicrobial activity gel formulated with essential oil of Rosemary against the same
pathogens.
Conclusion: The gel showed promising antibacterial and antifungal activity against studied germs.
Keywords: Essential oil, Rosemary, disinfectant gel, hands’ hygiene, antimicrobial activity.
[1]
T. Lograda, M. Ramdani, P. Chalard, G. Figueredo, Global J. Res. Med. Plants & Indigen. Med., 2014,
3(6), 232.
[2]
N. Bousbia, Extraction des huiles essentielles riches en anti-oxydants à partir de produits naturels et de
co-produits agroalimentaires. El Harrach: Ecole Nationale Supérieure Agronomique; Aix-Marseille :
Université d’Avignon; 2011.
[3]
Z. Faixova, S. Faix, Folia vet., 2008, 52, 135.
[4]
A. Pandey, J.V. Jagtap, S.A. Polshettiwar, Int. J. Pharm. Pharm. Sci., 2011, 3, 234.
135
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DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF D-RING

OPENED 17-β ESTRADIOL ANALOGUES AS ESTROGEN RECEPTOR
SUBTYPE-SELECTIVE LIGANDS
Sun Young Lee,[a] Yun Seon Song,[a] Minsun Chang[b]

and Hee-Doo Kim[a],*
[a] College of Pharmacy, Sookmyung Women’s University, Yongsan-Ku, Seoul, 04310, Korea
[b] Division of Biological Science, Sookmyung Women’s University, Seoul, 04310, Korea
* hdkim@sm.ac.kr
Since the discovery of the estrogen receptor subtype beta (ER beta), the search for subtype selective
estrogen receptor modulators (SERMs) has attracted attention in an attempt to achieve an
advantage over non-subtype selective SERMs.[1] ER subtype-selective ligands could be valuable to
manage various pathological conditions such as cancer, neuropathies, cardiovascular disease,
osteoporosis, and metabolic disorders.[2] Although the ligand binding domains of ER alpha and ER
beta share only modest homology (58% identity), their ligand binding cavities are highly conserved,
differing by only two amino acid residues.[3] While this slight difference in the binding cavities poses
a great challenge in developing ER subtype-selective ligands, medicinal chemistry efforts in recent
years have yielded a number of structural motifs with impressive subtype selective SERMs.[4]
As a part of our program to develop novel subtype-selective SERMs, we present here the ER
subtype-selective ligands with a novel oxime scaffold that resembles 17 beta-estradiol (E2), but with
the D-ring opened. Because scaffold hopping is one of the important approaches in discovering
structurally new compounds by starting from known compounds, we planned to deconstruct the D-
ring of E2 to make it jump into different chemical space of E2-related ER ligands. We also envisioned
that conformational flexibility resulting from the D-ring opening might enhance the ligand’s ability to
recognize the slight difference in the binding cavities between the two receptors subtypes. The
biological activities and the selectivity for the receptor subtype of new oxime analogues as well as
their prototype D-ring opened E2 analogue have been studied by radioligand competitive binding
assay and cell-based transcription assays.
In summary, our approach is successful to generate the novel and promising scaffold with
subnanomolar concentrations range of EC50 and higher subtype-selectivity than E2 and we propose
that they may serve the lead structure to develop subtype-selective ER ligands useful in treating ER
and/or estrogen-associated diseases.
[1]
S. Mosselman, J. Polman, R. Dijkema, FEBS Lett., 1996, 392, 49.
[2]
G. G. Kuiper, J. A. Gustafsson, FEBS Lett., 1997, 410, 87.
[3]
A. C. Pike, A. M. Brzozowski, R. E. Hubbard, T. Bonn, A. G. Thorsell, O. Engstrom, J. Ljunggren, J. A.
Gustafsson, and M. Carlquist, EMBO J., 1999, 18, 4608.
[4]
G. H. Veeneman, Curr. Med. Chem., 2005, 12, 1077.
136
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SYNERGISTIC ANTICANCER EFFECT OF T-TYPE CALCIUM CHANNEL

BLOCKER AND CHEMOTHERAPEUTIC AGENTS IN HUMAN LUNG
CANCER
Jin Han Kim, Hong Bin Yoon, Da Woon Jung and Jae Yeol Lee*
* ljy@khu.ac.kr
We synthesized new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F and

evaluated for T-type calcium channel inhibitory activity, cytotoxicity, and cell cycle arrest against
human lung cancer (A549) cells. KCP10043F showed both weaker T-type Ca2+ channel inhibitory
activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4-
(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N’,N’-trimethyl-1,5-pentanediamino)-3,4-
dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S
in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase
(CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27KIP1 as
a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2,
CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of
KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a
synergistic cell death (combination index = 0.2–0.8) via the induction of apoptosis compared with
either agent alone. Taken together with these overall results and the favorable in vitro ADME
(absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be
used as a potential agent for the combination therapy on human lung cancer.
Figure: Structures of T-type Ca2+ channel inhibitor and chemotherapeutic drug.
137
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DISCOVERY OF PHENYLSULFONYL HYDRAZIDE DERIVATIVES AS

NOVEL AND SELECTIVE mPGES-1 INHIBITORS
Sun Young Kim, Hui Rak Jeong and Jae Yeol Lee*
* ljy@khu.ac.kr
A novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high
throughput screening hit compound 1 (IC50 = 5700 nM against PGE2 production), for a potent
inhibitor of mPGES-1 is described. Compound 8n turned out to be most potent lead compound
with IC50 value of 4.5 nM and 6.9 nM , respectively, against LPS-1 induced PGE2 and NO
production in RAW 264.6 macrophage cells. In addition, 8n was about 30- and > 150-fold more
potent against mPGES-1 enzyme in a cell-free assay (IC50 = 70 nM) than MK-886 and hit
compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2
production by blocking the PGH2 binding site of human mPGES-1 enzyme.
138
P-63
RUTHENIUM-BASED CATALYSTS FOR ASYMMETRIC TRANSFER

HYDROGENATION
Andrea Kišić,[a] Michel Stephan,[b] Barbara Mohar,[a],* Andrej Emanuel Cotman[a] and
Dominique Cahard[c]
[a] National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
[b] PhosPhoenix SARL, 115, rue de l’Abbé Groult, 75015 Paris, France
[c] Université de Rouen, F-76821 Mont Saint Aignan, France
* barbara.mohar@ki.si
The importance of asymmetry in medicinal chemistry can be understood when we know that 80% of
all pharmaceuticals on the market (2006) are chiral molecules among which 75% are single
enantiomers. Many biologically active compounds or organic building-blocks used by the
pharmaceutical industry consist of chiral secondary alcohols wherein the stereogenic carbon bears
a hydrogen atom and a hydroxyl group. A convenient asymmetric chemical transformation for
obtaining chiral secondary alcohols is the enantioselective reduction of their corresponding prochiral
ketones which are widely available or easy to synthesize. Such reduction can be catalytically
performed by the use of metal complexes of enantiopure organic ligand molecules.
ansa-Ru(II) complex wherein the 6-arene is alkylene-tethered to R2NSO2DPEN from the N'-terminal
(Figure 1), and their asymmetric transfer hydrogenation (ATH) results against various types of
prostereogenic aryl ketones is presented (Figure 2).[1,2]
Me
N (CH2)n SO2NR2
O2S Ph N H
Ph N R'
Rn Ru
Ru NR2 = NMe2, N
N Ph N
Ph Cl n = 2, 3 n = 3, 4
H2 H n
R n = H, Me, iPr R' = H, Me, iPr
ansa-Ru(II) complex I ansa-Ru(II) complex II
Figure 1: Ansa-ruthenium(II) complexes of multidentate ligands.
Figure 2: Various classes of aryl ketones and stereoarrayed CF3-substituted 1,3-diols evaluated in Ru(II)
catalyzed ATH.
[1]
A. Kišić, M. Stephan, B. Mohar, Adv. Synth. Catal., 2015, 357, 2540.
[2]
A. E. Cotman, D. Cahard, B. Mohar, Angew. Chem. Int. Ed., 2016, 55, 5294.
139
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THE PREPARATION OF THE FOUR STEREOISOMERS OF 16-

HYDROXYMETHYL-13-EPI-ESTRA-1,3,5(10)-TRIEN-17-OL-3-METHYL-,
AND 3-BENZYLETHERS
Anita Kiss,* János Wölfling and Gyula Schneider

Department of Organic Chemistry, University of Szeged, Dóm tér 8., Szeged, Hungary, H-6720
* kissa@chem.u-szeged.hu
In connection with our earlier investigations,[1,2] we are interested in compounds with an inverted
configuration at C-13, i.e. derivatives of 16-hydroxymethyl-13-epi-estra-1,3,5(10)-trien-17-one-3-
methyl, and 3-benzylether containing a cis junction of rings C and D. The natural estrone and its
derivatives have hormonal effect, which could be a disadvantage during the development of new
anticancer drug candidates, while the epi-estrone and its derivatives show no estrogen properties at
all.
Treatment of 2 and 4 with sodium methoxide and ethyl formate on Claisen condensation gave 5 and
6. The formyl compounds 5a and 6a were reduced with potassium borohydride in methanol to give
7a, 8a and 9a, 10a, respectively. Two new chiral centers were formed in this reaction, but only the
two trans isomers of the possible four isomers could be obtained, in 6:1 ratio. After selective
acetylation and Jones oxidation of the separated isomers resulted the 16α-hydroxymethyl-17-keto-,
and the 16β-hydroxymethyl-17-keto compounds (11, 12 and 13, 14). The Luche reduction of 11 and
13 gave the 16-hydroxymethyl-17α -hydroxy isomers 15 and 17. The reduction of 12 and 14 with
potassium borohydride in methanol resulted the 16β-hydroxymethyl-17β-hydroxy isomers (16 and
18).
For confirmation of the configurations assumed for 15, 17 and 16, 18 transformation were carried
out with the individual isomers. The O O O OR2
isomers resulted the corresponding
H H H
16-bromo-, and 16-iodomethyl
H H H H H H
derivatives in Appel reaction. On R1O R1O R1O
5, 6 R2
alkaline methanolysis of 19a,b; 21a,b 1 R1=Me
1
2 R =Me
1
5 R1=Me a H
3 R1=Bn 4 R =Bn 6 R1=Bn
and 20a,b; 22a,b the β oxetanes 23, b Ac
25 and 24, 26 condensed to the D-ring OH OAc OH OAc O OAc O OAc
in the sterane were formed. The +

process can be regarded as a 6:1 H H H
H
neighbouring group participation 7 R1=Me 8 R1=Me 11 R1=Me 12 R1=Me
10 R1=Bn 13 R1=Bn 14 R1=Bn
characterized by the general symbol 9 R1=Bn
(O – 4). Despite to the trans isomers 7, 8, 9, 10 R2 R3

a H H OR3 OR2 OR3 OR2
(7a-10a), the cis isomers gave the b Ac H
c Ac Ac
corresponding acetonides (15c-18c) H H
and phenylboronate esters (15d-18d) 15, 16, 17, 18 2

R R 3 H H H H
a R1O R1O
too. The investigations of b
H H
Ac Ac 15 R1=Me 16 R1=Me
antiproliferative activites of the H C CH 17 R 1
=Bn 18 R1=Bn
c 3 3
C
structurally related compounds are in Ph
O O
progress. d B
CH2 1 CH2
23 R1=Me 24 R =Me
19, 20, 21, 22 X = R2, R3 = H 25 R1=Bn 26 R1=Bn
a Br H H
b I
[1]
E. Mernyák, J. Wölfling, G. Bunkóczi, L. Luo, T. R. Schneider, Gy. Schneider, Chech. Chem. Comm., 2003,
68, 1141.
[2]
J. Wölfling, E. Mernyák, É. Frank, G. Falkay, Á. Márki, R. Minorics, Gy. Schneider, Steroids, 2003, 68, 277.
140
P-65
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF CXCR3 AND

CXCR4 MODULATORS WITH PYRAZOLOPYRIDINE SCAFFOLD
Anja Kolarič,[a,b] Urban Švajger,[c] Tihomir Tomašič,[b] Nikola Minovski,[a]

Nuška Tschammer[d] and Marko Anderluh[b]
[a] Department of Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana,
Slovenia
[b] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva
7, 1000 Ljubljana, Slovenia
[c] Blood Transfusion Center of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia
[d] Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich
Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
* marko.anderluh@ffa.uni-lj.si
The overexpression of chemokine receptors CXCR3 and CXCR4 was linked to severe diseases
such as inflammation, autoimmune diseases, transplant rejection, cancer and HIV.[1] These
receptors are found to be natural allosteric proteins, where small molecule modulators can modify
the binding and function of chemokines.[2] Based on the previously published dual negative allosteric
modulator of chemokine receptors CXCR3 and CXCR4 (Figure),[3] we designed, synthesized and
biologically characterized a set of novel negative allosteric modulators with preserved
pyrazolopyridine scaffold, connected with lipophilic moiety of the molecule through three different
linkers. The ability of negative modulation has been evaluated by three biological assays (β-arrestin
2 recruitment assay, BRET-based cAMP assay and the transwell migration assay) on both
chemokine receptors. We have successfully identified dual binders (27), as well as compounds
selective for either one of the receptors (Figure), able to negatively modify chemokine-mediated
signaling. Furthermore, initial structure-based calculations were performed in order to predict binding
mode and identify crucial interactions for establishment of structure-activity relationship, which will
help in the on-going drug discovery research of chemokine receptor small molecules.
Figure: Formula of previously published dual negative CXCR3 and CXCR4 allosteric modulator with
structure fragmented into 3 building blocks that constitute a focused library of novel pyrazolopyridine CXCR3
and CXCR4 modulators.
[1]
F. Balkwill, Nat. Rev. Cancer, 2004, 4, 540.
[2]
D. Wootten, A. Christopoulos, P. M. Sexton, Nat. Rev. Drug Discov., 2013, 12, 630.
[3]
D. Schmidt, V. Bernat, R. Brox, N. Tschammer, P. Kolb, ACS Chem. Biol., 2014, 10, 715.
141
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CHEMICAL PROTEOMICS IN THE EVALUATION OF THE EGFRI

LAPATINIB PHARMACOLOGY
Tatjana Kovačević,* Krunoslav Nujić and Milan Mesić

Fidelta Ltd. Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia
* tatjana.kovacevic@glpg.com
Understanding drug interaction with a biological target and the mechanism of action is important in
modern drug discovery. However, testing all unknown-targets is challenging as either target
prediction is poor or vast off-target screening campaigns are expensive.
This work is focused on the identification of potential anti/off-targets of lapatinib, inhibitor of EGFR
and ErbB2.[1,2] In this chemical proteomics approach lapatinib was modified with specific tags that
can be used for identification of proteins in cell lysate.[3]
Scheme 1: Proposed tagged analogue of an EGFRi based on protein-ligand x-ray structure.
The poster will show analogues of lapatinib with various linkers and functionalities (amino group,
click chemistry motifs and finally the dual tags with photoaffinity labelling group) that were prepared
(Scheme 1). These inhibitors were used in the protein fishing experiments using SKBR3, T47D and
A431 cell lysates. Initially, the lapatinib dual tag was linked to a matrix using click chemistry. Proteins
from the lysate that has the highest affinity to the tagged lapatinib are covalently bound to it using
UV illumination (Scheme 2) and unbound are washed out. Finally, captured proteins are identified
using MALDI-TOF after in-gel or in-solution tryptic digestion.
PRG PRG
PRG UV
=365 MATRIX
MATRIX P MATRIX P ligand
ligand
ligand
Scheme 2: The two step process of link dual tagged lapatinib to unknown proteins.
We will report the finding that modified lapatinib (dual tag) identified the expected EGFR protein in
cell lysates. We will also report four putative protein targets that bound our modified ligand.
Interestingly, these proteins are not kinases. Future work will involve validation of those proteins as
new potential targets or anti-targets of lapatinib with various biochemical and cellular assays.
[1]
K. Petrov et al., Bioorg. Med. Chem. Lett., 2006, 16, 4686.
[2]
C. Yewale et al., Biomaterials, 2013, 34, 8690.
[3]
J. Wang et al., Pharmacol. Ther., 2016, 162,10.
142
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MEDICAL CHEMICAL DEFENCE AGAINST CHEMICAL NERVE AGENT

THREATS
Zrinka Kovarik, Nikolina Maček-Hrvat and Tamara Zorbaz

Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb, Croatia
* zkovarik@imi.hr
The high toxicity of organophosphorus compounds (OP; tabun, sarin, VX, cyclosarin and soman)
originates from the irreversible inhibition of acetylcholinesterase (AChE), an essential enzyme in
cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations call for
immediate treatment, which usually consists of a combined administration of anticholinergic drugs
and an aldoxime as the reactivator of AChE. Finding an optimal reactivator for prophylaxis against
and post-treatment of OP toxicity is a continuing challenge. We identified several oximes with
significantly improved human AChE reactivating efficacy against several OP and antidotal efficacy
in mice when compared to standard reactivators. Further ex vivo testing of selected oximes and
AChE mutants confirmed efficient oxime-assisted catalytic bioscavenging and neutralizing of OP
exposure in whole blood. Therefore, our findings offer a platform for further antidote and scavenger
development for nerve agents exposure.
Acknowledgments: Supported by the Croatian Science Foundation (4307).
143
P-68
ANTITUMOR ACTIVITY OF ANTHROLS THAT PHOTOCHEMICALLY

GENERATE QUINONE METHIDES OR REACTIVE OXYGEN SPECIES
AND THEIR SELECTIVITY TOWARDS CANCER STEM CELLS
Lidija Uzelac,[a] Đani Škalamera,[b] Kata Mlinarić-Majerski,[b] Nikola Basarić[b] and Marijeta
Kralj[a],*
[a] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb,
Croatia
[b] Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10000 Zagreb,
Croatia
* marijeta.kralj@irb.hr
Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic
stem cells like pluripotency and self-renewal. They are responsible for tumor formation, relapse and
metastasis and also exhibit resistance to a whole range of drugs with different cellular targets.
Mechanisms of resistance include enhanced survival pathways, increased activation of drug efflux
pumps and enhanced capability for reactive oxygen species (ROS) defense. Targeting CSC, rather
than cancer cells in general, is a novel and highly promising strategy for cancer treatment.[1,2]
As a result of current treatments failing to target CSCs, novel therapies such as photodynamic
therapy (PDT) are being investigated. PDT involves the treatment of cancer cells with an inactive
and nontoxic photosensitizer (PS), which is activated by light with specific wavelength, matching its
absorbance spectrum. This leads to reactive oxygen species (ROS) generation, which causes
cancer cell death. Further development of cancer treatment approaches and search for new targets
and compound leads, requires discovery and elucidation of novel phototherapy mechanisms on
molecular level. A promising group of phototherapeutic agents are reactive intermediates - quinone
methides (QMs). One of the methods for the generation of QMs is photodehydration or
phototautomerization of phenol derivatives.[3,4]
The objective of the proposed research is to test anticancer potential of anthracene derivatives 1-4
that can generate either QMs, or ROS upon the irradiation with near visible light at λ > 400 nm.
Special attention was put to demonstrate the potential selectivity of these compounds towards the
cells with CSC-like properties. We performed a detailed photochemical and photobiological
investigation on anthrol derivatives 1-4. While upon the excitation 1-2 can give QMs, 3-4 cannot
undergo photodehydration and deliver QM, but lead to the singlet oxygen formation. Their activity
was tested on a panel of human tumor cell lines (HCT116, MCF-7, H460 and SUM 159), as well as
on a unique transgenic CSC model (HMLEshEcad/HMLEshGFP).[2] The antiproliferative ability was
tested by MTT assay, colony formation assay, and cell cycle analysis. Confocal microscopy was
used to demonstrate the localization of compounds in the cells, and ROS measurements were
conducted to evaluate the ability of 3 and 4 to induce oxidative stress.
We demonstrated an intriguing cytotoxic activity of
R1 1 R1 = OH, R 2 = CH2OH
2 R1 = OH, R 2 = CPh2OH anthrols, and selectivity towards CSC cell model of those
3 R1 = OH, R 2 = H that produced ROS. This study forms the basis for
R2 4 R1 = H, R2 = CH2OH further research on cancer phototherapy, as well as for
the elucidation of CSC selectivity based on oxidative stress activation.
[1]
L.V. Nguyen, R. Vanner, P. Dirks, C.J. Eaves, Nat. Rev. Cancer, 2012, 12,133.
[2]
P.B. Gupta, T.T. Onder, G. Jiang, K. Tao, C. Kuperwasser, R.A. Weinberg, E.S. Lander, Cell, 2009, 138,
645.
[3]
[4]
M. Kralj, L. Uzelac, Y-H. Wang, P. Wan, M. Tireli, K. Mlinarić-Majerski, I. Piantanida, N. Basarić,
Photochem. Photobiol. Sci., 2015, 14, 1082.
144
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SURFACE INTERACTIONS BETWEEN OLIGOPEPTIDE DERIVATIVES OF

SALICYLIC ACID AND CALCITE AS A MODEL OF AN INORGANIC DRUG
DELIVERY SYSTEM
Marko Ukrainczyk,[a] Lara Štajner,[a] Zlatko Brkljača,[a,b] Robert Stepić,[c]

David Smith,[a] Ana Sunčana Smith,[a,c] Matija Gredičak,[a] Ivanka Jerić,[a]
Andreja Jakas[a] and Damir Kralj[a],*
[a] Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
[b] University of Zagreb, Croatia
[c] FA University, Erlangen, Germany
* kralj@irb.hr
Targeted or sustained drug delivery is a promising strategy for improving the therapeutic efficiency
of existing active pharmaceutical molecules. Typically, liposomal, micellar or biodegradable
polymeric matrices are used for encapsulation of model drug molecules and/or design of new drug
delivery systems. Recently, however, porous inorganic materials have been proposed as suitable
carriers. Calcium carbonate is a rather common mineral, which has been considered as a mineral
drug carrier due to recognized biocompatibility, nontoxicity and biodegradability. Indeed, it has been
suggested that CaCO3 may significantly improve drug stability and bioavailability, as well as to
control the release of active compounds by influencing their desorption and/or dissolution rates.
However, the understanding of the basic molecular interactions of model pharmaceutical compounds
with mineral surfaces is a critical step in the development of efficient CaCO3 based hybrid materials
that could be used as biocompatible carriers in drug delivery systems. Previously, we studied the
molecular interactions between well defined calcite surfaces and salicylic acid (Sal), as well as its
derivatives, which were selected as a simple models of anti-inflammatory drug substances.[1,2] The
inspiration for derivatization of salicylic acid molecules with glutamic acid (Glu) or aspartic acid (Asp)
is taken from the process of biomineralization, in which organic-inorganic hybrid materials are
composed of CaCO3 polymorphs (calcite or aragonite) and Asp-rich acidic glycoproteins. The
synthesized amino acid adducts with Sal exerted significantly enhanced binding to specific calcite
surfaces, in comparison to free Sal.
The aim of this study is to design new salicylic acid adducts, which should be biocompatible and
water-soluble. The adducts should also enable stronger Sal binding by means of multiple carboxylic
groups, while the linkers should be easily cleaved after binding to CaCO3 surface. Thus, we designed
and synthesized 6 tripeptides (L-Asp-L-Asp-L-Asp; D-Asp-D-Asp-D-Asp; L-Asp-D-Asp-L-Asp; L-Asp-
Gly-L-Asp; L-Asp--Ala-L-Asp and L-Asp-Gly-D-Asp), as well as the respective adducts with salicylic
acid (Sal-Gly-L-Asp-D-Asp-L-Asp; Sal-L-Asp-D-Asp-L-Asp; Sal-Gly-L-Asp-L-Asp-L-Asp and Sal-L-
Asp-L-Asp-L-Asp) in order to test the efficiency of their binding with rhombohedral calcite crystals
bounded by the stable {1 0 4} faces. The efficiency has been correlated with the number of carboxylic
groups, their orientation in space, charge separation effect and chirality of α-carbon atom. The
qualitative compliance of the results of molecular dynamics calculations (MD) of binding energies
(Eb = -755 kJ mol-1) and the Langmuir adsorption constants (Kad = 0.56 dm3 mmol-1), determined from
the crystal growth kinetics of calcite crystals in the presence of respective adducts, indicated the
strongest interactions of L-Asp-D-Asp-L-Asp. Similarly, the MD and the crystal growth kinetic data
showed the strongest surface interactions of Sal-Gly-L-Asp-D-Asp-L-Asp (Kad = 1.58 dm3 μmol–1). The
obtained results and proposed systematic approach (MD and crystal growth kinetics) can contribute
to a better understanding of molecular interactions between model drug derivatives containing
carboxylic functional groups with mineral surfaces, thus being the basis for the design of efficient
mineral drug delivery systems.
[1]
M. Ukrainczyk, M. Gredičak, I. Jerić, D. Kralj, J. Colloid Interface Sci., 2012, 365, 296.
[2]
M. Ukrainczyk, M. Gredičak, I. Jerić, D. Kralj, Cryst. Growth Des., 2014, 14, 4335.
145
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OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCO-

BACTERIAL ACTIVE AGENTS AND THEIR CONJUGATES
Martin Krátký,[a],* Zsuzsa Baranyai,[b] Szilvia Bősze,[b] Nóra Szabó[c] and

Jarmila Vinšová[a]
[b] MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter Sétány 1/A, Budapest, H-1117,
Hungary, P.O. Box 32, 1518 Budapest 112, Hungary
[c] Laboratory of Bacteriology, Korányi National Institute for Tuberculosis and Respiratory Medicine,
Pihenő út 1, Budapest, H-1122, Hungary
* martin.kratky@faf.cuni.cz
The global tuberculosis epidemic and increasing emergence of drug-resistant Mycobacterium

tuberculosis (Mtb.) strains as well as non-tuberculous mycobacteria (NTM) call for intensive research
on novel therapeutic interventions. Drug delivery systems (DDS) may help to overcome inconvenient
properties of bioactive molecules, e.g., poor solubility, bioavailability or selectivity. Additionally, they
are useful in targeted drug delivery.[1] We selected tuftsin-based oligopeptides as potential carriers
for small antimycobacterial active molecules. Tuftsin derivatives are non-toxic, non-immunogenic
and biodegradable. They also enhance immune response and target macrophages specifically, thus
increasing cellular uptake, activity and reducing toxicity.[2,3] A pilot study with isoniazid indicates that
this concept is viable.[2]
Salicylanilides (2-hydroxy-N-phenylbenzamides) have exhibited interesting antimicrobial properties
including drug-resistant Mtb. and NTM (MIC ≥ 0.5 µM), but their potential use is prevented due to
limited solubility and comparatively higher toxicity.[4] These obstacles can be overcome, i.a., by
employment of DDS. That is why salicylanilides bearing a carbonyl group were selected as model
compounds for the evaluation of oligotuftsine carriers.
Oligotuftsin-based carriers ([TKPKG]n, n=1-4) were synthesized by solid-phase synthesis (Fmoc/tBu
strategy, rink amide MBHA resin, diisopropylcarbodiimide/HOBt, NMP). N-Terminus and/or side
chain lysine ε-amino group(s) were substituted to obtain carriers with various properties. Carboxylic
acids (acetic, succinic, palmitic etc.) modify lipophilicity, short peptide spacers (G5, GFLG cleavable
by cathepsin B) were used to control the cellular site where the drug is released, whereas fluorescein
enables to determine cellular uptake by flow cytometry and fluorescent microscopy. One or more
aminooxyacetic acid molecule(s) were coupled with peptides to provide a reactive group for the
attachment of active molecules. After these modifications, peptide carriers were cleaved from the
resin TFA and purified. Then, carriers were coupled with salicylanilide derivatives to form acid stable
oxime bond. Novel conjugates were purified and characterised.[3]
Generally, salicylanilide-oligotuftsin conjugates exhibited a significant extracellular antimyco-
bacterial activity including against drug-resistant Mtb. Moreover, they are more effective against
intracellular mycobacteria than parent salicylanilides. Cellular uptake was enhanced substantially,
too, together with decreased cytostatic and cytotoxic effects on mammalian cells. In conclusion, our
tuftsine peptides are perspective carriers for antimycobacterial agents.
27514Y.
[1]
G. Tiwari, R. Tiwari, et al., Int. J. Pharm. Invest., 2012, 2, 2.
[2]
K. Horvati, G. Mezo, et al., J. Pept. Sci., 2009, 15, 385.
[3]
Z. Baranyai, M. Krátký, et al., Eur. J. Med. Chem., 2017, under revision.
[4]
Z. Baranyai, M. Krátký, J. Vinšová, et al., Eur. J. Med. Chem., 2015, 101, 692.
146
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NOVEL 1,2,3-TRIAZOLYL-7-SUBSTITUTED COUMARINS AND

BIS(COUMARIN-TRIAZOLYL)BENZENES: SYNTHESIS,
PHOTOPHYSICAL PROPERTIES AND CYTOSTATIC EVALUATION
Kristina Bobanović,[a] Ema Horak,[a] Lidija Furač,[a] Marijeta Kralj,[b] Lidija Uzelac,[b] Ivana
Murković Steinberg[a] and Svjetlana Krištafor[a],*
[a] Department of General and Inorganic Chemistry, Faculty of Chemical Engineering and Technology,
University of Zagreb, Marulićev trg 19, 10000 Zagreb, Croatia
[b] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb,
Croatia
* svjetlana.prekupec@fkit.hr
Coumarins, with the structure of benzopyrone, are widely studied heterocyclic structures in the fields
of biology, medicine, perfumes, cosmetics and environmental chemistry. The favourable
photophysical properties validated coumarin derivatives as fluorescent probes in cellular imaging
and as good chemosensors of some transition metal ions essential for human health. In addition,
“click”-derived 1,2,3-triazole has become a very common motif from the biological fields to the
material sciences. It can interact with biological molecules, organic and inorganic surfaces and
materials. Triazole rings have been used as components of fluorogenic probes and as chelating
ligands in fluorescent metal sensors.[1]
Herein, we report the synthesis, spectroscopic study and cytostatic evaluation of some novel
coumarin-triazole conjugated heterocycles as well as 1,3- and 1,4-bis(coumarin-triazolyl)benzenes
based on Cu(I)-catalyzed azide-alkyne cycloaddition reaction (Figure).
Figure: 1,2,3-Triazolyl-substituted coumarins (1) and 1,3- and 1,4-bis(coumarin-triazolyl)benzenes (2).
All synthesised compounds are tested against human carcinoma cell lines. Interaction of some
representatives with ct-DNA is also studied by UV-vis and fluorescence spectroscopy. In order to
reveal the influence of substitutions at position 7 of coumarin probes on their pH and metal ion
sensing properties, detailed spectroscopic titrations are performed and fluorescence intensity
changes are discussed as part of our ongoing research.[2]
[1]
a) C. Le Droumaguet, C. Wang, Q. Wang, Chem. Soc. Rev., 2010, 39, 1233.; b) Y. H. Lau, P. J Rutledge,
M. Watkinson, M. H. Todd, Chem. Soc. Rev., 2011, 40, 2848.
[2]
M. Hranjec, E. Horak, D. Babić, S. Plavljanin, Z. Srdović, I. Murković Steinberg, R. Vianello, N. Perin, N. J.
Chem., 2017, 41, 358.
147
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DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL

POTENT MDM2/P53 SMALL MOLECULE INHIBITORS
M. E. Kukushkin,[a],* V. K. Novotortsev,[a] V. E. Filatov,[a] A. A. Beloglazkina,[a]

N. A. Vorobyeva,[b] D. A. Skvortsov,[a] E. K. Beloglazkina,[a] N. V. Zyk[a] and
A. G. Majouga[a,b]
[a] Moscow State University, Chemistry Dept., 119991 Moscow, Leninskie Gory, Building 1/3, GSP-1,
Russian Federation
[b] National University of Science and Technology MISiS, Moscow 119049, Leninskiy prosp. 4,
Russian Federation
* kukmevg@gmail.com
The search of non-peptide small-molecules that block protein-protein p53-MDM2 interaction is being
actual problem and appears as a new strategy for anticancer drug design. The first is tumor
suppressor plays a key role in controlling cell cycle progression and apoptosis. Another is
endogenous oncoprotein cellular inhibitor of p53. This referred small-molecular inhibitors binds to
MDM2 whereby released p53 activating the process of destruction of the tumor cells. Compounds
inhibitors of MDM2 containing spiro-oxindole core in structure is relatively new class biological active
materials which has been proven ability to effectively block the interaction p53-MDM2.[1]
We developed synthetic approaches to the spiro-oxindoles of two structural types from commercially
available reagents through 1,3-dipolar cycloaddition:[2,3]
To elucidate the possible binding affinity of the synthesized compounds towards MDM2, a static 3D
molecular docking study was performed in ICM-Pro software based on several X-Ray data of known
oxindoles. Although the cell-based assay that was carried out in this work did not elucidate the
underlying mechanism of action for the evaluated compounds, this scaffold brings novelty and
possesses the 3D-pharmacophore elements crucial for binding as compared to the reported
MDM2/p53 PPI inhibitors, including spiroindolinones.
After biogical testing more than 100 obtained compounds on the HCT116 p53(+/+) and HCT116 p53(-
/-)
as well as LNCap and PC3 cell lines the leader was determined. Then, thаt compound was tested
on HCT116 Nude mice model that showed 93% inhibition compared with the control group.
Acknowledgments: The work was supported by the Russian Foundation for Basic Research, grant
number 16-33-60166.
[1]
K. Ding, et al. JACS, 2005, 127, 10130.
[2]
Y.A. Ivanenkov, et al. Bioorg. Med. Chem. Lett., 2015, 25, 404.
[3]
Y.A. Ivanenkov, et al. Bioorg. Med. Chem., 2016, 24, 802.
148
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SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL LONG CHAIN

ARYLOPIPERAZINES (LACPs) WITH PYRIDYL MOIETY AS LIGANDS
FOR SEROTONIN RECEPTORS
Damian Kułaga,[a] Jolanta Jaśkowska,[a],* Anna Drabczyk,[a] Grzegorz Satała[b] and

of Organic Chemistry and Technology, 24 Warszawska St. 31-155 Cracow, Poland
[b] Department of Medicinal Chemistry , Institute of Pharmacology Polish Academy of Science, 12
Buspiron is a typical anxiolytic drug that contains long-chain arylopiperazine (LACPs) moiety and
exhibits binding with 5HT receptor.[1] Other drugs with a very similar activity to Buspiron are Gepiron
or Ipsapiron and they have the same moiety. LACPs contain a long flexible carbon chain (C2-and
more) connected with e.g. imid, amide, sulphonamide moiety at the one side of the chain and with
arylopiperazine on the other side.[3,4] One of the most characteristic features for these ligands is
binding with serotonin receptors.[2] In recent study, a few compounds were synthesized with pyridyl
moiety in LACPs, which are an analogue of Buspiron. Molecules were examined toward binding with
serotonin receptors 5HT in in vitro assay.
Novel long chain arylopiperazines were obtained in a three-step reaction. At the beginning, LACPs
were obtained with imide moiety. The compounds were obtained in the reaction between
bromoalkylphtalimide and 1-(2-pyridyl)piperazine. It is a new, eco-friendly method, supported under
microwave irradiation. At this stage, the compounds were transformed into HCl salts and examined
in in vitro. The rest of the free base was used in the next step - Gabriel’s reaction to obtain amine.
The third step is coupling amine with 1- and 2-naphthalenesulfonyl chloride or benzoyl chloride to
yield LACPs with sulphonamide and amide moiety. The final compound was transformed into HCl
salt and examined in in vitro assay.
The preliminary results showed high affinity to 5HT-1a. The more preferable result is LACPs with
imide moiety, and in terms of sulphonamides, more preferable is 2-naphtalenesulfonyl.
[1]
J. Malmkvist, S.W. Hansen, B.M. Damgaard, Physiol. Behav., 2003, 78, 229.
[2]
R. Perrone,F. Berardi, et al., J. Pharm. Pharmacol., 2005, 57, 1319.
[3]
G. Caliendo, et al., Curr. Med. Chem., 2005, 12, 1721.
[4]
P. Kowalski, et al., Arch. Pharm., 2013, 346, 339.
149
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DIFFERENT ROLES OF HALOGEN SUBSTITUENTS IN LIGAND-

RECEPTOR INTERACTIONS – A CLASS A GPCRS CASE STUDY
Rafał Kurczab
Department of Medicinal Chemistry, Institute of Pharmacology Polish Academy of Sciences, 12 Smętna
Street, 31-343 Krakow, Poland
* kurczab@if-pan.krakow.pl
Substitution of halogen atoms is a common and frequently used strategy in hit and/or lead
optimization since many years.[1,2] Moreover, the incorporation of halogen atoms is usually used to
increase membrane permeability and hence, improve the oral absorption,[3] to enhance the blood-
brain barrier permeability, what is a requirement for the CNS drugs.[4] However, the applicability of
halogen atoms in drug design is still far from been completely explored, e.g. the most SAR
discussions of halogenated compounds have only considered the classical steric parameters,
ignoring other contributions and effects of such atoms. In recent years the role of halogen atoms in
protein–ligand complexes has been attributed to the formation of specific and direct interactions
called halogen bonding.[6,7]
Herein, the different roles of halogen atoms were studied regarding the influence of: the type of
halogen atom used (Cl, Br and I), the position of substitution in aromatic ring and the number of
halogen atoms used, on the biological activity. The all crystalized GPCRs A were used as a testing
set. For a given target, sets containing halogenated and unsubstituted derivatives were extracted
from ChEMBL database using in-house scripts. The sets were next docked and analyzed by using
previously tested QM/MM-GBSA procedure.[5]
The results showed that, in majority of cases, increasing the size of halogen atom (Cl < Br < I)
substituted in the same position of aromatic ring increased the compound’s activity, however, a sort
of plateau effect was observed, where the most active derivative contained chlorine, whereas activity
decreased for the bromine and iodine derivatives. A significant correlation between the position of
substitution of halogen atom in aromatic ring was found. For instance, switching Br position in phenyl
ring can decrease 11-fold, as well as, increase 27-fold (compared to unsubstituted compounds) an
activity of the compound. Also very interesting dependencies between the number of halogen
substituents in one aromatic ring and biological activity were noted.
It is suggested, that the reported effects can be a result of interplay between hydrophobic, halogen
bonding and entropic contributions to the ligand binding energy.
Acknowledgments: The study was supported by the National Science Center, Poland, Grant No
2014/15/D/NZ7/01782.
[1]
S. Buchini, A. Buschiazzo, S. G. Withers. Angew. Chem. Int. Ed., 2008, 47, 2700.
[2]
A. C. L. Leite, D. R. M. Moreira, M. V. O. Cardoso, et al. ChemMedChem, 2009, 2, 1339,.
[3]
G. Gerebtzoff, X. Li-Blatter, H. Fischer, A. Frentzel, A. Seelig. ChemBioChem, 2004, 5, 676.
[4]
C. L. Gentry, R. D. Egleton, T. Gillespie, et al. Peptides, 1999, 20, 1229.
[5]
R. Kurczab, Acta Cryst. B, 2017, manuscript accepted.
[6]
P. Politzer, J.S. Murray, T. Clark, Phys. Chem. Chem. Phys., 2010, 12, 7748.
[7]
T. Clark, M. Hennemann, J.S. Murray, P. Politzer, J. Mol. Model., 2007, 13, 291.
150
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SYNTHESIS AND BIOLOGICAL POTENTIAL OF SERIES A AND B

MODIFIED STEROIDAL D-LACTONES
Ivana Kuzminac,[a],* Marina Savić,[a] Dimitar Jakimov,[b] Olivera Klisuric,[c]

Andrea Nikolić[a] and Marija Sakač[a]
[a] Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences,
University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
[b] Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia
[c] Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3,
21000 Novi Sad, Serbia
* ivana.kuzminac@dh.uns.ac.rs
During recent years a number of new steroidal D-lactones with modifications in A and B-rings has
been reported by our research group.[1-3] Among those modifications it can be observed that
introduction of 5α or 6β hydroxy and/or 6-keto groups has shown significant influence on biological
activity, especially on anticancer activity.[1,3] With this in mind, various steroidal derivatives with
hydroxy, keto and/or metoxy groups in positions 3, 5 and 6 were synthesized starting from
corresponding androstane-17a-lactone,[2] obtained according to a known procedure. Molecular and
crystal structures were confirmed by detailed NMR (1H, 13C, HSQC 2D, 2D HMBC, NOE-
experiments) and X-ray analysis.
For eleven compounds, seven new and four that were already reported, antiproliferative activity was
tested against a panel of human cancer cell lines and one healthy human cell line. In order to
investigate the effect of different polar groups in synthesized molecules on cytotoxic activity, in
analysis of the results has been established correlations between structure and activity of the tested
compounds. Bioavailability of these compounds was assessed by comparing calculated molecular
properties with the criteria for Lipinski[4] and Veber[5] rules.
[1]
M.P. Savić, E.A. Djurendić, E. Petri, A. Ćelić, O.R. Klisurić, M.N. Sakač, D.S. Jakimov, V.V. Kojić, K.M.
Penov Gaši, RSC Advances, 2013, 3, 10385.
[2]
E. Djurendić, M. Savić, O. Klisurić, M. Sakač, G. Bogdanović, D. Jakimov, K. Penov Gaši, Struct. Chem.,
2012, 23, 1761.
[3]
I. Kuzminac, O. Klisurić, D. Škorić, D. Jakimov, M. Sakač, Struct. Chem., 2016, DOI 10.1007/s11224-016-
0815-9
[4]
C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Adv. Drug Deliv. Rev., 2001, 46, 3.
[5]
D.F. Veber, S.R. Johnson, H.Y. Cheng, B.R. Smith, K.W. Ward, K.D. Kopple, J. Med. Chem., 2002, 45,
2615.
151
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IN SILICO & IN VITRO EVALUATION OF NOVEL INHIBITORS OF

MITOCHONDRIAL F1F0-ATPASE
Dimitrios Karagiannis, Panagiotis Efentakis, George Lambrinidis, Ioanna Andreadou and

Emmanuel Mikros
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and
Kapodistrian University of Athens, Greece
ATP synthase is a significant multiprotein complex, proven to be a small rotor machine, either
producing or hydrolyzing adenosine triphosphate. So far there is no crystal structure of mitochondrial
ATP synthase of mus musculus, which is a very common model for in-vitro and in-vivo tests.
Selective inhibition of ATP hydrolase, is of major significance during myocardial ischemia where ATP
synthase switch to hydrolyzed activity, wasting ATP, causing dysfunctional mitochondria.[1]
In this work, we present the discovery of ATP synthase inhibitors based on virtual and experimental
screening methods. In a first step, we constructed for the first time a holistic model of ATP synthase
of mus musculus based on homology modeling using all known subunits from PDB. Structure-based
screening has been performed targeting the three major inhibition sites already known from literature:
a) the ATP-ADP catalytic site b) the oligomycin binding site and c) inside the surface of an annulus
made from loops in the 3α and 3β subunits (quercetin & resveratrol binding site). In parallel ligand-
based virtual screening, has been carried out based on similarity research to known binders like
BMS-199264.[1]
The workflow has been implemented on our in-house library of 2000 Natural Products & and
synthetic compounds. 48 molecules were selected and further screened in-vitro on isolated murine
heart mitochondrial fractions, assessing ATP synthase hydrolytic activity. Mitochondrial fractions and
ATP synthase hydrolytic activity was attained after a freeze-thaw cycle of the organelles.
Subsequently the hydrolytic activity was measured photometrically. 35 out of 48 (73%) tested
compounds exhibited various inhibitory activities at 0.2 mM. 7 molecules appeared to have common
scaffold displaying enhanced activity (48–82.5% inhibition) among the other molecular scaffolds.
The IC50 of these compounds has been further determined, provided confirmatory evidence that this
scaffold achieve an inhibitory action which is premised on the assumption that it can lead us to a
novel drug against myocardial ischemia.
[1]
G.J Grover, J. Malm, Cardiovasc Ther., 2008, 26, 287.
152
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3-AROYL-1,4-DIARYLPYRROLES INHIBIT CHRONIC MYELOID

LEUKEMIA CELL GROWTH THROUGH AN INTERACTION WITH
TUBULIN
Giuseppe La Regina,[a],* Valentina Naccarato,[a] Antonio Coluccia,[a]

Addolorata Maria Luce Coluccia,[b] Ernest Hamel[c] and Romano Silvestri[a]
[a] Institut Pasteur Italy - Cenci Bolognetti Foundation, Dipartimento di Chimica e Tecnologie del
Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy
[b] Clinical Proteomics, Polo Oncologico Giovanni Paolo II, ASL - University of Salento, Piazza Muratore
1, I-73100 Lecce, Italy
[c] Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer
Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer
Institute, National Institutes of Health, Frederick, Maryland 21702, USA
* giuseppe.laregina@uniroma1.it
Microtubules are an attractive target for the development of effective anti-leukemia agents.[1]
Evidence has accumulated correlating inhibition of tubulin polymerization and leukemic cell
proliferation.[2] The activity of colchicine site agents in chronic myeloid leukemia (CML) has not been
adequately explored.
Recently, starting from previously reported aroylindoles (ARI, 1)[3] we developed a class of 3-aroyl-
1-arylpyrroles (ARAPs, 2) via benzocracking approach by shifting the indole benzene moiety to
position 1 of the pyrrole ring.[4] ARAPs proved to be potent inhibitors of both tubulin assembly and
cancer cells growth, by binding the colchicine binding site. Pursuing our study on tubulin targeting
agents, we designed 3-aroyl-1,4-diarylpyrroles (ARDAPs, 3-16) as potential anticancer agents
bearing different substituents at the 1- or 4-phenyl ring (Figure).
ARDAPs exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin and
cancer cell growth. (4-(4-Aminophenyl)-1-phenyl-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone
inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from CML patients in
blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive
KBM5-WT or its IM-resistant KBM5-T315I mutation. The same compound minimally affected the
proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad
tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. New ARDAP significantly
decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria-
dependent pathway and increased the cytotoxic effects of IM in human CML cells.
Figure: Chemical structures of ARI (1), ARAP (2) and ARDAP (3-16) derivatives.
[1]
E.C. de Bruin, J.P. Medema, Cancer Treat. Rev., 2008, 34, 737.
[2]
D. Bates, E.J. Feris, A.V. Danilov, et al., Cancer Biol. Ther., 2016, 17, 291.
[3]
G. La Regina, T. Sarkar, R. Bai, et al., J. Med. Chem., 2009, 52, 7512.
[4]
G. La Regina, R. Bai, A. Coluccia, et al., J. Med. Chem., 2014, 57, 6351.
153
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INHIBITION OF DENGUE VIRUS BY NOVEL INHIBITORS OF

RNA-DEPENDENT RNA POLYMERASE AND PROTEASE ACTIVITIES
Giuseppe La Regina,[a],* Valeria Famiglini,[a] Domiziana Masci,[a] Antonio Coluccia,[a] Jin-

Ching Lee,[b] John Hiscott[a] and Romano Silvestri[a]
[a] Institut Pasteur Italy - Cenci Bolognetti Foundation, Dipartimento di Chimica e Tecnologie del
Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Rome, Italy
[b] Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung,
Taiwan
* giuseppe.laregina@uniroma1.it
Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than
390 million new infections annually, and up to 1 million clinical cases with severe disease
manifestations, there is an urgent need to develop new antiviral agents that inhibit DENV infectivity.[1]
Currently, no licensed antiviral drugs are available to block DENV infection and vector control efforts
remain the only means to stop the spread of the infection.
In the present study, we focused our attention on the identification of potential anti-DENV inhibitors
by targeting the enzymatic activities of the NS5 RdRp polymerase and NS3 protease, in vitro and in
vivo. As part of a continuation of our studies,[2,3] we developed new pyrazole derivatives 1-3 as
inhibitors of NS5 RdRp polymerase (Figure). Furthermore, virtual screening studies on the
NS2B/NS3 protease led us to identify indole derivatives 4-5 as inhibitors of NS3 protease (Figure).
New compounds exhibited anti-DENV replication activity without cytotoxicity; two compounds
exhibited anti-DENV activity in ICR suckling mouse model of DENV infection. Interestingly,
combination treatment with several compounds demonstrated a synergistic inhibitory effect on
DENV replication.
Figure: Chemical structures of new anti-DENV agents.

[1]
A. Wilder-Smith, E.E. Ooi, S.G. Vasudevan, et al., Curr. Infect. Dis. Rep., 2010, 12, 157.
[2]
R. Silvestri, M.G. Cascio, G. La Regina, et al., J. Med. Chem., 2008, 51, 1560.
[3]
V. La Pietra, G. La Regina, A. Coluccia, et al., J. Med. Chem., 2013, 56, 10066.
154
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PHENOXYMETHYL DERIVATIVES OF 1,3,5-TRIAZINE AS NOVEL CLASS

OF 5-HT6 RECEPTOR LIGANDS
Dorota Łażewska,[a],* Małgorzata Więcek,[a] Michał Stelmasiński,[a] Grzegorz Satała,[b]

Rafał Kurczab,[b] Andrzej J. Bojarski,[b] Katarzyna Kieć-Kononowicz[a] and
Jadwiga Handzlik[a]
[a] Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9
Medyczna Street, 30-688 Kraków, Poland
[b] Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12
Smętna Street, 31-343 Kraków, Poland
* dlazewska@cm-uj.krakow
The serotonin 5-HT6 receptor (5-HT6R) is the most recently identified member of the 5-HT receptor
superfamily. The 5-HT6R, distributed in the central nervous system, is especially involved in the
regulation of cognitive and mood processes as well as eating behaviors. Intensive medicinal
chemistry efforts led to obtain many potent 5-HT6R ligands and some of them have reached to clinical
studies, even to phase III as e.g. LUAE58054 (idalopirdine; Alzheimer’s disease).[1]
For proper understanding of the complicity of 5-HT6R pharmacology more potent and selective
ligands are necessary. Recently, we have developed a new class of 5-HT6 receptor ligands – benzyl
derivatives of 1,3,5-triazine.[2] The most active compounds displayed 5-HT6R affinities in the
nanomolar range (Ki = 20-30 nM).
As a continuation of that work, a series of phenoxymethyl derivatives of 1,3,5-triazine was
synthesized and tested for 5-HT6 receptor affinity. Among obtained structures a potent compound -
4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (MST4) -
was identified. MST4, while having high nanomolar binding affinity (Ki = 11 nM) for 5-HT6R
demonstrated also good selectivity towards other 5-HT receptors (5-HT1A, 5-HT2A, 5-HT7) and starts
a new class of potent 5-HT6R ligands.
Acknowledgments: Supported by the Polish National Science Centre (NCN) grants: UMO-
2015/17/B/NZ7/02973 and DEC-2011/02/A/NZ4/00031.
[1]
D. Karila, T. Freret, V. Bouet, M. Boulouard, P. Dallemagne, C. Rochais, J. Med. Chem., 2015, 58,
7901.
[2]
D. Łażewska, R. Kurczab, M. Więcek, K. Kamińska, G. Satała, A.J. Bojarski, K. Kieć-Kononowicz, J.
Handzlik, Eur. J. Med. Chem. – manuscript submitted.
155
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BLOCKADE OF RAS ACTIVITY BY INHIBITORS OF THE ENZYME

ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE (ICMT)
S. Ortega-Gutiérrez,[a] M. Martín-Fontecha,[a] N. Marín-Ramos,[a] F.J. Ortega,[a]

A. Gil,[a] M. Balabasquer,[a] I. Cushman,[b] I.R. Torrecillas,[c] L. Pardo,[c]
P.J. Casey,[b] M.R. Philips[d] and M.L. López-Rodríguez[a]
[a] Dpto. de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de
Madrid, Madrid, Spain
[b] Dept. of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North
Carolina, USA
[c] Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat
Autònoma de Barcelona, Barcelona, Spain
[d] NYU Cancer Institute, Smilow Research 1205, NYU School of Medicine, 550 First Avenue, New
York, NY 10016, USA
* mluzlr@ucm.es
Activating mutations in Ras proteins have been found in almost 30% of all cancers. In absence of its
post-translational modifications, Ras losses its ability to induce tumour transformation. Therefore,
the blockade of the enzymes involved in these modifications represents an attractive strategy to
inhibit Ras activity. Among them, isoprenylcysteine carboxyl methyltransferase (ICMT), which
catalyses the last step of the post-translational modifications of Ras, has surged as a new therapeutic
target in oncology.[1] However, the lack of inhibitors with in vivo efficacy has impaired its clinical
validation.
In the search of new ICMT inhibitors, we built a structure-based pharmacophore model using the
Methanosarcina acetivorans ICMT (Ma-ICMT) structure[2] as template. After the identification of an
initial hit, we carried out an extensive medicinal chemistry program, which led to compound UCM-
1336, which inhibits more than the 90% of ICMT activity at 50 mM with an IC50 value of 2 mM and
shows adequate pharmacokinetic properties. In addition, UCM-1336 (i) enhances programmed cell
death, affecting specially those cell lines expressing oncogenic mutant K-Ras; (ii) induces
mislocalization of all Ras isoforms; (iii) reduces Ras activity and blocks the activation of the
downstream MEK/ERK and PI3K/AKT signalling pathways; and (iv) impairs the migratory capacity
of tumour cells. All these promising results suggest that UCM-1336 could be a new ICMT inhibitor
that would help to definitively validate this enzyme as a therapeutic target of interest for the treatment
of cancers characterized by high Ras overactivation, a current unmet clinical need.[3]
Acknowledgments: This work has been supported by grants from the Spanish Ministerio de
Economía y Competitividad (MINECO, SAF2016-78792-R).
[1]
J.T. Teh, W.L. Zhu, et al., Oncogene, 2015, 34, 3296.
[2]
J. Yang, K. Kulkarni, et al., Mol. Cell, 2011, 44, 997.
[3]
M.L. López-Rodríguez, S. Ortega-Gutiérrez, M. Martín-Fontecha, M. Balabasquer, F.J. Ortega, N.I. Marín-
Ramos, PCT Int. Appl. WO2014118418 A1 (2014)
156
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STUDY FOR THE DEVELOPMENT OF NEW PURINE ANALOGUES AS

HIGHLY SPECIFIC LIGANDS AGAINST FUNGAL NUCLEOBASE
TRANSPORTERS
Efthymios-Spyridon Gavriil,[a] Spyridon Dimitrakis,[a] Nikolaos Lougiakis,[a]

George Lambrinidis,[a] Emmanuel Mikros,[a] Panagiotis Marakos,[a]
Nicole Pouli[a] and George Diallinas[b]
[a] Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National
and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece
[b] Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Athens
15784, Greece
Fungal pathogens, and especially Aspergillus fumigatus, constitute an emerging threat due to the
increasing number of immunosuppressed patients. The use of specific purine transporters by fungi
provides a potential target for the development of new antifungal agents recognized by specific
fungal, but not by host, transporters. However, it is surprising that emerging knowledge on fungal
transporters has not been rationally exploited until now. In previous works, we have studied
structure-function relationships in nucleobase/nucleoside transporters in A. nidulans, a genetically
tractable fungus, where we have identified, cloned and fully characterized all 7 major transporters,
catalyzing the uptake of purines, pyrimidines, nucleosides and purine analogues, namely UapA,
UapC, AzgA, FurD, FurA, FcyB and CntA. In line with our research efforts, based on previously
theoretical models describing purine-transporter interactions, we aim to rationally design and
synthesize analogues, which will be recognized by specific nucleobase transporters of A. nidulans.
We have already developed a number of synthetic derivatives possessing the 3-deazapurine
scaffold, that have been found to specifically inhibit FcyB-mediated [3H]-adenine uptake. As a
continuation of our research efforts we have designed a number of new 2,4-disubstituted-3-
deazapurines, which have been efficiently synthesized, starting from 2-chloro-4-aminopyridine and
evaluated for substrate competition assays related to FcyB and AzgA transporters, both of which
recognize and transport purines with high affinities at the low μΜ range.
Acknowledgments: This work has been funded by the Special Research Account (ELKE) of the
National and Kapodistrian University of Athens.
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SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL SMALL-

MOLECULE PSMA-TARGETED PACLITAXEL CONJUGATES
A. E. Machulkin,[a],* A. P. Ber,[a] I. V. Saltykova,[a] E. K. Beloglazkina,[a]

N. V. Zyk,[a] V. E. Koteliansky,[a] and A. G. Majouga[a,b]
[a] Lomonosov Moscow State University, Chemistry Dept., Leninskie gory, Building 1/3, GSP-1, Moscow,
119991, Russian Federation
[b] National University of Science and Technology MISiS, 9 Leninskiy pr, Moscow, 119049, Russian
Federation
* alekseymachulkin@rambler.ru
The last year, statistical output was greatly unfavorable and sad since prostate carcinoma (PCa) was
the most spread malignant tumor commonly diagnosed around the world and as a leading cause of
cancer-related lethal outcomes registered among men in the US with an estimated 233K diagnoses
and 30K deaths.[1]
Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA)
has recently emerged as a prominent biomarker of this pathological state and as an attractive protein
trap for drug targeting. [2, 3]
In present work we synthesized the series of paclitaxel conjugates, modified with residues of 5-
hexynoic acid (7-OH substituted or with modified phenylisoserine residue) with different PSMA
ligands was synthesized. Cytotoxic effect of these conjugates was estimated on LNCaP and PC-3
cell lines, structure-activity relationships were studied. Cytotoxicity of the conjugates with amide 1
and 2 bond type between linker and PSMA ligand was (IC50 = 25 nM) significantly higher than
corresponding value for the urea residue 4 (IC50 = 1670 нМ), on LNCaP cells. We demonstrated that
amide bond type between linker and PSMA ligand is preferable than urea bond type. All ligands and
conjugates in this work were isolated individually and described with 1H and 13C NMR methods,
mass-spectrometry and LC/MS.
For the conjugate 2 primary in vivo studies were performed. This conjugate demonstrated the same
tumor growth inhibition as for paclitaxel, in this experiment.
Synthetic approaches and biological evaluation of synthesized structures would be minutely
discussed in the report.
O O
O OH
O NH O
H O
O
OH O O
O
O O
N N O
NH X N O
n
O OH
1, n=4, X=CH2 Paclitaxel
O 2, n=9, X=CH2
O O 3, n=4, X=NH
N N
H H 4, n=9, X=NH
OH OH
PSMA-vector
Figure: Structure of targeted conjugates of paclitaxel with PSMA ligands.
Acknowledgments: This work was kindly supported by Russian scientific fund № 14-34–00017
[1]
R. Siegel, J. Ma, Z. Zou, A. Jemal, CA Cancer J. Clin. 2014, 64, 9−29.
[2]
C. A. Foss et al., Curr. Med. Chem. 2012, 19, 1346−1359.
[3]
A. E. Machulkin, et al. J. Drug Target. 2016, 24, 679-93.
This work was kindly supported by Ministry of Education and Science of the Russian Federation № IP-
MSU/10-14 (NKR 185/17)
158
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DESIGN, SYNTHESIS AND IN VITRO EVALUATION OF MODULATORS

OF PFKFB3 AUTOREGULATORY DOMAIN
H. Macut,[a],* X. Hu,[a] D. Tarantino,[b] S. Pellegrino[a] and M. L. Gelmi[a]

[a] DISFARM - Section of General and Organic Chemistry "A. Marchesini", University of Milan, Via
Venezian 21, 20133 Milan, Italy
[b] Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milan, Italy
* helena.macut@unimi.it
Artery and cerebrovascular diseases are the two most common causes of illness and death in
developed countries and their primary cause is atherosclerosis, which is characterized by the
thickening of the arterial wall. Although beneficial, recent therapeutic strategies have limited
efficacy.[1] Current research has shown that targeting dysregulated endothelial cell (EC) metabolism
could be a new therapeutic strategy.[2]
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) enzyme plays a crucial role in the
regulation of the EC glycolytic flux and it is up-regulated during angiogenesis,[3] representing thus an
innovative target for atherosclerosis therapy. PFKFB3 is a dimeric bifunctional enzyme and
possesses a very high kinase to phosphatase activity ratio. Its activity is controlled by the N-terminus
autoregulatory domain (AD) in the kinase region. In the crystal structure this domain adopts a β-
hairpin shape.[4]
We performed virtual screening on the targeted autoregulatory binding site and here we present the
synthesis and biological evaluation of the selected library of compounds. In vitro activity and binding
assays were carried out on the isolated PFKFB3 enzyme.
[1]
J. Goveia, P. Stapor, P. Carmeliet, EMBO Mol. Med., 2016, 6, 1105.
[2]
D. J. Rader, A. Daugherty, Nature, 2008, 541, 904.
[3]
J. Chesney, R. Mitchell, F. Benigni, M. Bacher, L. Spiegel, Y. Al-Abed, J.H. Han, C. Metz, R. Bucala, Proc.
Natl. Acad. Sci. U S A, 1999, 96, 3047.
[4]
S.G. Kim, N.P. Manes, M.R. El-Maghrabi, Y.H. Lee, J. Biol. Chem., 2006, 281, 2939.
159
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ISOXAZOLE DERIVATIVES AS IMMUNOMODULATORS
Marcin Mączyński,[a],* Angelika Drynda,[b] Stanisław Ryng[a] and

Bożena Obmińska-Mrukowicz[b]
[a] Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, Borowska
211A str., 50-556 Wrocław, Poland
[b] Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University
of Environmental and Life Sciences, Norwida 31 str., 50-375 Wrocław, Poland
* marcin.maczynski@umed.wroc.pl
The homeostasis of the organism is determined by the cooperation of the immune, nervous and
endocrine system. The proper functioning of those systems provides the maintenance of the balance
of good health. Immune system principally destroys and eliminates identified foreign structures or
abnormal structures of the body. Furthermore, it ensures the integrity and protection of its own
normal tissues and supports the tissue regeneration process. Immune-mediated diseases pose a
serious challenge for today’s medicine. Substances that would be able to modify the functions of the
immune system have been sought for years. Among the substances obtained by chemical synthesis,
special attention deserve derivatives of five-membered isoxazole ring. They are the object of interest
to many scientists, both chemists seeking to obtain newer compounds, as well as pharmacologists
studying their properties.
To this fact contribute both that the isoxazole ring is relatively easy to obtain by chemical synthesis,
and that the obtained derivatives are non-toxic and have many biological activities, which means
that they could have potential application in medicine. The most characteristic for this group of
compounds is ability to modify the function of the immune system.
In this work we present the immunomodulatory properties of the best described isoxazole derivatives
synthesized in recent years.
Compound Chemical structure
Leflunomide
RM-33
RM-11
5-amino-3-methyl-4-
isoxazolecarboxylic acid
hydrazide
160
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PYRROLYL NON-DKA DERIVATIVES AS NOVEL INHIBITORS OF HIV-1

REVERSE TRANSCRIPTASE-ASSOCIATED RIBONUCLEASE H
FUNCTION
V. N. Madia,[a],* F. Saccoliti,[a] G. Pupo,[a] V. Tudino,[a] F. Esposito,[b] A. Corona,[b]

N. Grandi,[b] E. Tramontano,[b] R. Costi[a] and R. Di Santo[a]
[a]
Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, “Sapienza”
University of Rome, p.le Aldo Moro 5, I-00185 Roma, Italy
[b]
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09142
Monserrato Cagliari, Italy
* valentinanoemi.madia@uniroma1.it
The AIDS is a complex of pathological manifestations characterized by progressive degeneration of

the immune system caused by the HIV virus. An essential enzyme for the retroviral life cycle is
reverse transcriptase (RT), an heterodimeric enzyme with two associated activities: the DNA
polymerase activity and the ribonuclease H (RNase H) activity that selectively degrades the RNA
strand of the hybrid RNA/DNA formed during the synthesis of the minus (-) strand DNA that uses (+)
RNA as a template.[1] Despite such a large armamentarium, both acute and chronic toxicities limit
the prolonged use of several antiretroviral agents, and this is even more a concern because of the
life-long character of the therapy. In addition, the selection of drug-resistant strains and the spreading
of such strains in newly infected patients is also an increasing concern, underscoring the pressing
demand of novel anti-HIV agents, with a better therapeutic index and a very broad spectrum of
activity against the mutants, possibly targeting viral functions not yet explored.[2]
In such a scenario, an attractive target turns out to be the RNase H function of HIV-1 reverse
transcriptase (RT), which has been little explored although it could be potentially vulnerable to a
specific inhibition.[3-6] Although RT is a multifunctional enzyme, all RT inhibitors currently approved
for the treatment of HIV infection target only the RT-associated polymerase function, while none of
them block the RT RNase H activity. Nevertheless, several studies have demonstrated that the
abolition of the HIV-1 RNase H function stops the virus replication, proving to be, therefore, a
validated and attractive target for the development of new anti-retroviral agents, in order to enhance
the anti-HIV-1 drug armamentarium effectiveness. Despite this, it has been little explored and it
needs to be further developed through the support of new HIV/AIDS drug discovery programs, in
order to identify more efficient anti-HIV drugs that could be used for therapy.[7,8]
To date, only few compounds have been described to inhibit the HIV-1 RNase H function. Among
them, aryldiketo acid derivatives proven to inhibit both integrase enzyme and RNase H function of
the RT.[9,10] Pursuing our studies on pyrrolyl DKA derivatives as dual inhibitors of IN and RNase H
we developed non DKA scaffold and found a new class of compounds that selectively inhibited the
RNase H. The data coming from the biological assays will be shown and discussed.
[1]
W. S. Hu, S.H. Hughes, Cold Spring Harb Perspect Med., 2012, 2, 1.
[2]
J. P. Moore, et al., Nature Rev. Mol. Cell Biol., 2000, 1, 40.
[3]
K. Klumpp, et al., Nucleic Acids Res., 2003, 31, 6852.
[4]
S.R. Budihas, et al., Nucleic Acids Res., 2005, 33, 1249.
[5]
E. De Clercq, et al., J. Med. Chem., 2005, 48, 1297.
[6]
E. Tramontano, Mini Rev. Med. Chem., 2006, 6, 727.
[7]
E. Tramontano, F. Esposito, R. Badas, R. Di Santo, R. Costi, R., P. La Colla, Antiv. Res., 2005, 65, 117.
[8]
E. Tramontano, et al., Antiviral Res., 2005, 65, 117.
[9]
A. Corona, et al., Antimicrob. Agents Chemother., 2014, 58, 6101.
[10]
L. Pescatori, et al., J. Med. Chem., 2015, 58, 4610.
161
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NOVEL ANTIMALARIALS FROM NATURE: EVOLUTIONARY

GENERATED VIRTUAL COMPOUND LIBRARIES FROM NATURAL
PRODUCTS WITH ANTIPLASMODIAL ACTIVITIES
Samuel Egieyeh,[a,b] James Syce,[a] Alan Christoffels[b] and Sarel F. Malan[a],*

[a] School of Pharmacy, University of the Western Cape, Cape Town, 7535 South Africa
[b] South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics
Institute, University of the Western Cape, Cape Town, 7535, South Africa
* sfmalan@uwc.ac.za
Purpose: There is an urgent need to develop novel antimalarial drugs in view of the mounting
disease burden and emergent resistance to the presently used drugs against the malarial parasites.
A large number of natural products, especially those used in ethnomedicine for malaria, have shown
varying in vitro antiplasmodial activities. Generation of virtual compound libraries based on these
natural products presents an opportunity to identify novel potential antimalarial compounds.
Methods: Virtual compound libraries were generated with an evolutionary algorithm using unique
scaffolds identified from the natural products with in vitro antiplasmodial activities as templates. The
virtual compounds generated were characterized by evaluating selected molecular descriptors in
comparison to currently registered antimalarial drugs. Other descriptive studies performed included
assessment of the toxicity profile, diversity of the compound set, similarity to currently registered
antimalarial drugs and prediction of antiplasmodial activity.
Results: Two sets of virtual compound libraries were generated: Approved Drug-Like and Natural
Product-Like. The results of the characterization showed significant difference (p value < 0.05) in
some molecular descriptors (molecular weight, log partition coefficient, hydrogen bond donors and
acceptors, polar surface area, shape index, chiral centers, and synthetic feasibility) between the
virtual compound libraries and currently registered antimalarial drugs. Tumorigenic and mutagenic
substructures were absent in most (> 90%) of the virtual compounds. The virtual compounds showed
sufficient structural diversity and the majority were structurally diverse from currently registered
antimalarial drugs. Finally, a good fraction of the virtual compound libraries (up to 70%) were
predicted as active antiplasmodial agents.
Conclusions: A large number of the virtual compounds generated were structurally diverse from
currently registered antimalarial drugs and were predicted as active antiplasmodial agents. Filtering
and optimization led to a collection of virtual compounds with unique chemotypes that may be
synthesized and added to the screening deck against Plasmodium.
162
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THE SYNTHESIS OF NEW ARYLPIPERAZINES FOR CNS DISORDERS
Magdalena Malinowska,* Jolanta Jaśkowska, Anna Drabczyk and Damian Kułaga

Organic Chemistry and Technology Insitute, Cracow University of Technology, 24 Warszawska st.,
Cracow 31-155, Poland
* mmalinowska@chemia.pk.edu.pl
Central nervous system (CNS) diseases are one of the most problematic disorders, which cause
various neurological impairments from depression and intellectual disability to epilepsy, autism, and
schizophrenia.[1] The current pharmacotherapy takes advantage of the arylpiperazine ligands activity
for 5-HT receptors which have a significant role in the occurrence of pathological processes in the
neurotransmitter system.[2,3] The ligands can be obtained in various reaction conditions.
Conventional syntheses in organic solvent at 150-180°C give the reaction yield from 60-90% and
require long process time (14-18h).[4-5] Microwave conditions allow significant reduction of the
reaction time to few minutes and, moreover, the synthesis can be solvent-free.[6] In this study we
describe the synthesis and evaluation of the reaction conditions of a series of arylpiperazines used
for the synthesis of new ligands from the Long Chain Arylpiperazines family for CNS diseases. The
syntheses were carried out according to the procedure presented on the Figure.
Cl NH2
N
NH .
HCl +
HN R
R .
Cl HCl
Figure: The main synthesis procedure of arylpiperazine derivatives.
The evaluation of the synthesis conditions included the influence of the kind of a solvent, the reaction
temperature and time, as well as the presence of microwave radiation on the process progress. The
obtained compounds were identified using chromatographic (HPLC) and spectroscopic methods (IR,
1
HNMR). The described procedure is efficient and the products are isolated by simple filtration like
hydrochloride salts. It is applicable to various substituted anilines to give corresponding N-
phenylpiperazine hydrochlorides. All the products are found to be above 95% pure by HPLC.
[1]
G-H. Huang, Z-L. Sun, H-J Li, D-F. Feng, Mol. Cell Neurosci., 2017, 80, 18.
[2]
D. Hoyer, J.P. Hannon, G.R. Martin, Pharmacol. Biochem. Behav., 2002, 4, 533.
[3]
J.S. Dileep Kumar, V.J. Majo, J. Prabhakaran, J.J. Mann, Bioorg. Med. Chem. Lett., 2014, 24, 4759.
[4]
L. Ravilla, V.S. Naidu, K. Nagarajan, Tetrahedron Lett., 2015, 56, 4541.
[5]
C.A. Boateng, O.M. Bakare, J. Zhan, A.K. Banala, C. Burzyński, E. Pommier, T.M. Keck, P. Donthamsetti,
J.A. Javitch, R. Rais, B.S. Slusher, Z-X. Xi, A.H. Newman, J. Med. Chem., 2015, 58, 6195.
[6]
I. Konstantinov, K. Bukhryakov, Y. Gezentswey, M. Krasavin, Lett. Org. Chem., 2011, 8, 628.
163
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BIOLOGICAL EVALUATIONS OF AMIDINE AND AMIDOXIME

SUBSTITUTED HETEROCYCLES WITH 1,2,3-TRIAZOLYL SPACER
Silvija Maračić,[a] Petra Grbčić,[b] Mirela Sedić,[b,c] Sandra Kraljević Pavelić[b,c] and Silvana
Raić-Malić[a],*
[a] University of Zagreb, Department of Organic Chemistry, Faculty of Chemical Engineering and
Technology, Marulićev trg 19, HR-10000 Zagreb, Croatia
[b] University of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia
[c] University of Rijeka, Centre for high-throughput technologies, Radmile Matejčić 2, HR-51000
Rijeka, Croatia
* sraic@fkit.hr
Molecular hybridization is a new concept in drug design and development based on the combination
of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound
with improved affinity and efficacy, when compared to the parent drugs.[1] This approach was
adopted for design and synthesis of diversified library of benzofused heterocycle–1,2,3-triazole
conjugates to evaluate their cytostatic and antibacterial activities. Thus, coumarin–1,2,3-triazole–
benzofused heterocycle hybrids emerged as the class of compounds exhibiting the highest
antiproliferative activity.[2] While 5,6-disubstituted furo[2,3-d]pyrimidine-2-one derivative exhibited
selective activity against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cells with
higher potencies than the reference drug 5-fluoruracil, benzothiazole–1,2,3-triazole–coumarin hybrid
showed potent anti-Moraxella catarrhalis activity.[3,4] Novel hybrids of aromatic nitrile and heterocycle
linked via 1,2,3-triazole scaffold were syntesized by regioselective Cu(I)-catalyzed azide-alkyne 1,3-
dipolar cycloaddition. Nitrile derivatives were used as precursors for synthesis of amidine and
amidoxime substituted selected heterocycles. Results of antiproliferative evaluations for newly
synthesized compounds on human tumor and normal cell lines will be presented.
[1]
S. Raić-Malić, A. Meščić, Curr. Med. Chem., 2015, 22, 1462.
[2]
T. Gazivoda Kraljević, A. Harej, M. Sedić, S. Kraljević Pavelić, V. Stepanić, D. Drenjančević, J. Talapko, S.
Raić-Malić, Eur. J. Med. Chem., 2016, 124, 794.
[3]
T. Gregorić, M. Sedić, P. Grbčić, A. Tomljenović Paravić, S. Kraljević Pavelić, M. Cetina, R. Vianello, S.
Raić-Malić, Eur. J. Med. Chem., 2017, 125, 1247.
[4]
S. Maračić, T. Gazivoda Kraljević, H. Čipčić Paljetak, M. Perić, M. Matijašić, D. Verbanac, M.Cetina,
S. Raić-Malić, Bioorg. Med. Chem., 2015, 23, 7448.
164
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DESIGN, SYNTHESIS AND CYTOTOXIC ACTIVITY EVALUATION OF

NEW AMINOSUBSTITUTED PYRAZOLOPYRIDINES
Nikolaos Lougiakis,[a] Vasiliki Giannouli,[a] Ioannis K. Kostakis,[a]

Panagiotis Marakos,[a] Nicole Pouli,[a] Orestis Argyros[b] and
Constantin Tamvakopoulos[b]
[a] National and Kapodistrian University of Athens, School of Health Sciences, Department of Pharmacy,
Division of Pharmaceutical Chemistry, Panepistimiopolis-Zografou, Athens 15771, Greece
[b] Division of Pharmacology-Pharmacotechnology, Biomedical Research Foundation, Academy of
Athens, Soranou Efesiou 4, Athens 11527, Greece
Numerous purine derivatives have been designed and used as selective inhibitors of enzymes and
receptors. Depending on their substitution pattern and the wide variety of the substituents, these
compounds were found to exhibit a broad range of biological and pharmaceutical properties.
Isosteric purine analogues, have also been developed in the attempt to explore the therapeutic
potential or improve the physicochemical and pharmacokinetic properties of the parent derivatives.
Within a research project aiming in the discovery of new antiproliferative agents, we have
synthesized a number of new 7-arylaminosubstituted pyrazolo[3,4-c]pyridines and have determined
their cytotoxic activity against a panel of cancer cell lines. Certain compounds among these series
exhibited potent antiproliferative activity and blocked specifically the cell cycle.
As a continuation of our efforts here we present the design and synthesis of a number of new
substituted pyrazolo[3,4-c]pyridines and the evaluation of their cytotoxicity. The synthesis of the
derivatives was accomplished using N-(2-chloro-4-methyl-3-pyridin)acetamide as starting material,
which has derived from the commercially available 2-amino-4-picoline. The above mentioned
acetamide underwent intramolecular cyclization and upon suitable manipulation was converted to 7-
chloropyrazolo[3,4-c]pyridine-5-carbonitrile. This intermediate was used for the introduction of 3-
alkyl or 3-aryl substituents as well as for the insertion of 7-arylamino- and 5-alkylaminomethyl-
groups, in order to obtain the target derivatives. The new compounds underwent a preliminary
screening concerning the evaluation of their cytotoxic activity against a panel of human cancer cell
lines (MCF-7, T47D, MDA 231, HCC1954, PaCa2 and SCOV3). A number of the derivatives proved
to be active, showing IC50 values in the low µΜ range. The preliminary biological evaluation of the
derivatives revealed that the presence of a 3-isopropyl or 3-phenylgroup is in favor of the cytotoxic
activity of these compounds. Position 5- of the pyrazolopyridine ring system appears more flexible
in terms of substituents, since a variety of substituents were used and provided derivatives with
interesting antiproliferative activity.
Acknowledgments: This work has been funded by the Special Research Account (ELKE) of the
165
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IN VITRO CITOTOXITY AND ANTI-TUMOR INVESTIGATION OF

PHENYLBORONIC ACID
Maja Marasović,[a],* Mladen Miloš,[a] Siniša Ivanković[b] and Ranko Stojković[b]

[a] Department of Biochemistry Faculty of Chemistry and Technology, University of Split, Split, Croatia
[b] Division of Molecular Medicine, Ruđer Bosković Institute, Zagreb, Croatia
* majam@ktf-split.hr
The increased interest in recent years for the boronic acids and their derivatives is related to their
new applications as biologically active compounds. Our previous in vitro and in vivo studies have
demonstrated that dipotassium-trioxohydroxytetrafluorotriborate K2[B3O3F4OH] affects the growth of
cancer cells.[1] Based on promising results of K2[B3O3F4OH] and recent researches of other authors
on phenylboronic acid,[2,3] we decided to test cytotoxicity and antitumor effects of phenylboronic acid
in vitro on standard tumor cell lines: 4T1 mammary adenocarcinoma, B16F10 melanoma and
squamous cell carcinoma SCCVII.
Crystal violet method was performed to measure cell growth inhibition rate. Experiments were carried
out in microtiter plates with 96 wells and 1×104 tumor cells/250 ml of medium was applied in each
well. After 24 h, when the cells reached confluence, the old cultured medium was replaced with a
fresh one and phenylboronic acid was added to the cultures to the final concentrations of 0.1, 1.0
and 10 mg/ml. Control cells were incubated in RPMI medium without addition of the tested
substance. Absorbance was measured at 540 nm using a microplate reader. The absorbance at 590
nm is proportional to the number of surviving cells. Each experiment was done in quadruplicate.
Inhibition of cell growth relative to controls was calculated according to the formula: Inhibition of cell
growth (%)=(C-T)/C×100, where T denotes the mean absorbance of treated cells, and C indicates
the mean absorbance of untreated (control) cells. The LC50 concentrations were calculated using
probit analysis.
The detailed in vitro investigation undoubtedly showed that phenylboronic acid affects the growth of
cancer cells. The proliferation of cells depends on the concentration so that aqueous solution of
phenylboronic acid, in the concentrations less then 1 mg/ml, has weak influence on the cell growth,
but at the concentrations of 10 mg/ml, significantly slows cells growth. The 4T1 and SCCVII cells
show lower sensitivity to the cytotoxic effects of phenylboronic acid compared to B16F10 cells.
Although phenylboronic acid has a slightly weaker effect than K2[B3O3F4OH], the promising results
encourage further research.
[1]
S. Ivanković, R. Stojković, Z. Galić, B. Galić, J. Ostojić, M. Marasović, M. Miloš, J. Enzyme Inhib.
Med. Chem., 2014, 30, 354.
[2]
T.M. Bradke, C. Hall, S.W. Carper,G.E. Plopper, Cell Adhes. Migr., 2008, 2, 153.
[3]
X. Wang, H. Tang, C. Wang, J. Zhang, W. Wu, X. Jiang, Theranostics, 2016, 6, 1378.
166
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MICROWAVE ASSISTED SYNTHESIS OF SOME NEW THIAZOLIDINE-2,4-

DIONE DERIVATIVES AS POTENTIAL ANTIMICROBIAL AGENTS
Gabriel Marc,[a],* Ioana Ionuţ,[a] Dan Vodnar,[b] Adrian Pîrnău,[c]

Brîndușa Tiperciuc[a] and Ovidiu Oniga[a]
[a] Department of Pharmaceutical Chemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy,
12 Ion Creangă Street, RO-400012 Cluj-Napoca, Romania
[b] Department of Food Science, University of Agricultural Sciences and Veterinary Medicine, 3-5
Mănăștur Street, RO-400372 Cluj-Napoca, Romania
[c] National Institute for Research and Development of Isotopic and Molecular Technologies, RO
400293 Cluj-Napoca, Romania
* marc.gabriel@umfcluj.ro
Infections with resistant fungal or bacterial strains are nowadays a big challenge of treatment in all
health care systems worldwide. Especially in the immune-compromised hosts, it represents one of
the most life-threatening complications, giving a poor prognosis to the infected patients. For example,
the commensal Candida sp. or Staphylococcus sp. are common in humans, but frequent became
dangerous pathogens.[1] It is imperative that new substances with putative antimicrobial properties
are found. This approach came in order to avoid their resistance achieved during time. Inhibitors with
different mechanism than classic antibacterials and antifungals could be developed based on in silico
techniques. Molecular modelling and ADMET can be used in order to develop more potent
compounds at lower doses, with less toxicity or interactions and with better pharmacokinetics.[2]
Thiazolidine-2,4-dione derivatives were synthesized under microwave irradiation. First, Knoevenagel
condensation in position 5 of the thiazolidine-2,4-dione ring was performed using various carbonyl
compounds. Nitrogen atom was substituted using various α-halo-ketones. The purity of the new
synthesized thiazolidine-2,4-dione derivatives was confirmed by thin layer chromatography and
liquid chromatography. The structure of the new compounds was confirmed by spectral analysis: IR,
MS and 1H-NMR and by quantitative elemental analysis.
Compounds were screened in vitro for their ability to inhibit the growth of some standardized bacterial
and fungal strains. In silico evaluations were performed in order to find potential interactions of novel
molecules to some bacterial or fungal strains key proteins using AutoDock 4.2[3] and an ADMET
study using Swiss ADME. [4]
Our screening showed that the new compounds have promising antimicrobial activity.
[1]
S. Berne, L. Kovačič, M. Sova, N. Kraševec, S. Gobec, I. Križaj, et al., Bioorg. Med. Chem., 2015,
23, 4264.
[2]
C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Adv. Drug Deliv. Rev., 2001, 46, 3.
[3]
G.M. Morris, R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, et al., J. Comput.
Chem., 2009, 30, 2785.
[4]
A. Daina, V. Zoete, ChemMedChem, 2016, 11, 1117.
167
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WEB-4D-QSAR OF 17β-HYDROXYSTEROID DEHYDROGENASE TYPE 3

INHIBITORS
Eduardo B. de Melo,[a] Tuanny P. Schmidt[a] and João Paulo A. Martins[b],*

[a] Department of Pharmacy, Western Paraná State University (UNIOESTE), Cascavel, PR, Brazil
[b] Department of Chemistry, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
* joaopauloam@gmail.com
Prostate cancer is the most common cancer type found in men and, unfortunately, the treatment has
numerous side effects. It is believed that the enzyme 17β-hydroxysteroid dehydrogenase type 3 is
an interesting target of study in the development of new drugs against the disease. The objective of
this work was to perform a 4D-QSAR study with a set of 49 compounds (benzylidene
oxazolidinedione and thiazolidinediones derivatives), with inhibitory effect on this enzyme,
synthesized and published initially by Harada et al.[1] This study is accomplished with a new web
based software running LQTA-QSAR[2] methodology called Web-4D-QSAR
(https://github.com/rougeth/Web-4D-QSAR). After descriptors generation with this new web browser
interface, variable selection was carried out using Ordered Predictors Selection (OPS)[3] algorithm
implemented at QSAR Modeling[4] program. Model building was performed using Partial Least
Squares (PLS) regression. Based on this approach it was possible to obtain a model with the
following attributes: n= 42; R2= 0.779; RMSEC= 0.338; F= 68.735; Q2LOO= 0.655 RMSECV= 0.423;
nprediction= 7; R2pred= 0.784; RMSEP= 0.282; average rm2(pred)-scaled= 0.674; rm2-scaled= 0.147; k=
1.018; k’= 0.981; |R20-R2’0|= 0.039. These obtained results may be useful as a tool to allow a better
comprehension about the inhibitory mechanism of these compounds over 17β-hydroxysteroid
dehydrogenase, helping thus in the development of new inhibitors agents with potential to be
employed in the prostate cancer treatment. The authors would like to thank Brazilian Agencies
Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), Conselho Nacional de
Desenvolvimento Científico (CNPq) and Fundação Araucária for the support.
[1]
K. Harada, et al., Bioorg. Med. Chem., 2012, 55, 5951.
[2]
J.P.A Martins, J. Chem. Inf. Model., 2009, 49, 1428.
[3]
R.F. Teófilo, J.P.A. Martins, M.M.C. Ferreira, J. Chemom., 2009, 23, 32.
[4]
J.P.A. Martins, M.M.C. Ferreira, Quim. Nova, 2013, 36, 554.
168
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WEB-4D-QSAR OF URACIL DERIVATIVES DESCRIBED AS THYMIDINE

PHOSPHORYLASE INHIBITORS
João Paulo A. Martins[a] and Eduardo B. de Melo[b],*

[a] Department of Chemistry, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
[b] Department of Pharmacy, Western Paraná State University (UNIOESTE), Cascavel, PR, Brazil
* eduardo.b.de.melo@gmail.com
Thymidine phosphorylase (TP) is a multifunctional protein frequently overexpressed in many types

of cancer, as bladder, colorectal, esophageal, pancreatic, and others, and is associated with the
promotion of tumorigenesis, angiogenesis, metastasis, and the inhibition of apoptosis. As various
types of anticancer treatments stimulate TP expression, probably owing to their pro-angiogenic and
antiapoptotic properties, the suppression of this protein could hypothetically slow down or suppress
the recovery of cancer cells, thus providing beneficial supplementary effects. The objective of this
work was to perform a 4D-QSAR study with a set of 37 compounds (uracil derivatives), with inhibitory
effect on this enzyme, synthesized and published initially by Yano et al.[1,2] This study is
accomplished with a new web based software running LQTA-QSAR[3] methodology called Web-4D-
QSAR (https://github.com/rougeth/Web-4D-QSAR). After descriptors generation with this new web
browser interface, variable selection was carried out using Ordered Predictors Selection (OPS)[4]
algorithm implemented at QSAR Modeling[5] program. Model building was performed using Partial
Least Squares (PLS) regression. Based on this approach it was possible to obtain a model with the
following attributes: Descriptors: 23; latent variables: 1; n= 29; R2= 0.899; RMSEC= 0.375; F=
240.327; Q2LOO= 0.853 RMSECV= 0.453; nprediction= 8; R2pred= 0.901; RMSEP= 0.383; average
rm2(pred)-scaled= 0.829; rm2-scaled= 0.074; k= 1.031; k’= 0.968; |R20-R2’0|= 0.007. These obtained
results may be useful as a tool to allow a better comprehension about the inhibitory mechanism of
this class of compounds over thymidine phosphorylase, helping thus in the development of new
inhibitors agents with potential to be employed in the cancer therapy. The authors would like to thank
Brazilian Agencies Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), Conselho
Nacional de Desenvolvimento Científico (CNPq) and Fundação Araucária for the support.
[1]
S. Yano, et al., Bioorg. Med. Chem., 2004,
12, 3443.
[2]
S. Yano, et al., Bioorg. Med. Chem., 2004, 12, 3431
[3]
J.P.A. Martins, J. Chem. Inf. Model., 2009, 49, 1428.
[4]
R.F. Teófilo, J.P.A. Martins, M.M.C. Ferreira, J. Chemom., 2009, 23, 32.
[5]
J.P.A. Martins, M.M.C. Ferreira, Quim. Nova, 2013, 36, 554.
169
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SYNTHESIS AND DETERMINATION OF PHYSICOCHEMICAL

PROPERTIES OF NEW POTENTIAL ANTIMYCOBACTERIAL DRUGS
Pavlína Marvanová,[a],* Tereza Padrtová,[a] Klára Odehnalová,[a]

Otakar Humpa[b] and Petr Mokrý[a]
[a] Department of Chemical Drugs, University of Veterinary and Pharmaceutical Sciences Brno,
Palackého třída 1, 612 42 Brno, Czech Republic
[b] CEITEC—Central European Institute of Technology, Masaryk University, Kamenice 753/5, 62500
Brno, Czech Republic
* marvanovap@vfu.cz
Due to worldwide microbial resistance to commonly used therapeutic agents, antibiotics and
antifungals, there is a search for new active compounds even in different therapeutical groups of
drugs. The pharmacophore of N-arylpiperazine moiety can be found in chemical structure of many
compounds that showed promising antimycobacterial activity.I
In this study, new arylcarbonyloxyaminopropanole derivatives bearing substituted
N-phenylpiperazine moiety were prepared and their
physicochemical properties were determined.
R
The compounds, 3-(4-arylpiperazin-1-yl)-2-
+
hydroxypropyl 4-alkoxybenzoates (Figure) were OH N -
prepared as hydrochloride salts via multi-step H+ H Cl
O O N
synthesis starting from 4-alkoxybenzoic acids and - their
Cl
structure and purity were verified by available
methods of instrumental analysis (1H FT-NMR, 13C FT-
NMR, FT-IR, TLC, HPLC). The lipophilicity index Fig.1 (log
k) was determined by means of RP-HPLC and
ionizability (pKa) was determined by means of CZE.
The in vitro activity of final compounds against O
1
Mycobacterium tuberculosis, Mycobacterium R
smegmatis, Mycobacterium kansasii and Mycobacterium marinum will be evaluated and given into
correlation with their physicochemical properties.
Acknowledgments: Part of the work was carried out with the support of core facilities of CEITEC—
Central European Institute of Technology under CEITEC, open access project, ID number
LM2011020, funded by the Ministry of Education, Youth and Sports of the Czech Republic under the
activity “Projects of major infrastructures for research, development and innovations”.
[1]
I. Malík, et al. Molecules, 2016, 21, 1274.
170
P-95
EXPLORATION OF NEW ANTICANCER CHEMOTHERAPEUTIC AGENTS

BASED ON ANTITUMOR NATURAL PRODUCT ANDRASTINS
Shuqiang Yin, Quan Li, Aki Kohyama, Kenji Sugimoto and Yuji Matsuya*
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani,
Toyama 930-0194, Japan
* matsuya@pha.u-toyama.ac.jp
Andrastins, isolated from the cultures of Penicillium sp. FO-3929 in 1996, are reported to exert ras
protein farnesyltranferase inhibitory activity.[1] Thus, they are anticipated to be promising anti-cancer
agents because farnesylation of the ras oncogene protein is essential for its function. Andrastins
possess a unique sterically hindered cis-hydrindane ring system with vicinal quaternary carbons.
Although their unusual structure and promising biological activity has attracted broad synthetic
interest, no total syntheses and medicinal chemistry of andrastins have been reported so far. Herein,
we report an efficient method for the construction of key skeleton of Andrastins utilizing o-xylylene
cycloaddition strategy.
Me
C Me O
R3 Me D Me
A H OH
R1 CO2Me
R2 H
Me Me B
Andrastin A: R 1 = OAc, R2 = H, R3 = CHO

Andrastin B: R1 = OAc, R2 = H, R3 = CH2OH
Andrastin C: R1 = OAc, R2 = H, R3 = Me
Andrastin D: R 1 = R2 = O, R3 = CHO
Inspired by the power of intramolecuar cycloaddition of o-xylylenes thermolytically generated from

benzocyclobutenes for the synthesis of polycyclic system, we decided to construct the steroidal
skeletion of Andratins through a successive electrocyclic reactions. Coupling reaction of
benzocyclobutene unit with corresponding aldehyde furnished the AD fragment 1. After decyanation,
the product was subjected to intramolecular Diels-Alder reaction to give the key skeleton 2 via an o-
xylylene intermediate. This compound is versatile precursor of various Andrastins and analogous
derivatives, and medicinal chemistry based on these Andrastin compounds are now in progress in
our laboratory.
HO O
O
NC HO O
O 1) decyanation
Andratins
2) Diels-Alder reaction
MeO H CO2Me
CO2Me
1 MeO
2
[1]
S. Omura, et al. J. Antibiot., 1996, 49, 418; J. Antibiot., 1996, 49, 1278.
171
P-96
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL

PYRROLE-BASED AS EZH2 INHIBITORS
R. Mazzone,[a],* C. Zwergel,[a] M. Tafani,[c] A. Nebbioso,[d] L. Altucci,[d]

A. Mai[a] and S. Alente[a]
[a] Department of Drug Chemistry and Technologies, University “La Sapienza”, P. le A. Moro 5, 00185
Rome, Italy
[b] Department of Biology and Biotechnology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy
[c] Department of Experimental Medicine, University “La Sapienza”, Viale Regina Elena 324, 00161
Rome, Italy
[d] Naples 2nd University Department of Biochemistry Biophysics and General Pathology Via De
Crecchio 7, 800127 Naples, Italy
* roberta.mazzone@uniroma1.it
Polycomb repressive complex 2 (PRC2) mediates gene silencing of target genes involved in cell
cycle regulation, cell fate and differentiation, senescence and cancer.[1] Enhancer of Zeste
Homologue 2 (EZH2) is the catalytic subunit of PRC2 and, together with two other proteins (EED
and SUZ12), specifically catalyzes lysine methylation. Indeed, EZH2 induces methylation of histone
H3 on lysine 27 up to trimethylation by using S-adenosyl-L-methionine (SAM) as the co-substrate.
Actually, GSK126 and two other clinical candidates, Tazemetostat and CPI-1205, are in phase I or
I/II clinical trials for treatment of malignancies.[2] Prompted by this great clinical promise for cancer
treatment, we planned to perform a structural simplification and modification on the indazole
scaffold leading to novel pyrazole-based small molecules able to inhibit EZH2 as well as to
decrease H3K27m3 levels in cancer. Among newly obtained pyrazole derivatives of the first series,
1a (Figure) displayed growth arrest and autophagy induction in leukemia and solid cancer cells.[3]
Pursuing with a wider SAR investigation, pyrazole was replaced in the second series by a pyrrole
nucleus, and various substituents (alkyl, aryl or different aromatic rings and arylalkyl group) have
been inserted at the N1 position (1b, Figure Further optimization by introduction of various
substituents in ortho,
meta or para position of
IC50 15.4 M IC50 5.8-38.5 M IC50 0.33 M the N1-phenyl ring have
been carried out. All
new synthesized
pyrrole-based
compounds have been
screened against the
EZH2/PRC2 MT to
determine their
inhibition activities.
Selected compounds have been tested in different cancer cell lines (leukemia U937 and NB4,
human breast cancer cells MDA-MB231, neuroblastoma Kelly and SH-SY5Y) to determine their
effect on cell proliferation. Our biological results indicate that 1c (Figure) is the most potent
compound in our hands so far, according to its biochemical potency. We will go on with design and
synthesis of more potent derivatives, inspired by the meta-phenyl substitution carried by 1c, and
with further studies in other cancer cells including cancer stem cells.
[1]
I. Comet, E. M. Riising, B. Leblanc, K. Helin, Nat. Rev. Cancer, 2016, 16, 12.
[2]
G. Stazi, C. Zwergel, A. Mai, S. Valente, Exp. Opin. Ther. Pat., 2017, 27, 797.
[3]
P. Mellini, B. Marrocco, D. Borovika, L. Polletta, S. Saladini, G. Stazi, C. Zwergel, P. Trapencieris, E. Ferretti,
M. Tafani, S. Valente, A. Mai, submitted to J. Med. Chem., 2017.
172
P-97
SYNTHESIS OF NOVEL 13α-ESTRONE DERIVATIVES AS POTENTIAL

17β-HSD1 INHIBITORS
Ildikó Bacsa,[a] Rebeka Jójárt,[a] János Wölfling,[a] Gyula Schneider,[a]

Bianka Edina Herman,[b] Mihály Szécsi[b] and Erzsébet Mernyák[a],*
[a] Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary
[b] 1st Department of Medicine, University of Szeged, Korányi fasor 8–10, H-6720 Szeged, Hungary
* bobe@chem.u-szeged.hu
Novel 13α-estrone derivatives were synthesized by Sonogashira coupling. Transformations of 2- or

4-iodo regioisomers of 13α-estrone and its 3-methyl ether were carried out under different conditions
in a microwave reactor. 2-Iodo isomers were reacted with p-substituted phenylacetylenes using
Pd(PPh3)4 catalyst and CuI as a cocatalyst. Coupling reactions of 4-iodo derivatives could be
achieved by changing the catalyst to Pd(PPh3)2Cl2. The newly synthesized phenethynyl derivatives
were partially or fully saturated. Compounds bearing a phenolic OH group furnished benzofurans
under the conditions used for the partial saturation. The inhibitory effects of the compounds on
human placental 17β-hydroxysteroid dehydrogenase type 1 isozyme (17β-HSD1) were investigated
by an in vitro radiosubstrate incubation method. Certain 3-hydroxy-2-phenethynyl or -phenethyl
derivatives proved to be potent 17β-HSD1 inhibitors, displaying submicromolar IC50 values. These
compounds may serve as suitable tools for ligand-based enzyme studies. Further derivatizations
may lead to nanomolar inhibitors and may provide promising candidates for drug development.
I
R1O
1
Pd(PPh3)4
CuI, NEt 3 R2
R2 R2 O Pd/C
O 20 bar H2
6 C H
Pd(PPh3)2Cl 2 or C
Pd(OAc)2 H H
KOH/DMF R1O R1O
3 9
H H
C C
R1 = H or Me
R2 MeO R2 = H or Me or OMe or F or CF3
5
O Pd/C
O 20 bar H2
H
Pd(PPh3 )2Cl2 or
7 Pd(OAc)2 H H
KOH/DMF R1O R1O
R2 C 4
C
MeO
C H
H C R2
R2 10
Pd(PPh3 )2 Cl2
CuI, NEt 3
R2
8
R1O
I
2
Acknowledgments: The authors are grateful for financial support from the Hungarian Scientific
Research Fund OTKA K113150. The work of Erzsébet Mernyák in this project was supported by the
János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
173
P-98
ANTITUMORAL AND ANTIVIRAL ACTIVITIES OF NOVEL

1,2,3-TRIAZOLYL APPENDED L-ASCORBIC ACID DERIVATIVES
Andrijana Meščić,[a] Anja Harej,[b,c] Višnja Stepanić,[d] Sandra Kraljević Pavelić,[b,c]

Dominique Schols[e] and Silvana Raić-Malić[a],*
Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
[b] Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, HR-51000 Rijeka, Croatia
[c] Centre for High-throughput Technologies, University of Rijeka, Radmile Matejčić 2, HR-51000
Rijeka, Croatia
[d] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb
[e] Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
* sraic@fkit.hr
L-Ascorbic acid is known as a ubiquitous carbohydrate of vital importance in living beings. Some
pyrimidine and purine derivatives of 4,5-didehydro-5,6-dideoxy- and 6-deoxy-L-ascorbic acid
exhibited selective and efficient cytostatic activities and displayed antiviral activities.[1] The 1,2,3-
triazole moiety is extensively used in medicinal chemistry as a pharmacophore to modify known
bioactive molecules and to potentiate their biological activities.[2,3] Although click reactions are
traditionally conducted in batch process, the progress toward increased sustainability that requires
novel approaches with reduced environmental impact opened up in recent years continuous-flow as
a novel alternative to conventional batch-based synthesis.[4] Realizing the benefits of flow chemistry
as green and sustainable process and in continuation of our study towards the synthesis of 1,2,3-
triazole-containing heterocycle pharmacophores, our aim was to improve the practical applicability
of Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) to provide diverse C-6-
substituted 1,2,3-triazolyl 4,5-unsaturated L-ascorbic acid derivatives using innovative enabling
ultrasound and continuous flow hybrid system.
The results of in vitro screening and in silico analysis will be presented.

[1]
T. Gazivoda, M. Šokčević, M. Kralj, L. Šuman, K. Pavelić, E. De Clercq, G. Andrei, R. Snoeck, J. Balzarini,
M. Mintas, S. Raić-Malić, J. Med. Chem., 2007, 50, 4105.
[2]
S. Raić-Malić, A. Meščić, Curr. Med. Chem., 2015, 22, 1462.
[3]
S.B. Ötvös, I.M. Mándity, L. Kiss, F. Fülöp, Chem. Asian J., 2013, 8, 800.
[4]
A. Meščić, A. Šalić, T. Gregorić, B. Zelić, S. Raić-Malić, RSC Adv., 2017, 7, 791.
174
P-99
IDENTIFICATION OF NEW INHIBITORS OF PRMTs BY A MULTI-

SUBSTRATE-ADDUCT APPROACH
C. Milite,[a],* D. Rescigno,[a] A. Feoli,[a] S. Castellano[a,b] and G. Sbardella[a]

[a] Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084,
Fisciano (SA), Italy
[b] Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via S. Allende, 1, 84081
Baronissi (SA) Italy
* cmilite@unisa.it
The methylation of arginine residues is a prevalent posttranslational modification found in both

nuclear and cytoplasmic proteins, which is involved in a number of different cellular processes,
including transcriptional regulation, RNA metabolism, and DNA damage repair. Enzymes of the
protein arginine N-methyltransferase (PRMT) family catalyze the transfer of a methyl group from the
donor S-adenosyl-l-methionine (SAM or AdoMet) to the guanidinium side chain of arginine residues
in the target protein. Despite extensive research aimed at better understand the role of PRMTs in
physiological and pathological pathways, there have been only a few publications to date describing
small-molecule chemical modulators of the PRMTs. A few years ago, starting from AMI-1 (the first
selective inhibitor of PRMTs)[1] we identified EML108, which was characterized by an improved
selectivity profile among methyltransferases and a good cellular activity.[2] Moreover, docking studies
clearly showed that EML108 bind SAM and arginine pocket without fully occupying them. Starting
from this evidence, we herein report the design and the synthesis of new PRMTs inhibitors based
on the naphthalene scaffold of EML108. Firstly, we prepared some derivatives bearing a guanidine
moiety connected to the naphthalene scaffold via a variable linker. After optimization, we further
functionalized this scaffold with an adenosine moiety (Figure). This multi-substrate-adduct approach
lead to the identification of new sub-micromolar inhibitors of the arginine methyltransferase PRMTs.
Figure: Multi-substrate-adduct approach to the discovery of new inhibitor of PRMT1.
[1]
D. Cheng, et al., J. Biol. Chem., 2004, 279, 23892.
[2]
S. Castellano, et al., ChemMedChem, 2010, 5, 398.
175
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SYNTHESIS AND EVALUATION OF NEW N-ACYLETHANOLAMINES

PPAR-α LIGANDS PLANNED FROM CARDANOL
Camila de Oliveira Miranda,[a],* Carolyn Cummins[b] and Luiz A. Soares Romeiro[a]

[a] Post Graduate Program in Pharmaceutical Sciences, University of Brasilia, Faculty of Health
Sciences, Darcy Ribeiro Campus, Brasil
[b] Nuclear Hormone Receptors in Human Health and Disease Laboratory, University of Toronto,
Canada
* camilamiranda.unb@gmail.com
N-acylethanolamines are fatty acid amides that act on receptors and enzymes – notably PPAR and
FAAH enzyme – modulating pathophysiological conditions.[1,2] Novel perspectives for
neuroprotection involve the improvement of cognitive ability through mechanisms that include the
synergistic activation of PPAR and CB1 receptors; activation of CB1 receptor and inhibition of FAAH;
or by direct activation of PPAR-α by selective agonists.[1-3]
Considering that the phenolic lipids of Cashew Nut Shell Liquid have structural similarity to fatty acids
and that previous results have shown that anacardic and isoanacardic acids showed a weak agonist
profile for PPARs,[4,5] we synthesized, and evaluated preliminary in vitro activity of novel N-
acylethanolamines designed from cardanol. The synthetic strategy present here proved to be
effective for obtaining 13 intermediates and 9 target compounds in yields ranging from 47 % to 91
%.
O
OH O OH OH
1- O3 /O 2
DCM:MeOH O
Ac2O, H2PO4 CrO3 , H2SO4
2 x 40'
m.o. 3x1' 2- NaBH4 Me 2CO, 5oC
C 15 H 31-n C 15 H 31-n OH OH
MeOH:EtOH 7 7
10'
Cardanol mixture 16 h LDT 71 LDT 108
MeI, NaHCO3
Me 2CO, 90 oC
16 h
OR OR OH
O HO NH2 O O
RI/RBr, K 2CO 3
OH 90 oC,16 h DMF, 145 oC

N 7
O 13 h O
7 7
H
LDT 351 - 358 LDT 108-OMe
R= H, CH3 - C8H17
Figure: Synthetic route of the N-acylethanolamines, LDT 351 – 358.
Preliminary in vitro evaluation of the target compounds at 10 μM, 25 μM and 50 μM against luciferase
for PPAR-α by reporter gene assay in HEK293 human embryonic kidney cells allowed the
identification 4 derivatives (LDT352 – LDT355) as capable of activating PPAR transcription in relation
to solvent activity. LDT352 and LDT353 derivatives present EC50 equal to 12 μM and 14 μM,
respectively, while the other compounds are under EC50 determination and evaluation against to the
FAAH enzyme.
[1]
L.V. Panililio, Z. Justinova., S.R. Goldberg, Pharmacol. Ther., 2013, 138, 84.
[2]
C. Mazzola, J. Medalie, M. Scherma, Learn. Memory, 2009, 16, 332.
[3]
E. Di Tomaso, M. Beltramo, D. Piomelli, Nature, 1996, 382, 677.
[4]
P.S. Alves, Master’s Dissertation, Universidade de Brasília, Brasil, 2015.
[5]
F.J.G. Queiroz, Master’s Dissertation, Universidade de Brasília, Brasil, 2015.
176
P-101
DEVELOPMENT OF NOVEL REAGENTS FOR GENERATING ISLETS Β-

CELLS AND ENHANCING THEIR FUNCTION BASED ON CLUSTERED
NANOFORMULATION OF NEUROLIGIN-2 MIMETICS
Munder Anna,[a] Shtriker Efrat,[a] Viskind Olga,[a] Korshin Edward,[a]

Chessler Steven[b] and Gruzman Arie[a],*
[a] Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan, Israel
[b] Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of
California, Irvine, California, United States
* gruzmaa@biu.ac.il
Β-cell membrane and presynaptic zones of neurons have sites of similar protein complexes
mediating secretion of bioactive molecules. Synaptic proteins that mediate interactions between
neurons and guide the formation and functional maturation of synapses have been recently
identified. These synapse-inducing proteins include neuroligins and their binding partners:
neurexins. It was found that insulin secretion and the proliferation rate of β-cells increased when β-
cells were co-cultured with cells overexpressing neuroligins. We propose that neuroligin-derived
molecules arranged in clusters can enhance β-cell functions by increasing insulin secretion,
functional maturity and protecting in stress conditions. Several peptides were derived from crystal
structures of different neuroligins and neurexins using molecular modeling method. Based on these
results, we designed and fabricated poly(amidoamine) dendrimer decorated by the peptide. The
compound increased insulin secretion, induced the formation of islets-like cellular structures,
proliferation rate and protected β-cell line against oxidative and ER stresses. Identical effect on the
insulin secretion was also obtained in isolated mice islets. Moreover, diabetic mice treated by our
compound significantly reduced blood glucose level in comparison to untreated mice.
In summary, we report about the development of a new class of potential antidiabetic compounds.
Such systems might support β-cell differentiation and viability in vitro, which will increase survival of
further β-cell transplants in vivo. Such approach of using the neuron secretion machinery presented
in β-cells as a target for antidiabetic drug design was never reported before.
177
P-102
TARGETING PLASMODIUM FALCIPARUM GLUCOSE-6-PHOSPHATE

DEHYDROGENASE IN THE PURSUIT OF NOVEL ANTIMALARIAL
AGENTS
Diego Muñoz-Torrero,[a],* Nelson Alencar,[b] Irene Sola,[a] María Linares,[c]

Caterina Pont,[a] Luca Di Palma,[a] Carla Barbaraci,[a] Cristina Sampedro,[a]
Jordi Juárez-Jiménez,[b] Paloma Abad,[c] Susana Pérez-Benavente,[c]
Jerónimo Lameira,[d] José M. Bautista[c] and F. Javier Luque[b],*
[a] Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food
Sciences and Institute of Biomedicine (IBUB), University of Barcelona (UB), Av. Joan XXIII 27-31,
E-08028, Barcelona, Spain
[b] Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences,
and IBUB, UB, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain
[c] Departamento de Bioquímica y Biología Molecular IV and Instituto de Investigación Hospital 12 de
Octubre, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n, Ciudad Universitaria, E-
28040, Madrid, Spain
[d] Laboratório de Planejamento e Desenvolvimento de Fármacos-LPDF, Instituto de Ciências Exatas
e Naturais- ICEN, Universidade Federal do Pará – UFPA, Av. Augusto Correa, Nº 1- Bairro:
Guamá, Cep: 66.075-900, Belém-Pará, Brazil
* dmunoztorrero@ub.edu; fjluque@ub.edu
There currently exists a dire need for safe and inexpensive new antimalarial drugs, which are
effective against multiple life cycle stages of Plasmodium falciparum, and act through mechanisms
that differ from those of the available drugs to prevent drug resistance.
The enzyme glucose-6-phosphate dehydrogenase (G6PD) of P. falciparum has emerged as a
promising target for antimalarial drug discovery, in the light of its key role in parasite development
and survival and of the protective effect against malaria infection observed under human G6PD
deficiency conditions.
Here we describe the construction of a homology model of PfG6PD, which has enabled the
identification of key structural differences at the enzyme active site as compared with the human
enzyme. We have exploited these changes for rationally designing a novel family of selective
substrate analog-based inhibitors of PfG6PD, some of which display micromolar affinity, good
PfG6PD over hG6PD selectivity, and low cytotoxicity, but weak antiplasmodial activity in phenotypic
assays, likely as a consequence of a poor internalization of the compounds in the parasite cell. Work
is in progress for improving the physicochemical / pharmacokinetic properties of this class of
compounds.
178
P-103
A SYNTHESIS OF “DUAL WARHEAD” β-ARYL ETHENESULFONYL

FLUORIDES AND ONE-POT REACTION TO β-SULTAMS
Praveen K. Chinthakindi,[a] Kimberleigh B. Govender,[a] A. Sanjeeva Kumar,[a] Hendrik G.

Kruger,[a] Thavendran Govender,[a] Tricia Naicker[a],* and
Per I. Arvidsson[a,b]
[a] Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban, South Africa
[b] Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational
Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska
Institutet, Stockholm, Sweden
* naickert1@ukzn.ac.za
Herein, we report an operationally simple, ligand- and additive-free oxidative boron-Heck coupling
that is compatible with the ethenesulfonyl fluoride functional group. The protocol proceeds at room
temperature with chemoselectivity and E-isomer selectivity and offers facile access to a wide range
of β-aryl/heteroaryl ethenesulfonyl fluorides from commercial boronic acids. Furthermore, we
demonstrate a “one-pot click” reaction to directly transform the products to aryl-substituted β-
sultams.
[1]
P.K. Chinthakindi, H.G. Kruger, T. Govender, T. Naicker,P.I. Arvidsson, J. Org. Chem., 2016, 81, 2618.
[2]
J. Dong, L. Krasnova, M.G. Finn, K.B. Sharpless, Angew. Chem., 2014, 53, 9430.
[3]
A. Narayanan, L.H. Jones, Chem. Sci., 2015, 6, 2650.
179
P-104
SYNTHESIS AND CYTOTOXIC PROPERTIES OF NEW DERIVATIVES OF

BENZOFURANS
M. Napiórkowska,[a] M. Cieślak,[b] K. Królewska,[b]

J. Kaźmierczak-Barańska[b] and B. Nawrot[b]
[a] Chair and Department of Biochemistry, Medical University of Warsaw, 1 Banacha Str., 02-097
Warsaw, Poland
[b] Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish
Academy of Sciences, 112 Sienkiewicza Str., 90-363 Łódź, Poland
Benzofuran skeleton occupies an important position in organic chemistry and is considered as one
of the most important heterocyclic ring because of its diverse biological profile. This structural unit is
a central part of a variety of biological active compounds. Benzofuran derivatives have been reported
to possess several biological properties such as antiviral, immunosuppressive, antioxidant,
antifungal, anti-inflammatory, antimicrobial, antifungal, analgesic, antihyperglycemic, and antitumor
activities. Active compounds are both, synthetic as well natural derivatives. Well known natural
compounds are Cicerfuran, Conocarpan and Ailanthoidol.
In our previously studied[1,2] group of derivatives we have identified several benzofurans that
presented highest cytotoxicity to leukemia cells, lines K562, HL-60, respectively (IC50,* in the range
of 0.1-10 µM). On the contrary, these compounds were non-toxic to non-tumor endothelial cells
(HUVEC) and tumor adherent cells (HeLa).
Because high activity of evaluated compounds we decided to continue our work on the field of these
derivatives. The main stage of synthetic works was the modification of the structure of benzofuran
derivatives in order to obtain products with improved solubility and bioavailability, while retaining their
biological activity. In order to improve the solubility of the compounds hydrophilic groups such as -
OH, NH2, COOH were introduced to their structure. Thus we have synthesized 12 new derivatives
(Figure). The structures of all new compounds were established by 1HNMR, 13CNMR and HR MS
spectra.
-CH , -CH2 Br
CH23Br -COOH, -CONH2 -COOH, -CONH2
-Br,Br-H
H3CO -COOCH3
-COOCH3
HO
H3 CO
-COOH,
COCH3 -CONH2 ,
O
H3CO -COOCH3 -CH3, -CH2 Br -CH3, -CH2Br
Br 2HC Br 2 HC
COCH3 -CHOHCHBr2 O O
-CHOHCHBr2
-COCHBr2 -COCHBr2
O
O
Figure: Examples of modifications in the structures of the compounds.
The obtained compounds were tested for their cytotoxic properties in cervix carcinoma (HeLa),
chronic myelogenous leukemia (K562), acute lymphoblastic leukemia (MOLT-4) and normal
endothelial (HUVEC) cells using MTT assay. In these screening studies we have identified four
compounds that showed toxicity towards both HeLa, K562 and MOLT-4 cell lines. SAR analysis
showed that the presence of a halogen atom in the structure of benzofuran derivatives seems to be
a crucial factor inducing their toxicity.
[1]
M. Krawiecka, B. Kuran, J. Kossakowski, M. Cieslak, J. Kazmierczak-Barańska, K. Królewska, B. Nawrot,
EP 2631232 A1, 2013.
[2]
M. Krawiecka, B. Kuran, J. Kossakowski, M. Cieslak, J. Kazmierczak-Barańska, K. Królewska, B. Nawrot,
Anticancer Agents Med. Chem., 2014, 15, 115.
180
P-105
INVESTIGATION OF THE ANTIPROLIFERATIVE AND

ANTIHYPERGLYCEMIC ACTIVITIES OF NEW THIAZOLIDINEDIONE
DERIVATIVES
Cristina Nastasă,[a] Daniel Scherman,[b] Alina Pârvu,[c] Ovidiu Oniga[a] and

Brîndușa Tiperciuc[a]
[a] Department of Pharmaceutical chemistry, ”Iuliu Hațieganu” University of Medicine and Pharmacy,
Faculty of Pharmacy, Cluj-Napoca, Romania
[b] Unité de Pharmacologie Chimique et Génétique et d'Imagerie, INSERM U1022 - CNRS UMR8151,
Paris, France
[c] Department of Physiopathology, ”Iuliu Hațieganu” University of Medicine and Pharmacy, Faculty of
Medicine, Cluj-Napoca, Romania
* cmoldovan@umfcluj.ro
Cancer represents a global threat, each year millions of persons losing their lives because of this
disease.[1] For its limitation, an early diagnose, a careful monitoring and the finding of new efficient
drugs, with limited secondary effects, are urgently needed. Diabetes is an important issue for the
health system, due to its severe and life-threatening complications.[2]
Thiazole and its derivatives (thiazolidine, thiazolidinedione) are frequently cited in literature for their
antiproliferative,[3] antidiabetic[4] and antioxidant activities. Thiazolidinediones (glitazones) are drugs
already used in the treatment of type 2 diabetes.[5] This research project had as goals the
investigation of the antiproliferative and antihyperglycemic effects of a series of newly synthesized
thiazolidinediones. The antiproliferative activity of 16 thiazolidinedione derivatives, previously
synthesized,[6] was evaluated by the MTT test, calculating IC50 on 2 tumor cell lines (B16 and CT26).
For the antihyperglycemic potential, an experimental model of diabetes was induced by the
intraperitoneal injection of streptozotocin, in rats. After hyperglycemia was produced, animals
received, by gavage, suspensions of 6 thiazolidinedione derivatives, previously synthesized.[7-9]
Their effects were compared with the reference antidiabetic pioglitazone.
The compounds demonstrated promising inhibitory effects against the studied tumor cell lines.
Thiazolidinediones 3, 7 and 9 exhibited best antiproliferative activity against B16 cells and
compounds 1, 2 and 6, against CT26, respectively. Reduction of hyperglycemia, manifested in the
animals treated with the tested molecules, was superior to pioglitazone, the antidiabetic drug used
as reference.
This project was realized with the support of ”Iuliu Hațieganu” University of Medicine and Pharmacy
internal grant no. 4944/7/08.03.2016.
[1]
WHO Media Centre http://www.who.int/mediacentre/factsheets/fs297/en/.
[2]
F. Paneni, J.A. Beckman, M.A. Creager, F. Cosentino, Eur. Heart J., 2013, 34, 2436.
[3]
M.S. Abdel-Maksoud, M.-R. Kim, M.I. El-Gamal, M.M. Gamal El-Din, J. Tae, H. Choi, K.-T. Lee, K. Yoo,
C.-H. Oh, Eur. J. Med. Chem., 2015, 95, 453.
[4]
S.-J. Yang, W. Lee, E.-A. Kim, K. Nam, H.-G. Hahn, S. Choi, S.-W. Cho, Eur. J. Pharmacol., 2014, 736,
26.
[5]
L.A. Faine, M. Rudnicki, F.A. César, B.L. Heras, L. Boscá, E.S. Souza, M.Z. Hernandes, S.L. Galdino,
M.C.A. Lima, I.R. Pitta, D.S.P. Abdalla, Curr. Med. Chem., 2011, 18, 3351.
[6]
C. Nastasă, B. Tiperciuc, A. Pârvu, M. Duma, I. Ionuţ, O. Oniga, Arch. Pharm., 2013, 346, 481.
[7]
C. Nastasă, B. Tiperciuc, L. Vlase, A. Pîrnău, O. Oniga, Studia UBB Chemia, 2015, LX(4), 239.
[8]
C. Nastasă, M. Duma, C. Marie, D. Scherman, B. Tiperciuc, O. Oniga, Dig J Nanomater. Biostruct., 2013,
8, 1079.
[9]
C.M. Nastasă, M. Duma, A. Pîrnău, L. Vlase, B. Tiperciuc, O. Oniga, Clujul medical, 2016, 89, 122.
181
P-106
ANTICARCINOGENIC POTENTIAL OF PLUM (Prunus domestica L.)

KERNEL EXTRACTS OBTAINED BY SUBCRITICAL WATER
Nataša Nastić,[a],* Slavica Ražić,[b] Ana Damjanović,[c] Aleksandra Cvetanović,[a] Višnja

Gaurina Srček,[d] Igor Slivac,[d] Kristina Radošević[d] and
Jaroslava Švarc-Gajić[a]
[a] Faculty of Technology, University of Novi Sad, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia
[b] Faculty of Pharmacy, Department of Analytical Chemistry, University of Belgrade, Vojvode Stepe
450, 11221 Belgrade, Serbia
[c] Laboratory for Biological Response Modifiers, Department for Experimental Oncology, Institute of
Oncology and Radiology of Serbia, Belgrade, Serbia
[d] Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10000 Zagreb,
Croatia
* nat.nastic@gmail.com
Colorectal cancer is the third most common cancer and one of the leading causes of morbidity and
mortality.[1] Last years of the twentieth century were marked with increased worldwide interest in
herbal medicine and natural health-promoting preparations. Published research confirms that plants
and plant by-products are rich in valuable phytochemicals with health benefits against cancer and
other diseases. Consumption of plums (Prunus domestica L.) is believed to be beneficial for treat
blood circulation, digestive disorders, diabetes, and obesity.[2] High fibre content in plums promote
digestion and peristalsis thus it is beleived that regular consumption of this fruit may play a role in
the prevention of colorectal cancer. Kernels recovered from plum pit are still unexploited plant
resources and agricultural by-product. In recent years, valorisation of organic by-products by
different approaches has gained great interest. In this respect, the efforts have been directed to
development and application of environmentally-benign extraction techniques, such as subcritical
water extraction. The main goal of the present study was, therefore, to examine anticarcinogenic
potential of subcritical water extracts of plum kernels. Biological activity was tested by in vitro assay
using human colorectal adenocarcinoma cell line (LS-174T). Bioactive compounds from plum
kernels were extracted by subcritical water in house-made extractor at different temperatures (25-
100 °C), while other parameters were constant. Obtained extracts were assessed for their
anticarcinogenic potential using methyl thiazole tetrazolium (MTT assay).
Table 1: The influence of the extraction temperature on anticarcinogenic activity of plum kernel
extracts obtained by subcritical water
Temperature [oC] IC50 [µg/ml],*

25 12.28±1.46
40 13.41±1.72
60 8.81±0.52
80 14.90±0.93
100 /
*Mean value ± 2SD of three replications
Obtained results confirmed anticarcinogenic activity of the plum kernel extracts against colorectal
cancer (Table 1). The highest anticarcinogenic potential on LS-174T with the IC50 values of 8.81 ±
0.52 μg/ml was provided by the extraction at temperature of 60°C. In conclusion, this research
represents a pioneering work to further investigations directed towards identification of
pharmacologically-active compounds in plum kernels for the purpose of new anti-cancer drug design
and development.
[1]
F.A. Haggar, R.P. Boushey, Clin. Colon Rectal Surg., 2009, 22(04), 191.
[2]
T.S. Li, Vegetables and fruits: nutritional and therapeutic values. CRC Press, 2008.
182
P-107
IN VITRO SCREENING OF ANTICARCINOGENIC PROPERTIES OF

CHERRY STEM EXTRACTS OBTAINED BY SUBCRITICAL WATER
Nataša Nastić,[a],* Višnja Gaurina Srček,[b] Kristina Radošević,[b] Igor Slivac,[b] Aleksandra
Cvetanović,[a] Vesna Novakov[a] and Jaroslava Švarc-Gajić[a]
[a] Faculty of Technology, University of Novi Sad, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia
[b] Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10000 Zagreb,
Croatia
* nat.nastic@gmail.com
The development of new anticancer drugs based on naturally occurring biologically active
compounds continues to be a major focus in cancer research. The use of natural by-products from
agriculture and food production processes to extract valuable compounds has become more and
more common in recent years. Sweet and sour cherry (Prunus avium L. and Prunus cerasus L.)
stems attract the interest of scientific community due to their long use in alternative medicine as
sedative and diuretic in form of infusions and decoctions.[1,2] Due to high content of flavonoids and
potassium, it has been reported that cherry stems contribute to suppression of inflammation and
have positive effects on cardiovascular system and smooth muscles. In the present study, cherry
stem extracts were prepared by subcritical water and valorised by testing their biological activity in
vitro using hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines.
Bioactive compounds from sweet and sour cherry stems were extracted by subcritical water at
extraction temperature of 150 °C, extraction pressure of 30 bar, extraction time of 30 min and
convective mass transfer defined by vibration frequency of the reaction vessel of 3 Hz. The cancer
cells were exposed to the different volume ratios of extracts (1 v/v to 20 v/v) for 72 h and the effects
on cell growth were evaluated using the CellTiter 96® Aqueous One Solution Cell Proliferation Assay
(Promega, USA).
Table 1: IC50 values of sweet and sour cherry stem extracts obtained by subcritical water
IC50 [v/v]
HepG2 MCF-7
P. avium stems 18.29 17.99
P. cerasus stems >20 >20
Comparing the survival of HepG2 and MCF-7 cells treated with obtained extracts, and the calculated
IC50 values it can be concluded that subcritical water extracts of P. avium stems had higher
anticarcinogenic potential than P. cerasus stems.
[1]
N. Hooman, F. Mojab, B. Nickavar, P. Pouryousefi-Kermani, Pakistan J. Pharm. Sci., 2009, 22, 381.
[2]
S. Shamsi, Int. J. Green Pharm. (IJGP), 2017, 11(01).
183
P-108
DESIGN, SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW

PIPERAZINAMIDES DERIVED FROM 3-ISOBUTYL-2,5-
DIOXOPYRROLIDIN-1-YL-ACETIC ACID
Jolanta Obniska,[a],* Małgorzata Góra,[a] Sabina Rybka,[a] Krzysztof Kamiński[a] and Anna
Rapacz[b]
[a] Department of Medicinal Chemistry, Jagiellonian University, Medical College, 9 MedycznaStreet,
30-688 Kraków, Poland
[b] Department of Pharmacodynamics, Jagiellonian University, Medical College, 9 Medyczna Street,
30-688 Kraków, Poland
* mfobnisk@cyf-kr.edu.pl
Recent studies from our laboratory have demonstrated the various anticonvulsant activity among the
amides derived from 2,5-dioxopyrrolidin-1-yl-acetic acid with different substituents at position-3 of
pyrrolidine-2,5-ring.[1,2] In these series of derivatives the most active were compounds with methyl
and ethyl group at position-3 of imide ring. Taking into consideration these results, in search of new
anticonvulsant agents, in the present study new piperazinamides with the 3-isobutyl-2,5-dioxo-
pyrrolidin-1-yl-acetic acid as a core fragment have been synthesized (Figure).
O
O
F N R
N
H3C H3C N N
N N
H3C O O
O O
H3C
ED50 = 82.74 mg/kg (MES ip in mice)
R = H, 2-F, 4-F, 2-Cl, 2,3-Cl, 2-CF3, 2-CH3,
ED50 = 40.34 mg/kg (sc.PTZ ip in mice)
3-CH3, 2-OCH3, 3-OCH3
The target compounds were synthesized in two-step procedure. The starting 2-isobutyl-succinic acid
was prepared according to the method described previously.[1,2] In the next step the
cyclocondensation of obtained acid with 2-amineacetic acid yielded in 3-isobutyl-2,5-dioxo-
pyrrolidin-1-yl-acetic acid. The final compounds were obtained in the coupling reaction of 3-isobutyl-
2,5-dioxo-pyrrolidin-1-yl-acetic acid with equimolar amounts of appropriate 4-phenylpiperazines in
the presence of carbonyldiimidazole reagent.
All obtained compounds have been evaluated for their anticonvulsant activity in the MES and scPTZ
seizure tests.
Acknowledgments: This study was supported by the grant of National Scientific Centre, Poland
(Grant No DEC-No-2013/11/B/NZ7/02081).
[1]
J. Obniska, A. Rapacz, S. Rybka, B. Powroźnik, E. Pękala, P. Żmudzki, K. Kamiński, Eur. J. Med. Chem.,
2015, 102, 14.
[2]
J. Obniska, A. Rapacz, S. Rybka, M.Góra, K. Kamiński, K. Sałat, P. Żmudzki, Bioorg.Med. Chem., 2016, 24,
1598.
184
P-109
IDENTIFICATION OF 3-[3, 4-BIS-(TERT-BUTYL-DIMETHYL-

SILANYLOXY)-PHENYL]-PROPIONIC ACID AS AN ADIPONECTIN
EXPRESSION ENHANCER
Tsutomu Oikawa,[a],* Motomu Inoue,[a] Yurie Ueno,[a] Atsuko Motojima,[a]

Nobuyasu Matsuura,[b] Tomio Saito[c] and Hiroyuki Osada[c]
[a] School of Nutrition and Dietetics, Kanagawa University of Human Services, Yokosuka, Kanagawa 238-
8522, Japan
[b] Faculty of Science, Okayama University of Science, Okayama, Okayama 700-0005, Japan
[c] Chemical Biology Department, RIKEN Advanced Science Institute, Saitama 351-0198, Japan
* oikawa-t@kuhs.ac.jp
Patients with diabetes have been increasing worldwide, and the patient number has been estimated
to rise from 171 million in 2000 to 366 million in 2030. [1] Type 2 diabetes mellitus accounts for over
90% of all diabetes. Type 2 diabetes is characterized by decreased insulin secretion and insulin
resistance. Thus overcoming insulin resistance is an important issue in the prevention and/or
treatment of type 2 diabetes. Recent studies have shown that adiponectin, an adipocyte-derived
hormone-like protein, exerts insulin-sensitizing and anti-diabetic effects, indicating the protein
represents a potential target for treating and/or preventing type 2 diabetes. Also, expression of
adiponectin has been shown occur during adipogenesis. Based on our hypothesis that molecues
that induce adipocyte differentiation could also act as stimulators of adiponectin expression, we
screened a novel small-molecule stimulator of adiponectin expresssion, using the system involving
differentiation of ST-13 preadipocytes as an indicator, and found that some small molecules,
including nobiletin, norlichexanthone, testufuran A and nocapyrones, induced adipogenesis in ST-
13 cells and upregulated adiponectin expression.[2-5] Furthermore, using the cell-based screen
system, we carried out screening of 1,056 compounds from RIKEN NPDepo library, for finding out
compounds that caused adipocyte differentiation. Of them, several compounds remarkably caused
adipogenesis in ST-13 cells treated, as judged from a microscopic observation of celluar
accumulation of lipid droplets. They include 3-[3, 4-bis-(tert-butyl-dimethyl-silanyloxy)- phenyl]-
propionic acid (1), astemisole, corticosterone and glibenclamide. Herein, we report the identification
of 1 as an adiponectin expression enhancer. Oil red O staining showed that 1 promoted adipogenesis
in ST-13 cells. Real-time RT-PCR assay confirmed that 1 increased the mRNA expression of aP2
and PPARγ2, markers of adipocyte differentiation. Western blot analysis demonstrated that 1
enhanced the extracellular secretion of adiponectin protein. An increase in adiponectin mRNA level
was also observed in the ST-13 cells treated with 1. The increased adiponectin mRNA was blocked
by actinomycin D treatment, implying that the increase is the result of upregulated transcription.
These results identified 1 as an enhancer of adiponectin expression. Additionally 1 significantly
increased the mRNA expression of glucose transporter 4 that plays a key role in glucose uptake in
adipocytes and muscle cells, compared with the vehicle. These findings suggest the possibility that
1 has the potential to treat and/or prevent type 2 diabetes and other lifestyle-related diseases like
metabolic syndrome.
[1]
S. Wild, et al. Diabetes Care. 2004, 27, 1047.
[2]
K. Kunimasa, et al., Bioorg. Med. Chem. Lett., 2009, 19, 2062.
[3]
M. Ikeda, et al., Med. Chem., 2011, 7, 250.
[4]
T. Akiyama, et al., Tetrahedron, 2013, 69, 6560.
[5]
Y. Kim, et al., Mar. Drugs, 2014, 12, 4110.
185
P-110
SYNTHESIS AND BIOLOGICAL ACTIVITY OF

3-AMINOTHYMOQUINONE
Una Glamočlija,[a],* Subhash Padhye,[b] Selma Špirtović-Halilović,[a]

Amar Osmanović,[a] Elma Veljović,[a] Sunčica Roca,[c] Irena Novaković,[d]
Sandra Kraljević Pavelić,[e] Anja Harej[e] and Davorka Završnik[a]
[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sarajevo, Zmaja od Bosne
8, 71000 Sarajevo, Bosnia and Herzegovina
[b] Interdisciplinary Science and Technology Research Academy, University of Pune, 2390-B, Hidayatullah
Road, 411001 Pune, India
[c] NMR Centre, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
[d] IHTM, Center for Chemistry, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia
[e] Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia
* una.glamoclija@gmail.com
Thymoquinone (TQ) is a natural benzoquinone with various biological and medicinal activities. The
main disadvantage of TQ is its low aqueous solubility. In the present work we report the synthesis
and biological activities of TQ derivative, 3-aminothymoquinone (ATQ).
ATQ was prepared according to published literature reports,[1] with slight modifications (Figure). The
structure was identified by elemental analysis and characterized in solution by mass spectrometry
and NMR spectroscopy.
O O
CH3COOH
+ NaN3
Reflux 3 hours
NH2
O O
Thymoquinone 3-aminothymoquinone
Figure: Synthesis of 3-aminothymoquinone from starting compound thymoquinone.
Antimicrobial activity was determined against four Gram-positive and four Gram-negative bacteria
strains and three fungi using diffusion and micro-dilution methods. It was observed that antibacterial
activity is diminished in case of ATQ when compared to TQ. On the other hand, ATQ showed strong
antifungal activity in all tested fungi (Candida albicans ATCC 10231, Saccharomyces cerevisiae
ATCC 9763 and Aspergillus brasiliensis ATCC 16404) with minimal inhibitory concentration (MIC)
values significantly lower when compared to TQ and Nystatin which was used as the reference drug.
Antiproliferative activity of TQ and ATQ was evaluated in five different cell lines: SW620 (metastatic
human colon adenocarcinoma), CFPAC (ductal pancreatic adenocarcinoma), HepG2
(hepatocellular carcinoma), HeLa (cervical adenocarcinoma) and WI38 (human lung fibroblasts).
ATQ had stronger effects in all tested cell lines when compared to TQ.
In conclusion, ATQ, which is the C-3 amino derivative of TQ, exerts significantly higher antifungal
and antitumor activity, when compared to parent compound.
[1]
M. Yusufi, S. Banerjee, M. Mohammad, S. Khatal, K. Venkateswara Swamy, E. M. Khan, A.
Aboukameel, F. H. Sarkar, S. Padhye, Bioorg. Med. Chem. Lett., 2013, 23, 3101.
186
P-111
SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NEW

PHENOXYACETHAMIDE DERIVATIVES OF AMINES, AMINOALKANOLS
OR AMINO ACIDS
Katarzyna Pańczyk,[a],* Anna Waszkielewicz,[a] Dorota Żelaszczyk,[a]

Ewa Żesławska,[b] Karolina Słoczyńska,[c] Paulina Koczurkiewicz,[c]
Elżbieta Pękala[c] and Henryk Marona[a]
[a] Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical
College, Medyczna Str. 9, 30-688 Kraków, Poland
[b] Department of Chemistry, Institute of Biology, Pedagogical University, Podchorążych Str. 2, 30-084
Kraków, Poland
[c] Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, Medyczna
Str. 9, 30-688 Kraków, Poland
* katarzyna.panczyk@uj.edu.pl
Within the present study nineteen new 2,3-dimethyl-, 2,6-dimethyl- or 2,4,6-trimethylphenoxy-

acetamide derivatives of amines, aminoalkanols or amino acids were designed for potential
anticonvulsant activity (Figure).
O
O R: 2,3-(CH 3)2, 2,6-(CH3)2 or 2,4,6-(CH 3) 3
Z
R Z: amine, aminoalkanol or amino acid
Figure: General formula of title compounds.
All title compounds were obtained via multistep chemical synthesis. Firstly, appropriate phenols were
transformed into substituted phenoxyacetyl chlorides. The obtained acid chlorides were the subject
of aminolysis in order to obtain the final products. In case of several compounds, the reaction was
carried out with the use of amino acid ester hydrochlorides and was followed by reaction with either
NaHCO3, ammonia or methylamine.[1] The identity and purity of synthesized compounds was
confirmed by means of analytical HPLC analysis, LCMS and spectral methods (1H and 13C NMR).
Three active compounds were the subject of crystallography studies, which confirmed their
configuration.
Antiepileptic activity and neurological toxicity assays were carried out by the Epilepsy Therapy
Screening Program, ETSP, Epilepsy Branch, National Institute of Neurological and Communicative
Disorders and Stroke, National Institutes of Health in Rockville, USA. All compounds were the
subject of preliminary screening for anticonvulsant activity and neurotoxicity (rotarod) in mice after
i.p. administration, including 6 Hz[2] and MES or MES and scMET as models of convulsions. Several
most active compounds were the subject of additional studies, including MES in rats after p.o.
administration. For compound 7 (R-(-)-2-(2,6-dimethylphenoxy)-N-(1-hydroxypropan-2-
yl)acetamide) ED50 (12 mg/kg b.w., rats, p.o.) and TD50 (>500 mg/kg b.w., rats, p.o.) values have
been established.
The most active compounds were the subject of preliminary safety testing. Four active compounds
were evaluated for their potential mutagenic activity with the use of Ames test.[3] No mutagenicity
was observed, however all tested compounds showed moderate to strong antimutagenic effect.
Compound 7 was additionally tested in vitro for cytotoxicity against astrocytes and showed no toxic
effect in the used concentrations.
Acknowledgments: This work was supported by the National Science Centre, Poland, decision on
grant no. DEC-2015/17/N/NZ7/00966.
[1]
H. Marona, A. M. Waszkielewicz, E. Szneler Acta Pol. Pharm. - Drug Des., 2005, 62, 345.
[2]
M. E. Barton, B. D. Klein, H. H. Wolf, H. S. White Epilepsy Res., 2001, 47, 217.
[3]
K. Mortelmans, E. Zeiger Mutat. Res., 2000, 455, 29.
187
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THEORETICAL PREDICTION OF LIPOPHILICITY

OF THIOSEMICARBAZIDE DERIVATIVES
Agata Paneth,* Tomasz Plech, Dominika Janowska, Szymon Kosiek,

Nazar Trotsko and Monika Wujec
Department of Organic Chemistry, Medical University of Lublin, Poland
* agata.paneth@umlub.pl
Since it is important to carefully monitor logP values at the lead selection level and during lead
optimization to ensure that the clinical candidates are within an acceptable lipophilicity range, we
have focused our attention on finding a computational tool that would be applicable to rapid and
accurate predictions of lipophilicity of thiosemicarbazide-based compounds. From the
thermodynamical point of view the equilibrium constant K (at a given temperature and standard
concentration) is given by the equation:
∆ = −
where G is Gibbs free energy, R is universal gas constant and T – absolute temperature.
It thus should be possible to evaluate logKo-w values by computing Gibbs free energies of a given
molecule in aqueous/octanol solutions. Expanding recent reports[1] we have tested three continuum
solvent models (IEFPCM, CPCM, SMD) with the DFT B3LYP functional expressed in several basis
sets (6-31+G(p,d), 6-311++G(d,p), aug-cc-pVDZ, def2-DZVP, def2-TZVP). Initially RM-1 optimized
structures were reoptimized in the gas phase at the given theory level and then three types of
calculations were performed. Firstly, energies for the gas phase structures with inclusion of the
solvent model were calculated. Secondly, reoptimization with solvent model included has been
performed for both liquid phases. Finally, frequency calculations for the structures optimized with
solvent models have been carried out in order to calculate ZPEs and thermal corrections to Gibbs
free energies. Among tested methods SMD/B3LYP/def-TZVP turned out to be most promising in
terms of speed of calculations and agreement of the results with the experimental data. We have
found that results from the first two methods correlate linearly with the experimental values (see
Figure) with logP = 1.38logKo-w+0.92, where Ko-w is calculated equilibrium constant.
SP opt
4 2
2 1
0 0
0 2 4 6 0 2 4 6
Figure: Correlation of experimental logP with energy calculated (left panel) and reoptimized (right panel)
values obtained theoretically.
The results obtained with inclusion of thermal correction and ZPEs does not correlate with the
experimental results. This is probably the result of double-counting liquid solvent contribution since
continuum solvent models are parametrized to directly provide Gibbs free energies at the standard
state. Comparison of the above results shows that SMD/B3LYP/def2-TZVP// B3LYP/def2-TZVP
calculations are promising for theoretical prediction of lipophilicity for the class of compounds
considered herein.
Acknowledgements: The project was funded by the National Science Centre

(decision number: 2012/05/D/NZ7/02278).
188
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NOVEL SPIRO CARBOCYCLIC HYDANTOIN-DERIVATIVES WITH

POTENT ANTITRYPANOSOMAL ACTIVITY
Vasiliki Pardali,[a] Martin C. Taylor,[b] John M. Kelly[b] and Grigoris Zoidis[a],*

[a] School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and
Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771, Athens, Greece
[b] Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel
Street, London WC1E 7HT, U.K.
* zoidis@pharm.uoa.gr
Human African Trypanosomiasis (HAT) or sleeping sickness is a vector borne-parasitic disease,

resulting from infections with flagellated unicellular parasites of the species
T. brucei. Approximately, 65 million people in 36 countries in sub-Saharan Africa are at risk of HAT
infection, which has been recognized by World Health Organization as a Neglected Tropical Disease.
Nowadays, only a few clinically useful drugs are available which suffer from severe side effects.
Thus, the research has been focused on the discovery of new trypanocidal agents and the
identification of new drug-targets in T. brucei.[1]
Based on previous analogues of 2,6-diketopiperazine core which showed high potency against T.
brucei, we rationally designed and synthesized new derivatives of 2,4-diketoimidazolidine scaffold,
also known as hydantoin, endowed with the acetohydroxamic acid unit at the imidic nitrogen, as
potential metal-chelating moiety.[2] A variety of lipophilic carbocyclic rings have been used as spiro
substituents at position 5, in order to increase the affinity for the target.
A further structural modification was accomplished by attaching an additional methyl group at the
amidic nitrogen, so as to increase their binding capacity, which interestingly led to an increased
activity for almost all derivatives.
The novel compounds exhibited considerably potent activity against T. brucei with IC50 values in low
nanomolar range. The cytotoxicity of the newly synthesized analogues was extremely small for
mammalian cells and the selectivity indices were significantly high. The aforementioned findings
indicate that the novel 2,4-spiro carbocyclic diketoimidazolidine scaffold emerge as valuable platform
for developing antitrypanosomal agents and for further biological investigation.
[1]
R. Brun, J. Blum, F. Chappuis, C. Burri, Lancet, 2010, 375, 148.
[2]
C. Fytas, G. Zoidis, N. Tzoutzas, M.C. Taylor, G. Fytas, J.M. Kelly, J. Med. Chem., 2011, 54, 5250.
189
P-114
SYNTHESIS AND BIOLOGICAL EVALUATION OF HYDROXAMATE

COMPOUNDS AS HDAC6 INHIBITORS
Hui Yeon Mok, Han Pyo Son, Seung Yeop Baek, Hyun-Ju Park and
Young Hoon Jung*
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea
* yhjung@skku.edu
Epigenetic pathways are related to the cellular enzymes, including Histone deacetylase
inhibitors(HDACs), which have key role in regulation of gene expression. Abnormal epigenetic
pathways of cellular enzymes cause a human cancer, and this pathway was focused on target for
developing anticancer drugs.
HDACs catalyze the removal of acetyl group form the α-amino groups of lysine residues leads to
gene transcription. It is reported that HDAC is associated with decreased expression tumor
suppressor genes. Consequently, the identification of potential HDAC inhibitor is an important
therapeutic strategy for treatment of cancers. HDAC inhibition has emerged as an attractive target
for the development of new anti-tumor agents.
In previous study, the lead compound has been found from novel non-hydroxamate compounds as
prospective hits with significant HDAC inhibitor activities. In the present study, hydroxamate HDACs
inhibitor’s derivatives have been designed, synthesized and their activity will be evaluated by
enzymatic HDAC assay.
[1]
So-Jin Kim, Ki Seon Baek, Hyun-Ju Park, Young Hoon Jung and Sun-Mee Lee, Br. J. Pharmacol., 2016,
173, 1045.
190
P-115
DRUG DESIGN AND SYNTHESIS OF NEW INDOLYLARYLSULFONES AS

HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
S. Passacantilli,[a],* V. Famiglini,[a] G. La Regina,[a] A. Coluccia,[a] D. Masci,[a]

J. A. Estè,[b] G. Maga[c] and R. Silvestri[a]
[a] Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del
Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy
[b] AIDS Research Institute – IrsiCaixa, Hospitals Germans Trias i Pujol, Universitat Autònoma de
Barcelona, 08916 Badalona, Spain
[c] Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I-
27100 Pavia, Italy
* sara.passacantilli@uniroma1.it
HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active
antiretroviral therapy (HAART) in the clinical management of AIDS/HIV-1 infection. Our recent
studies showed that indolylarylsulfones (IASs) bearing a cyclic moiety at the 2-carboxamide nitrogen
linked through a short spacer group were endowed with potent antiretroviral activity.[1,2]
Based on the results previously obtained, we aimed to expand the SAR studies by the introduction
of new aryl or heteroaryl portions to the indole nucleus.
Interestingly, for the first time IASs endowed with asymmetric centre have shown significant
differences in term of antiretroviral potency. In particular, the (R)-enantiomer proved to be
exceptionally potent and uniformly superior to the (S)-enantiomer against the whole viral panel.
Docking studies showed that the methyl group of the (R)-enantiomer (Figure) pointed toward the
cleft created by the K103N mutation, differently from the corresponding group of (S)-counterpart. By
calculating the solvent accessible surface, we observed that the exposed area of the RT in complex
with (S)-enantiomer was larger than the area of the (R)-complex.[3]
[1]
G. La Regina, A. Coluccia, et al. J. Med. Chem,. 2012, 55, 6634.
[2]
V. Famiglini, G. La Regina, et al. Eur. J. Med. Chem., 2014, 80, 101.
[3]
V. Famiglini, G. La Regina, et al. J. Med. Chem., 2014, 57, 9945.
191
P-116
NEW (AMINOMETHYLENE)BISPHOSPHONATES OBTAINED FROM

HETEROCYCLIC AMINES AND THEIR BIOLOGICAL ACTIVITY
Patrycja Miszczyk,[a],* Ewa Chmielewska[a], Błażej Dziuk[b],

Joanna Wietrzyk[c] and Paweł Kafarski[a],*
[a] Department of Bioorganic Chemistry, Faculty of Chemistry, University of Science and Technology,
Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland
[b] Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland
[c] Ludwik Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences, Rudolfa
Weigla 12, 3-114 Wroclaw, Poland
* patrycja.miszczyk@pwr.edu.pl
The three-component condensation between amines, triethyl orthoformate and diethyl phosphate
(Figure 1) is perhaps the simplest and most commonly used preparation of N-substituted
(aminomethylene)bisphosphonic acids [1].
P(O)(OEt)2 P(O)(OH)2
R
 HCl/H2O
+ HP(O)(OEt)2 + HC(OEt)3 R R
NH2 N P(O)(OEt)2 N P(O)(OH)2
H H
Figure 1: The three-component condensation between amines, triethyl orthoformate and
diethyl phosphate.
The studies have shown that application of heterocyclic amines, such as triazole derivatives or purine
base, in three-component condensation can give unexpected products having very interesting
chemical structure. The biological studies have been shown that these compounds (Figure 2) can
play a role as potential antiosteoporotic agent in the treatment of diseases [2] associated with calcium
metabolism.
Figure 2: New bisphosphonate as antiosteoporotic agent.
[1]
E. Dąbrowska, A. Burzyńska, A. Mucha, E. Matczak-Jon, W. Sawka-Dobrowolska, Ł. Berlicki, P. Kafarski,
J. Organomet. Chem., 2009, 694, 3806.
[2]
E..Chmielewska, P. Kafarski, Open Pharm. Sci. J., 2016, 3, 56.
192
P-117
IS N-A ISOMERIZATION OF HUMAN SERUM ALBUMIN STILL

IMPORTANT FOR THE INTERACTION WITH LIGANDS?
Mariola Chudzik,* Bartosz Pawełczak and Małgorzata Maciążek-Jurczyk

Department of Physical Pharmacy, School of Pharmacy with the Division of Laboratory Medicine in
Sosnowiec, Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland
* mchudzik@sum.edu.pl
Many pathophysiological factors such as age, renal or hepatic diseases, cataract, dysfunction of
coronary artery, diabetes mellitus and also intensive workout alter the structure of serum albumin.[1]
This modification is known as isomerization N(non-modified) – A(aged). The N-A transition induces
the structural relaxation of the protein structure and thereby may influence the ligand binding
affinity.[2]
We compared the binding properties of A and N human serum albumin isoforms to sildenafil (SIL),
which is recommended for using in the erectile dysfunction and pulmonary arterial hypertension.
In vitro interaction of sildenafil (SIL) with aged (AHSA) and non-modified (HSA) human serum
albumin (HSA) was investigated by absorption and fluorescence spectroscopy. It has been
demonstrated that SIL forms complexes with A and N isoforms of HSA. The quenching of HSA
fluorescence by SIL was observed. The calculated quenching percentage was similar for both
tryptophayl (Trp-214) and tyrosyl (Tyr) residues of A and N serum albumin isoforms (at 1:10 serum
albumin:sildenafil molar ratio). At excitation wavelength λex 295 nm (when fluorescence of Trp-214
residue is observed) equals to 61.08 % for SIL-isoform A and 69.69 % for SIL-isoform N while at
excitation wavelength λex 275 nm (when fluorescence of Trp and Tyr residues is observed) equals
to 58.28 % for SIL-isoform A and 69.64 % for SIL-isoform N.
The association constant (Ka) for sildenafil – AHSA complexes is slightly lower, but with the same
order of magnitude in comparison to non – modified (HSA) human serum albumin (λex 295 nm and
λex 275 nm). It indicates that SIL forms stable complexes with A and N human serum albumin
isoforms.
The spectroscopic studies have been confirmed by the computational simulation using CLC Drug
Discovery Workbench software.
Acknowledgements: This work was supported by grants KNW-2-O15/N/6/K and KNW-1-034/K/6/O

from the Medical University of Silesia, Katowice, Poland. Calculations were carried out using
resources provided by Wroclaw Centre for Networking and Supercomputing (http://wcss.pl), grant
No. 382.
[1]
K. Oettl, R.E. Stauber, Br. J. Pharmacol., 2007, 151, 580.
[2]
M. Chudzik, M. Maciążek-Jurczyk, B. Pawełczak, A. Sułkowska Molecules, 2017, 22, 34.
193
P-118
THE INFLUENCE OF FATTY ACIDS ON THEOPHYLINE BINDING TO

GLYCATED SERUM ALBUMIN
Agnieszka Szkudlarek,* Bartosz Pawełczak and Małgorzata Maciążek-Jurczyk

Department of Physical Pharmacy, School of Pharmacy with the Division of Laboratory Medicine,
Medical University of Silesia, 41-200 Sosnowiec, Jagiellońska 4, Poland
* aszkudlarek@sum.edu.pl
Theophylline (Th), an xanthine derivative chemically similar to caffeine and theobromine, is used to
treat asthma, bronchospasm and COPD - chronic obstructive pulmonary disease. Theophylline
forms complex with serum albumin, which has an ability to bind and transport of various endo- and
exogenous compounds including fatty acids (FAs). Pathological states (e.g. diabetes), changes in
dietary habits and/or an overdose of dietary supplements alter the fatty acids amount in serum
albumin. These factors may influence the formation of drug-albumin complex.
The aim of the study was to investigate the affinity changes of glycated human serum albumin
(gHSA) towards theophylline (Th) in the presence of mixtures containing different amounts and
contents of saturated (PA - palmitic acid, MYR - myristic acid, SA - stearic acid) and unsaturated
(OA - oleic acid, LA - linoleic acid) fatty acids. We used fluorescence spectroscopy (SFM) and proton
nuclear magnetic resonance technique (1H NMR) to indicate the high and low affinity binding sites
between bound to albumin Th, in the presence and absence of FAs, respectively. For all observed
class of binding sites association [L∙mol-1] and Stern-Volmer [L∙mol-1] constants, the mean
number of drug molecules bound to 1 mole of macromolecule in a particular binding site n and Hill’s
coefficient nH were calculated. Moreover, the binding interaction between gHSA and Th in the
presence and absence of FAs has been studied by means of molecular docking simulation using the
CLC Drug Discovery Workbench (CLC DDWB) software.
Acknowledgements: This work was supported by grants KNW-2-O15/N/6/K and KNW-1-034/K/6/O

from the Medical University of Silesia, Katowice, Poland. Calculations were carried out using
resources provided by Wroclaw Centre for Networking and Supercomputing (http://wcss.pl), grant
No. 382.
194
P-119
SYNTHESIS, ANTIBACTERIAL ACTIVITY AND SAR STUDY OF NOVEL

AMIDINO 2-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES
Nataša Perin,[a] Marijana Hranjec,[a] Mihaela Perić,[b] Hana Čipčić Paljetak,[b]

Mario Matijašić,[b] Višnja Stepanić,[c] Donatella Verbanac,[b]
Grace Karminski-Zamola[a] and Kristina Starčević[d],*
Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
[b] Department for Intercellular Communication, University of Zagreb School of Medicine, Šalata 2, HR-
[c] Division of Molecular Medicine, Laboratory for Epigenomics, Ruđer Bošković Institute, Bijenička cesta 54,
HR-10000 Zagreb, Croatia
[d] Department of Animal Husbandry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55,
HR-10000 Zagreb, Croatia
* kristina.starcevic@vef.hr
Bacterial organisms causing infectious diseases represent an increasing public health problem
regardless of the current availability of numerous antimicrobial agents. Staphylococcus aureus
represents a major Gram-positive human pathogen while Moraxella catarrhalis is establishing its role
as an emerging respiratory Gram-negative pathogenic microorganism.[1]
A series of novel 2-substituted benzimidazole derivatives were synthesized and their antibacterial
activity was assessed against Gram-positive and Gram-negative bacteria.[2] The specific moiety at
the 2-position of the benzimidazole was extensively modified with several fused heterocyclic
functional groups containing nitrogen and sulphur heteroatoms.[3] In addition, the influence of
different amidino groups at the position 5 of benzimidazole scaffold was evaluated. The values of
clogP (a partition coefficient) and clogD7.5 (calculated distribution coefficient, pH 7.5) were
determined and the lipophilic character of compounds has been found to be important parameter for
the observed activity of the tested benzimidazole derivatives against M. catarrhalis. The indolo 2-
substituted benzimidazole 13a demonstrated solid activity against S. aureus (MICs 16 µg/mL) and
M. catarralis (MICs 2 µg/mL). Furthermore, the SAR results obtained in this study will be applied for
the further optimization of this heteroaromatic core and for the design of novel derivatives in order to
improve initially observed antibacterial activity.
[1]
R. Karalusa, A. Campagnari, Microbes Infect., 2000, 2, 547.
[2]
K. Starčević, M. Kralj, K. Ester, I. Sabol, M. Grce, K. Pavelić, G. Karminski-Zamola, Bioorg. Med. Chem.,
2007, 15, 4419.
[3]
M. Hranjec, M. Kralj, I. Piantanida, M. Sedić, L. Šuman, K. Pavelić, G. Karminski-Zamola, J. Med. Chem.,
2007, 50, 5696.
195
P-120
CHEMICAL COMPOSITION AND BIOACTIVE EFFECTS OF LAVENDER

ESSENTIAL OIL FROM MONTENEGRO
Svetlana Perović,[a],* Snežana Pantović,[b] Valentina Šćepanović,[a]

Andrej Perović[a] and Biljana Damjanović-Vratnica[c]
[a] Department of Biology, Faculty of Natural Science and Mathematics, Dz. Vasingtona bb, Podgorica,
Montenegro
[b] Faculty of Medicine, University of Montenegro, Krusevac bb, Podgorica, Montenegro
[c] Faculty of Metallurgy and Technology, University of Montenegro, Dz. Vasingtona bb, Podgorica,
Montenegro
* svetlanaperov@gmail.com
Essential oils, used as part of naturopathic therapy, have been found to be beneficial in the fields of
dermatology, gastritis, respiratory complaints, wound healing, and genital infections. The general
properties of lavender oil are antibacterial, antifungal, carminative (smooth muscle relaxant),
sedative, antidepressant, promoting wound healing, and increasing the detoxification of enzymes
associated with insecticide resistance.
This study investigates chemical composition and antimicrobial activity of hydrodistillated essential
oil of Lavandula officinalis from Montenegro and effects on autonomic nervous system (ANS). The
oil was analyzed by GC-MS technique in order to determine the majority compounds while dilution
method was used to determine minimal inhibitory concentration (MIC). Twenty healthy volunteers
participated in the experiments. The present study assessed autonomic parameters such as blood
pressure, heart rate, and skin temperature to determine the arousal level of the autonomic nervous
system. In addition, subjects were asked to estimate their mood responses such as feeling pleasant
or unpleasant, uncomfortable, sensuality, relaxation, or refreshing in order to assess subjective
behavioral arousal.
Chemical analysis by GC-MS identified 31 compounds in lavender essential oil representing 96.88
% of the total oil. Linalool (24.84%), was a major component, together with linalyl acetate (22.39%),
1,8 cineole (18.13 %) and camphor (12.88%). The investigated lavender oil from Montenegro
consisted mostly of oxygenated monoterpenes (87.95%) and monotepene hydrocarbons (7%).
The essential oil exhibited antimicrobial activity against Escherichia coli (ATCC 25922),
Staphylococcus aureus (ATCC 25923), Listeria monocytogenes (ATCC 19111), Proteus mirabilis
(ATCC 25933) and Candida albicans (ATCC 10231) with an MIC of 1.4ml/ml.
The results revealed that lavender oil caused significant decreases of blood pressure, heart rate,
and skin temperature, which indicated a decrease of autonomic arousal. In terms of mood
responses, the subjects in the lavender oil group categorized themselves as more active, fresher
and relaxed.
Acknowledgements: Financial support of this work to Montenegrian Ministry of Science (Project

E!9906) is gratefully acknowledged.
196
P-121
NOVEL СONJUGATES OF DOXORUBICIN WITH ASGP-RECEPTOR

LIGANDS FOR TARGETED DELIVERY
R. A. Petrov,[a] S. A. Petrov,[a] E. E. Ondar,[a] S. Yu. Maklakova,[a] I. V. Saltykova,[a]

E. K. Beloglazkina,[a] A. G. Majouga[a,b] and V. E. Koteliansky[a,c]
[a] Chemistry Dept., Moscow State University, Moscow, Leninskie gory, building 1/3, 119991
[b] National University of Science and Technology “MISIS”, Moscow, Leninsky pr., building 4, 119049.
[с] Skolkovo Institute of Science and Technology, Moscow, Skolkovo Innovation Center, Building 3,143026
* petrovrostaleks@gmail.com
Hepatocellular carcinoma is the most common liver tumor, as a result of malignant transformation of
hepatocytes. Every year more than 700 000 cases of this disease are diagnosed in the world[1]. One
of the most promising ways to increase the efficiency of chemotherapy is the targeted delivery of
drugs into the hepatocytes using the ASGP-receptor which recognize galactose derivatives. This
receptor is located predominantly on liver cells surface and binds selectively to the hydroxyl groups
in the 3rd and the 4th position of galactose. The outer part of the receptor consists of three subunits,
each of them binds to galactose. In this work we investigate the synthetic approaches to the
conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose moiety demonstrating high affinity
to the ASGP-receptor for the delivery of doxorubicin into hepatocytes[2,3]. Obtained conjugates have
been studied in vitro by MTT assay on HepG2 cell line.
HOOC
N
N
N
N3
O O
O O COOH CH2
CH2
HC HO NHAc
HO NHAc
OH 3 Doxorubicin
OH
1
Or CuI, Et3N, Or EDC, NHS,
OH OH
DMF, rt rt
O O O O
N3 N
N N
HO NHAc HO NHAc COOH
OH 2 OH 4
N
OH N 5
N
O
O OH O O
OH CH2
HO NHAc
OH
O O OH O NH
H3C R OH 6
O O O O
OH N
CH3 N N
HO NHAc
OH
[1]
Y.Kumar, P.Sharma, N.Bhatt, K.Hooda. Asian Pac J Cancer Prev, 2016 17 (2), 473-478.
[2]
S. Yu. Maklakova, F. A. Kucherov, R.A. Petrov, V. V. Gopko, G. A. Shipulin, T. S. Zatsepin,E. K.
Beloglazkina, N. V. Zyk, A. G. Majouga, and V. E. Kotelianskya, 2015 Russ. Chem. Bull., International
Edition, 64(7), 1655.
[3]
Mamidyala S. K et al. J. Am. Chem.Soc., 2012, 134, 1978−1981
The work was supported by the RSF grant №17-14-01316.
197
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SYNTHESIS, CHARACTERIZATION AND CYTOTOXICITY OF PHENOLIC

COPPER(II) COMPLEXES
Vladimir P. Petrović,[a],* Dušica Simijonović,[a] Zorica D. Petrović,[a]

Marko N. Živanović[b] and Snežana D. Marković[b]
[a] University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovića 12, 34000
Kragujevac, Serbia
[b] University of Kragujevac, Faculty of Science, Department of Biology and Ecology, Radoja Domanovića
12, 34000 Kragujevac, Serbia
* vladachem@kg.ac.rs
In continuation of examination of the anticancer activity of metal-Schiff bases complexes,[1] we

synthesized three chelate complexes of phenolic Schiff bases and the life important Cu2+ ion.[2] The
obtained complexes were structurally characterized using experimental (IR and elemental analysis)
and theoretical tools (Density Functional Theory). Comparison of experimental and calculated
spectra of all complexes did not provide enough data to conclude which isomer prevails. On the
basis of relative free energies, it is revealed that biologically the most active complex, with free
phenolic OH group in ortho position, possess trans-square planar geometry (Figure).
Figure: The optimised structure of the biologically the most active complex 1.
Biological in vitro testings on two cancer cell lines and one line of healthy cells (HCT-116, MDA-MB-
231, and MRC-5, respectively) indicated that all examined complexes induced enormous
oxidative/nitrosative stress followed with enhanced cytotoxicity of healthy and cancer cells.
[1]
V.P. Petrović, M.N. Živanović, D. Simijonović, J. Đorović, Z.D. Petrović, S.D. Marković, RSC. Adv., 2015,
5, 86274.
[2]
R.A. Festa, D.J. Thiele, Curr. Biol., 2011, 21, R877.
198
P-123
THIOSEMICARBAZIDE DERIVATIVES WITH 4-NITROPHENYL GROUP

AS MULTI-TARGET DRUGS
Monika Pitucha,[a],* Małgorzata Miazga-Karska,[b] Agnieszka A. Kaczor,[c,d]

Katarzyna Klimek,[b] Zbigniew Karczmarzyk,[e] Maciej Woś,[a] Waldemar Wysocki,[e]
Grazyna Ginalska,[b] Zofia Urbanczyk-Lipkowska[f] and Maja Morawiak[f]
[a] Department of Organic Chemistry, Faculty of Pharmacy with Division of Medical Analytics, Medical
University, 4A Chodzki St., PL-20093 Lublin, Poland
[b] Department of Biochemistry and Biotechnology, Faculty of Pharmacy with Division of Medical Analytics,
Medical University, 1 Chodzki St., PL-20093 Lublin, Poland
[c] Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer
Modeling Lab, Faculty of Pharmacy with Division for Medical Analytics, 4A Chodźki St., PL-20059 Lublin,
Poland
[d] University of Eastern Finland, School of Pharmacy, Department of Pharmaceutical Chemistry,
Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland
[e] Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54 St. , PL-
08110 Siedlce, Poland
[f] Institute of Organic Chemistry, Polish Academy of Sciences, 44/52 Kasprzaka St., PL-01224 Warsaw,
Poland
* monika.pitucha@umlub.pl
The thiosemicarbazide derivatives (Figure) with 4-nitrophenyl group were obtained and tested for
their antibacterial and antiproliferative activity. Our results showed that some compounds possessed
antibacterial activity against S. aureus, S. epidermidis, S. mutans and
S. sanguinis. The cytotoxicity of these compounds is moderate, thus the compounds display good
therapeutic safety in vitro. Additionally, two substances inhibited A549, HepG2 and MCF-7 cell
division. Moreover, PASS software was used to detect another biological activity. It turned out that
novel compounds can cause α-glucosidase inhibition. This was confirmed in vitro. To investigate the
mode of interaction with the molecular target, compounds exhibiting α-glucosidase inhibition were
docked to glucose binding site and exhibited a similar binding mode as glucose. In conclusion we
obtained a series of new thiosemicarbazide derivatives with 4-nitrophenyl group with high multi-
target biological activity in vitro. Structure-Activity analysis revealed that - depending of the
substituent - thiosemicarbazides can be used as a potential antibacterial, antiproliferative and anti-
diabetic substances.
O 2
R
NH 1
S R S NH
NH
HN NH
NH
O
NO 2 NO 2
199
P-124
DESIGN AND SYNTHESIS OF NEW SUBSTITUTED NUCLEOSIDES AS

POTENTIAL ANTI-HCMV AGENTS
Maria Gerasi, Georgios Papadakis, Nikolaos Lougiakis,

Panagiotis Marakos and Nicole Pouli
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and
Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece
Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that belongs to the family
of DNA herpesviruses (HHV-5). Cytomegalovirus infections are associated with severe morbidity
and mortality in high risk patients because of immune system disabilities. There are currently
available only three systemic drugs for treatment or prophylaxis of HCMV diseases, all targeted at
the viral DNA polymerase, namely Ganciclovir and its prodrug Valganciclovir, Foscarnet and
Cidofovir. However, their clinical effectiveness is limited due to severe side effects and the
development of resistance. Accordingly, there is a need for the discovery of new anti-HCMV agents
that are less toxic, more effective, orally bioavailable and endowed with novel mechanism of action.
Within this context, research efforts have led to the development of a number of polyhalogenated
benzimidazole nucleosides, exemplified by 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole
(TCRB), that strongly inhibit viral replication targeting a DNA maturation and processing step, which
does not occur in normal eukaryotic cells. The structurally related Maribavir proved even more potent
against HCMV and has entered clinical trials. In an effort to contribute in the structure-activity
relationship studies of these series and explore the spatial limitation of the target enzymes we have
designed a number new derivatives which can be considered as Maribavir isosters. Thus, we report
in this presentation the preparation of the target nucleosides, which are 2-aminosubstituted
analogues of the 1- and 3-position isomers of imidazo[4,5-b]pyridine.
Acknowledgments. This work has been funded by the Special Research Account (ELKE) of the
200
P-125
SCREENING PHYSIOLOGICALLY RELEVANT SUBSTRATES OF

ALDOSE REDUCTASE: ENZYME ACTIVITIES AND DIFFERENTIAL
INHIBITION
Marta Soltesova Prnova,[a],* Jana Ballekova,[a] Yoel Rodriguez,[b,c]

Magdaléna Májeková[a] and Milan Stefek[a]
[a] Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska
cesta 9, 841 04 Bratislava, Slovakia
[b] Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison
Avenue, New York, NY 10029, USA
[c] Department of Natural Sciences, Hostos Community College of CUNY, Bronx, NY 10451, USA
* marta.prnova@savba.sk
Aldose reductase (AR) is an NADPH-dependent reductase of rather poor selectivity, which is

apparently disposed to accommodate both hydrophilic and hydrophobic aldehyde substrates.
However, this enzyme seems to be not fully permissive owing to its capability to discriminate
between different substrates of the same group. The ability of a variety of substrates to interact with
AR at different efficacy indicates that these molecules may interact with the enzyme in multiple
interactive modes. This characteristic of AR enzyme offers the possibility of identifying aldose
reductase inhibitors allowing to discriminate among different substrates. Recently, a new generation
of aldose reductase differential inhibitors (ARDIs) has been proposed aimed at preferentially
inhibiting the reduction of either hydrophilic or hydrophobic substrates.[1,2] Thus, ARDIs may be
projected to the selective inhibition of AR with the preference to normalize fluxing of glucose through
the polyol pathway in diabetic patients without interfering with the detoxification of toxic products of
lipid peroxidation.
O
O
N
N N
H3CO
SH
N
N
N
O OH
OH O
1 2
In the present study, the enzyme activities of rat lens aldose reductase saturated with physiologically
relevant substrates including glyceraldehyde, glucose, galactose, xylose, erythrose, methylglyoxal,
4-hydroxynonenal (HNE), 4-hydroxynonenal glutathione (GS-HNE) were screened. Idose, glucose
close congener, and the reference p-nitrobenzaldehyde were used as substrates for comparison.
Two novel aldose reductase inhibitors, 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (1)
and 2-(2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)acetic acid (2), were
subjected to differential inhibition assessment. Computational molecular modeling was used to
understand the experimental data. Different interactive modes with the aldose reductase enzyme for
the tested molecules were suggested. The results may contribute to the efforts in searching for
pharmacological/therapeutical applications of ARDIs.
Acknowledgments: This work was supported by Slovak Research and Development Agency under
the contract NO. APVV-15-0455, SAS-Tubitak JRP 2015/7, VEGA 2/0033/14 and VEGA 2/0041/15.
[1]
A. Del-Corso, et al., PLoS One, 2013, 8 (9), e74076.
[2]
M. Cappiello, et al., Biochem. Biophys. Res. Commun., 2014, 445 (3), 556.
201
P-126
POST HEROIN DOSE TISSUE DISTRIBUTION OF 6-

MONOACETYLMORPHINE (6-MAM) WITH MALDI IMAGING
Belin G. Teklezgi,[a] Annapurna Pamreddy,[a] Sooraj Baijnath,[a] Nirmala D. Gopal,[b] Tricia

Naicker,[a] Hendrik G. Kruger[a] and Thavendran Govender[a],*
[a] Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Westville Campus, Durban, South
Africa
[b] Department of Criminology, University of KwaZulu-Natal, Durban, Republic of South Africa
* govenderthav@ukzn.ac.za
Heroin is an illicit opioid drug which is commonly abused and leads to dependence and addiction.
Heroin is considered a pro-drug and is rapidly converted to its major active metabolite 6-
monoacetylmorphine (6-MAM) which mediates euphoria and reward through the stimulation of opioid
receptors in the brain.[1] The aim of this study was to investigate the distribution and localization of
6-MAM in the healthy Sprague Dawley rat brain following intraperitoneal (i.p.) administration of
heroin (10 mg/kg), using matrix-assisted laser desorption/ionization mass spectrometric imaging
(MALDI-MSI), in combination with quantification via liquid chromatography mass spectrometry (LC-
MS/MS). These findings revealed that 6-MAM is present both in plasma and brain tissue with a Tmax
of 5 min (2.8 µg/mL) and 15 min (1.1 µg/mL), respectively. MSI analysis of the brain showed high
intensities of 6-MAM in the thalamus-hypothalamus and mesocorticolimbic system including areas
of the cortex, caudate putamen, and ventral pallidum regions.[2] This finding correlates with the
distribution of opioid receptors in the brain, according to literature.[3] In addition, we report a time-
dependent distribution in the levels of 6-MAM, from 1 min with the highest intensity of the drug
observed at 15 min, with sparse distribution at 45 min before decreasing at 60 min 1. This is the first
study to use MSI as a brain imaging technique to detect a morphine’s distribution over time in the
brain.
[1]
J.M. Andersen, Å. Ripel, J. Pharm. Exp. Ther., 2009, 331, 153.
[2]
B. Teklezgi, A. Pamreddy, J. Mol. Histol., 2017,doi:10.1007/s10735-017-9726-3.
[3]
J. Le Merrer, J.A. Becker, Physiol. Rev., 2009, 89, 1379.
202
P-127
RATIONAL DESIGN OF NEW POTENT NON-NUCLEOSIDE INHIBITORS

OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE ACTIVE IN
LEUKEMIC CELLS
G. Pupo,[a],* A. Coluccia,[a] A. Messore,[a] V. N. Madia,[a] F. Saccoliti,[a]

L. Pescatori,[a] R. Costi,[a] G. Maga,[b] E. Crespan[b] and R. Di Santo[a]
[a] Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” University of Rome, p.le Aldo
Moro 5, 00185, Rome, Italy
[b] Istituto di Genetica Molecolare, IGM-CNR, National Research Council, Pavia, via Abbiategrasso,
207, 27100, Pavia, Italy
* giovanni.pupo@uniroma1.it
Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed

polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination
during lymphocyte and repertoire development. Elevated TDT activity is showed in leukemic cells
of acute lymphocytic leukemia and in the chronic myelogenous leukemia crisis. This finding is
connected to a poor prognosis and response to chemotherapy. DNA polymerase lambda (Pol ),
homolog to TDT,[1] can synthesize DNA in a template-independent pathway. Pol  might be
involved in the nonhomologous end joning (NHEJ) recombinational repair pathway of DNA double
strand breaks. During a random screening on various polymerases we found some aryl diketo
hexenoic acids (DKHAs) (RDS 2119, RDS 2153, RDS 2184) (see Figure), previously synthesized
by us as anti-viral agent, as hits showing interesting activity against mammalian terminal
deoxyribonucleotidyl transferases.[2,3]
O OH O O OH
COOH COOH
N COOH N
N
O OH
RDS 2119 RDS 2153 RDS 2184

Figure: Hit compounds obtained from
random screening.
Thus, we started SAR studies on DKHAs and found compounds that specifically target TdT
behaving as nucleotide-competitive inhibitors.[4] These compounds showed a selective toxicity
toward MOLT-4 overespressing TdT, compared to HeLa cells, that well correlate with in vitro
selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization
with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide
triphosphate (dNTP). These studies opened the possibility to the rational design of TdT inhibitors.
Starting form the observed binding pose of inhibitors cocrystallized within the catalytic core, we
noted that the phenyl substituent or the benzyl group on pyrrole ring could occupy two different
pockets. Thus, we decidesd to design and synthesize compounds bringing two aryl moieties. The
design, synthesis and biological assays performed on newly synthesized compounds will be
reported and discussed.
[1]
U. Hübscher, G. Maga, G. Spadari, Ann. Rev. Biochem., 2002, 71, 133.
[2]
G. A. Locatelli, R. Di Santo, E. Crespan, R. Costi, Mol. Pharmacol., 2005, 68, 538.
[3]
R. Di Santo, G. Maga, Curr. Med. Chem., 2006, 13, 2353.
[4]
R. Costi, G. Cuzzucoli Crucitti, L. Pescatori, A. Messore, L. Scipione, S. Tortorella, A. Amoroso, E.
Crespan, P. Campiglia, B. Maresca, A. Porta, I. Granata, E. Novellino, J. Gouge, M. Delarue, G. Maga, R.
Di Santo, J. Med. Chem., 2013, 56, 7431.
203
P-128
SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL 2-

(HETERO)ARYL-6-(2-IMIDAZOLINYL)BENZOTHIAZOLES AS
ANTICANCER AGENTS
Livio Racané,[a],* Lucija Ptiček,[a] Mirela Sedić,[b] Petra Grbčić,[b]

Sandra Kraljević Pavelić,[b] Irena Sović[c] and Grace Karminski-Zamola[c]
[a] Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna
Filipovića 28a, 10000 Zagreb, Croatia
[b] Department of Biotechnology, Centre for high-throughput technologies, University of Rijeka, Radmile
Matejčić 2, 51000 Rijeka, Croatia
[c] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of
Zagreb, Marulićevtrg 20, P. O. Box 177, 10000 Zagreb, Croatia
* lracane@ttf.hr
Benzothiazole as an important pharmacophore, has recently emerged as a privileged scaffold in

drug discovery[1] due to a variety of pharmacological properties, and its derivatives offer a high
degree of structural diversity that has proven useful for the search of new therapeutic agents.[2]
Through the last decade, our scientific focus has been placed on this particular series of heterocyclic
compounds, with an emphasis on their synthesis, study of anticancer activities and DNA binding
properties. Recently, we efficiently synthesized a series of 2-thienyl- and 2-benzothienyl-substituted
6-(2-imidazolinyl)benzothiazole derivatives, investigated their antitumor effects and explored the
possible involvement of key enzymes regulating sphingolipid metabolism.[3] We have found in this
group of sulphur-containing heterocycles the 2-benzothienyl derivative to have remarkable and
selective cytostatic activity. One of the major mechanisms accounting for observed cytostatic effects
was induction of apoptosis, probably due to specific inhibition of acid ceramidase activity. Based on
these results a novel series of title compounds are synthesized and evaluated for their potential as
anticancer agents.
An efficient synthesis is achieved by the condensation reaction of 2-amino-5-(2-

imidazolinium)benzenethiolate with the corresponding aldehydes or carboxylic acid and compounds
were isolated as monocationic highly water soluble mesylates. The in vitro antiproliferative activity
against several human cancer cell lines is tested.
[1]
A.A. Weekes, A.D. Westwell, Curr. Med. Chem., 2009, 16, 2430.
[2]
R.S. Keri, M.R. Patil, S.A. Patil, S. Budagupi, Eur. J. Med. Chem., 2014, 89, 207.
[3]
L. Racané, M. Sedić, N. Ilić, M. Aleksić, S. KraljevićPavelić, G. Karminski-Zamola, Anti-Cancer Agents Med.
Chem., 2017, 17, 57.
204
P-129
NEW PRIMAQUINE AMIDES WITH HYDROXYPHENYL AND

HALOGENPHENYL SUBSTITUENTS
Zrinka Rajić Džolić, Maja Beus and Branka Zorc*

Department of Medicinal Chemistry, University of Zagreb, Faculty of Pharmacy and Biochemistry, A.
Kovačića 1, 10000 Zagreb, Croatia
* bzorc@pharma.hr
Cancer is one of the leading causes of death worldwide.[1] Moreover, cancer is a very heterogenous
disease, and cancer cells are prone to mutagenesis which leads to drug resistance. Therefore, novel
and more efficient therapies are needed.
Antimalarial drugs are known to exhibit antiproliferative activity, with several antimalarials in the
clinical trials.[2] Almost a decade our group is focused on the synthesis and evaluation of primaquine
derivatives as anticancer agents.[3] Recently, we have reported synthesis and biological activity of
urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents, which
exerted strong antiproliferative activity against a panel of tumour cell lines, with significant selectivity
towards breast cancer cell line, MCF-7.[4] This work aims at simplifying the spacer between PQ and
hydroxyphenyl or halogenphenyl substituents, which would provide simpler structures and more
straightforward synthesis.
Synthetic pathway to PQ derivatives 3 is outlined in the Scheme and it involves three steps: coupling
of PQ with monomethyl succinate, hydrolysis of the obtained methyl ester 1, and coupling of the
carboxylic acid 2 with the desired aniline derivative. In both cases, coupling was achieved by the
activation of carboxylic acid with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU), in the presence of N-ethyl-N,N-diisopropylamine (DIEA).
All reactions were performed at room temperature, reaction times were short and synthetic yields
were high. Purification of the target compounds was straightforward, and their structures were
confirmed by 1H and 13C NMR, IR and MS spectroscopy.
O O O
HO CH 3
O
O
NH NH O LiOH, MeOH, H 2O
HATU, DIEA, DCM
H
N NH2 N N CH 3
O
PQ 1 O
O O
X, OH, CF3
H 2N
X, OH, CF3
NH O NH O
H H
N N HATU, DIEA, DCM N N
OH N
2 3 H
O O
Cytostatic evaluation on a panel of cancer cell lines is in progress.
Acknowledgments: This work has been fully supported by the Croatian Science Foundation
under the project number IP-09-2014-1501.
[1]
http://www.who.int/mediacentre/factsheets/fs297/en/
[2]
R. Duffy, et al, Drug Discov. Today, 2012, 17, 942.
[3]
G. Džimbeg, et al, Eur. J. Med. Chem., 2008, 43, 1180; M. Šimunović, et al, Bioorg. Med. Chem., 2009, 17,
5605; Z. Rajić, et al, Acta Pharm., 2010, 60, 325; I. Perković, et al, Eur. J. Med. Chem., 2012, 52, 227; I.
Perković, et al, J. Enz. Inhib. Med. Chem., 2013, 28, 601; K. Pavić, et al, Eur. J. Med. Chem., 2014, 86, 502;
K. Pavić, et al, Molecules, 2016, 21, 1629.
[4]
I. Perković, et al, Eur. J. Med. Chem., 2016, 124, 622.
205
P-130
SYNTHESIS AND EVALUATION OF MULTI-TARGET LIGANDS PLANNED

FROM CARDANOL FOR THE TREATMENT OF ALZHEIMER'S DISEASE
Giselle de Andrade Ramos,[a],* Luiz A. Soares Romeiro,[a] Manuela Bartolini,[b]

Paul E. Fraser[c] and Ling Wu[c]
[a] Graduate Program in Pharmaceutical Sciences, University of Brasilia, Faculty of Health Sciences,
Darcy Ribeiro Campus, Brasilia.
[b] Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna.
[c] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard
Avenue, M5T 2S8.
* giselle.ramos7@gmail.com
Alzheimer's disease is a progressive neurodegenerative disorder that presents dementia as a classic

clinical manifestation among other symptoms.[1,2] In the context of a research line aimed to the
development of new multi-target ligands, is described the synthetic route of new compounds planned
from cardanol, as well the preliminary evaluation of their inhibitory profiles against hAChE/hBChE
and the anti aggregation A activity. Thus, the cardanol mixture was converted to the acetylated
compound by alkylation, the obtained mixture was subjected to oxidative cleavage via ozonolysis,
followed by reductive treatment obtaining the alcohol LDT71. The primary alcohol was converted to
the corresponding acid LDT108 by treatment with Jones reagent. This acid derivative was also
converted to the corresponding amide intermediates via mixed anhydride reaction. Therefore, these
derivatives were reduced to the correspondent amines by reduction reaction. Finally, these
amide/amine intermediates was subjected to the Mannich reaction. The acetylcholinesterase assay
showed the ligands ability to inhibit the enzymes. For Series 3, LDT638 (AChE IC50 30,0 μM, BChE
IC50 6,12 μM) showed the best dual profile; meanwhile LDT636 and LDT544 showed selectivity for
hBChE. For Series 1/2, LDT577 (AChE IC50 7,2 μM; BChE IC50 1,28 µM) and LDT579 (AChE IC50
6,68 μM; BChE IC50 0,47 µM) were the best. Tests against A aggregation for Series 3 showed that
LDT544, LDT636 and LDT640 were able to destabilizing the secondary structures of the protein.
However, LDT638 induced a -sheet transition. The conclusion of the biological evaluation regarding
the anticholinesteric and anti-aggregant profile are underway, which will allow us to rationalize the
results and establish the structure-activity relationship. The antioxidant potential is one of the
prospects in this work.
[1]
A. Darvesh S.B. Hopkins, A.C. David, C. Geula, Nature Rev. Neurosci., 2003, 4, 2.
[2]
L.F. Nunes Lemes, et al, Eur. J. Med. Chem., 2015, 108, 687.
206
P-131
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL G9A

INHIBITORS FROM A SCAFFOLD HOPPING APPROACH
D. Rescigno,[a],* C. Milite,[a] M. Viviano,[a] S. Castellano[a,b] and G. Sbardella[a]

[a] Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, I-84084
Fisciano, Italy
[b] Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via Salvador Allende, I-
84081 Baronissi, Salerno, Italy
* drescigno@unisa.it
The lysine methyltransferase G9a (also known as EHMT2) catalyses the addition two methyl groups
to lysine 9 of histone H3. Due to its central role in epigenetic control, the aberrant activity of this
enzyme is associated to several diseases including cancer. In particular, recent evidences revealed
G9a involvement in the progression of REST-expressing (repressor element (RE)-1 silencing
transcription factor) medulloblastomas.[1] Only a few among the selective inhibitors of G9a reported
to date are useful chemical probes for cell-based and animal studies.[2]
Starting from the inhibitor UNC0638,[3] we applied a scaffold hopping approach to develop novel
chemical entities endowed with high affinity towards G9a. In particular, we replaced the quinazoline
core, common to most of the reported inhibitors, with 1,4-benzodiazepine nucleus, known to be a
privileged structure. We chose the 3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one scaffold, that can be
obtained through an efficient and gram-scale continuous-flow protocol, previously optimized by our
group.[4] Moreover, this scaffold could be easily decorated to provide a number of highly
functionalized potential ligands (Figure). To validate our approach, we designed and synthesized a
small library of UNC0638 analogues. The UNC0638 benzodiazepine analogue (EML741) showed a
good activity in a peptide-based AlphaLISA, together with a promising membrane permeability profile
(PAMPA-BBB).
Figure: General scheme of our scaffold hopping approach.
[1]
P. Taylor, J. Fangusaro, V. Rajaram, S. Goldman, I. B. Helenowski, T. MacDonald, M. Hasselblatt, L.
Riedemann, A. Laureano, L. Cooper, V. Gopalakrishnan, Mol. Cancer Ther., 2012, 11, 1713.
[2]
H. Ü. Kaniskan, J. Jin, ACS Chem. Bio. 2015, 10, 40.
[3]
M. Vedadi, D. Barsyte-Lovejoy, F. Liu, S. Rival-Gervier, A. Allali-Hassani, V. Labrie, T. J. Wigle, P. A.
DiMaggio, G. A. Wasney, A. Siarheyeva, A. Dong, W. Tempel, S.-C. Wang, X. Chen, I. Chau, T. J. Mangano,
X.-P. Huang, C. D. Simpson, S. G. Pattenden, J. L. Norris, D. B. Kireev, A. Tripathy, A. Edwards, B. L. Roth,
W. P. Janzen, B. A. Garcia, A. Petronis, J. Ellis, P. J. Brown, S. V. Frye, C. H. Arrowsmith, J. Jin, Nat. Chem.
Biol., 2011, 7, 566.
[4]
M. Viviano, C. Milite, D. Rescigno, S. Castellano, G. Sbardella, RSC Adv., 2015, 5, 1268.
207
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SYNTHESIS OF MULTIANTENNARY MANNOSE DERIVED

DESMURAMYL PEPTIDES
Rosana Ribić,[a] Marija Paurević,[b] Nora Tir[a] and Srđanka Tomić[a],*

[a] University of Zagreb, Faculty of Science, Department of Chemistry, Horvatovac 102a, HR-10000 Zagreb,
Croatia
[b] University of Josip Juraj Strossmayer, Department of Chemistry, Ulica cara Hadrijana 8/A, HR - 31000
Osijek, Croatia
* stomic@chem.pmf.hr
Muropeptides are fragments of unique polymers that build up the cell wall of bacteria called
peptidoglycans. Muramyl dipeptide (MDP), N-acetylmuramyl-L-alanyl-D-isoglutamine, is the smallest
structural unit of peptidoglycans showing the immunostimulating activity and desmuramyl peptides
are MDP analogues lacking the hydrophilic carbohydrate moiety. Numerous derivatives with different
groups at C- and N-terminus of the L-Ala-D-isoGln moiety are known.[1] We have designed, prepared
and evaluated desmuramyl peptides with incorporated lipophilic adamantyl group as well as their
mannosylated derivatives.[2] Mannose derived desmuramyl peptides showed great
immunostimulating potential. Attached mannose allows the targeting of cell surface mannose
specific lectins, while adamantane group enables the anchoring of the peptidoglycan ‘cargo’ to the
membrane lipid bilayer. In the prepared liposomal vehicles adamantane group penetrated into the
lipid bilayer while mannose was exposed at the liposome surface and served in targeting mannose
receptors.[3] In order to improve lectin-carbohydrate binding we have developed methodology for the
stereoselective synthesis of di- and tri-antennary mannose derivatives of desmuramyl peptides.
Strength of overall mannose – lectin interaction will be enhanced by increasing the number of
mannose subunits. Method efficiency will be presented on the synthesis of di- and tri-antennary
mannose derivatives of desmuramyl peptides, including novel adamantyl triazole derivative.
[1]
C. Ogawa, Y.-J. Liu, K. S. Kobayashi, Curr. Bioact. Compd., 2011, 7, 180.
[2]
R. Ribić, L. Habjanec, B. Vranešić, R. Frkanec, S. Tomić, Chem. Biodivers., 2012, 9, 777.
[3]
A. Štimac, S. Šegota, M. Dutour Sikirić, R. Ribić, L. Frkanec, V. Svetličić, S. Tomić, B. Vranešić, R.
Frkanec, Biochim. Biophys. Acta - Biomembr., 2012, 1818, 2252.
208
P-133
MOLECULAR MODELING AND SYNTHESIS OF PYRUVATE

DEHYDROGENASE KINASE INHIBITORS AS A POTENTIAL
ANTICANCER TARGETS
Agata Rosińska,* Urszula Kijkowska-Murak and Dariusz Matosiuk

Chair and Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical
University of Lublin, Raclawickie 1 Street, 20-059 Lublin, Poland
* agata.rosinska@umlub.pl
PDH (pyruvate dehydrogenase) is a key enzyme controlling the rate of glucose oxidation, and the
availability of gluconeogenetic precursors. Activation of PDH in skeletal muscle and liver may
increase glucose uptake and reduce glucose production.
Recent studies shown that metabolic switch (Warburg effect) in cancer cells is regulated by pyruvate
dehydrogenase kinase (PDK)[1-3].PDK is one part of the pyruvate dehydrogenase complex, which
contains various catalytic and regulatory enzymes, which are responsible for the conversion of
pyruvate into acetyl-CoA. The activity of pyruvate dehydrogenase is regulated by its phosphorylation
status. The phosphorylation of PDH by PDK inhibits its activity and trigger metabolic shift from
mitochondrial respiration to cytoplasmic glycolysis [4-6].
PDK2 or Pyruvate Dehydrogenase Kinase 2 is a member of the PDHK family that phosphorylates
and inactivates the Pyruvate Dehydrogenase (PDH) and it has been suggested that PDK2 also
involves in the proliferation of cancer cells.
In these study we design pyruvate dehydrogenase kinase inhibitors in silico and using BioSolveIT
GmbH software.
The PDK2 structure were discovered using ReCore module and two fragments databases: ZINC a
free database of commercially-available compounds for virtual screening and The Cambridge
Structural Database (CSD). The results were validated through docking in FlexX and Surflex
programs.
[1]
C.W. Lu, S.C. Lin, K.F. Chen, Y.Y. Lai, S.J. Tsai, J. Biol. Chem., 2008, 283, 2106.
[2]
J.W. Kim, I. Tchernyshyov, G.L. Semenza, C.V. Dang, Cell Metab., 2006, 3, 177.
[3]
I. Papandreou, R.A. Cairns, L. Fontana, A.L. Lim, N.C. Denko, Cell Metab., 2006, 3, 187.
[4]
M. Kato, R.M. Wynn, J.L. Chuang, S.C. Tso, M. Machius, J. Li, D.T. Chuang, Structure, 2008, 16, 1849.
[5]
M.S. Patel, L.G. Korotchkina, Exp. Mol. Med., 2001, 33, 191.
[6]
T.E. Roche, Y. Hiromasa, Cell. Mol. Life Sci. 2007, 64, 830.
209
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DISCOVERY OF NOVEL DIARYL SULFIDE DERIVATIVES AS

INHIBITORS OF TRYPANOTHIONE REDUCTASE ENZYME
F. Saccoliti,[a],* V. N. Madia,[a] G. Pupo,[a] V. Tudino,[a] G. Colotti,[b] G. Angiulli,[b]

A. Fiorillo,[b] P. Baiocco,[b] T. Di Muccio,[c] M. Gramiccia,[c] L. Scipione,[a]
R. Costi,[a] A. Ilari[b] and R. Di Santo [a]
[a] Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti,
“Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Roma, Italy
[b] Istituto di Biologia e Patologia Molecolari – CNR, and Dipartimento di Scienze Biochimiche,
“Sapienza” Università di Roma p.le Aldo Moro 5, I-00185 Roma, Italy
[c] Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanità, viale
Regina Elena 299, I-00161 Roma, Italy
* francesco.saccoliti@uniroma1.it
Trypanosomatidae protozoa are the causative agents of several tropical diseases, such as African
sleeping sickness, Chagas’s disease and various forms of leshmaniasis, causing millions of deaths
every year mainly in the developing world.[1] Nowadays, no safe and efficacious drugs are available
for the treatment of most of these neglected tropical diseases, and, furthermore, high costs and
increasing number of drug-resistant pathogens render the treatment even difficult.[2,3] Therefore,
there is a strong need to develop more efficient and affordable antiprotozoal compounds and identify
new promising targets. In this context an innovative approach is targeting protein essential for the
parasite survival but absent in the human host. Instead of the mammalian redox defense machinery
based on glutathione, the trypanosomatid parasites possess trypanothione as the main defending
system against oxidative damage.[4–6] Trypanothione (TSH2) is kept in its reduced state by
trypanothione reductase (TR), a NADPH dependent flavoprotein which acts as key enzyme of the
trypanothione pathway, being critical for the protozoan survival, thus representing an attractive and
promising target for the development of new potential drugs.[6,7] Furthermore, due to structural
differences between the protozoan enzyme and the human homolog glutathione reductase (GR), a
selective therapeutic approach might be possible. Following the discovery of some related
compounds described in literature as TR inhibitors,[7] we evaluate the antiprotozoal activities of our
in-house diaryl sulfide derivatives and some of the them proved to be active in whole cell assays,
showing inhibitory activities within the micromolar range on different protozoa. Moreover, we found
that our derivative RDS 777 was able to inhibit TR of L. infantum (LiTR) with good efficiency, showing
a Ki of 0.25 mM that is six times lower than that of Sb(III), the active form of antimonials being the
most used drug against leishmaniasis.[8] Thus, we solved the X-ray structure of LiTR in its oxidized
state in complex with RDS 777 at 3.5 Å resolution, disclosing its mechanism of action. Indeed, this
structure shows that the compound localizes at the catalytic site, engaging interactions with the
residues more involved in the catalysis namely: Glu466', Cys57, Cys52 and Tyr110 thereby inhibiting
the trypanothione binding. These data provide important insight that could be very helpful for future
development of this class of inhibitors endowed with focused structural modifications in order to
increase affinity and potency against protozoan target.
[1]
M. H. Gelb, W. G. Hol, Science, 2002, 297, 343.
[2]
R. L. Krauth-Siegel, et al., Angew. Chem., 2005, 44, 690.
[3]
R. L. Krauth-Siegel, et al., Parasitol. Res. 2003, 90, 77.
[4]
M. Comini, et al., Free Radic. Biol. Med. 2014, 73, 229.
[5]
G. Colotti, et al., Future Med. Chem. 2013, 15, 1861.
[6]
A. Fiorillo, et al., PLoS Negl. Trop. Dis. 2012, 6, e1781.
[7]
B. Stump, et al., Org. Biomol. Chem., 2008, 6, 3935.
[8]
F. Saccoliti, et al., J. Enzyme Inhib. Med. Chem. 2017, 32, 304.
210
P-135
PSORALENE DERIVATIVES INHIBITORS OF THE β5i SUBUNIT OF THE

IMMUNOPROTEASOME
Eva Shannon Schiffrer, Izidor Sosič, Martina Gobec, Irena Mlinarič-Raščan and Stanislav
Gobec*
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
* stanislav.gobec@ffa.uni-lj.si
The eukaryotic 26S proteasome is the heart of the ubiquitin-proteasome system. The system is
responsible for maintaining protein homeostasis and regulation of many cellular processes, such as
antigen processing, signal transduction, cell differentiation and apoptosis. Its 20S core particle has
three enzymatically active subunits which have distinct substrate specificities. Two types of
proteasome exist, the constitutive proteasome which is expressed in all eukaryotic cells and the
immunoproteasome which is predominantly expressed in cells of hematopoietic origin. The β5i
(chymotrypsin-like) subunit of the immunoproteasome prefers neutral, hydrophobic residues at the
cleavage site and β5i-selective compounds are currently being investigated for possible application
in autoimmune and inflammatory diseases, where the immunoproteasome activity is upregulated.[1,2]
The majority of currently available inhibitors have a peptidic backbone which makes them prone to
poor metabolic stability and low bioavailability. In a previous study it was established that psoralene
derivatives with an oxathiazolone “warhead” act as nonpeptidic covalent and irreversible inhibitors
of the β5i subunit.[1] With the intent of establishing a structure-activity relationship, a series of
oxathiazolone-substituted psoralene-based derivatives with variations at R1 of the parent compound
was synthesised. The compounds will be characterised in in vitro and cell-based assays to assess
their potency and selectivity in comparison with other subunits.
Figure: Simplified general scheme for the synthesis of oxathiazolone-substituted psoralene-based

derivatives with variations at R1 and the parent compound with its characteristics.
[1]
I. Sosič, M. Gobec, B. Brus, D. Knez, M. Živec, J. Konc, S. Lešnik, M. Ogrizek, A. Obreza, D. Žigon, D.
Janežič, I. Mlinarič-Raščan, S. Gobec, Angew. Chem., 2016, 55, 5745.
[2]
T. Muchamuel, M. Basler, M. Aujay, E. Suzuki, K. Kalim, C. Lauer, C. Sylvain, E. Ring, J. Shields, J. Jiang,
P. Shwonek, F. Parlati, S. Demo, M. Bennett, C. Kirk, M. Groettrup, Nat. Med. 2009, 15, 781.
211
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THE APPLICATION OF FMO-EDA CALCULATION TO STUDY THE

SELECTIVITY OF 2-CHLOROPHENYL-PIPERAZIN DERIVATIVE TO
SEROTONIN AND DOPAMINE RECEPTORS
Paweł Śliwa,[a],* Jolanta Jaśkowska[a] and Rafał Kurczab[b]

[a] Faculty of Chemical Engineering and Technology, Cracow University of Technology, Warszawska 24, 31-
155 Cracow, Poland
[b] Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12,
31-343 Cracow, Poland
* pawel.sliwa@chemia.pk.edu.pl
Long-chain arylpiperazines (LCAP) are one of the commonly studied class of bioactive compounds
due to their potential therapeutic effects caused by interactions with different subtypes of serotonin
receptors. A number of studies have been aimed at examining the impact of LCAP structure
modifications on the affinity, selectivity and function at a given receptor protein.[1]
In this study the structure of 2-{6-[4-(2-chlorophenyl)piperazin-1-yl]hexyl}-2,3-dihydro-1H-isoindole-
1,3-dione complexed with five receptors (5-HT1AR, 5-HT2AR, 5-HT6R, 5-HT7R, D2R) has been
investigated by means of quantum mechanical methods. At the beginning, the test compound was
docked to receptors (homology models based on …) and next optimized with ONIOM method. For
thus obtained structures FMO-EDA calculations were performed.
Results shed some lights on the interpretation of the experimental results concerning the affinity to
receptors, as well as they provided the reasonable binding energies and binding patterns of ligand-
protein interactions.
Acknowledgments:The study was financially supported by the National Centre for Research and
[1]
P. Kowalski. et al., Arch. Pharm. Chem. Life Sci., 2013, 346, 339.
212
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AN ASPARTATE-AMINE SALT BRIDGE – THE ETS-NOCV STUDY
Paweł Śliwa,[a],* Rafał Kurczab[b] and Andrzej J. Bojarski[b]

[a] Faculty of Chemical Engineering and Technology, Cracow University of Technology, Warszawska 24, 31-
155 Cracow, Poland
31-343 Cracow, Poland
* pawel.sliwa@chemia.pk.edu.pl
The human G-protein-coupled receptors (GPCRs) represent the most important set of potential
therapeutic targets.[1] It is well known that the ligand binding site of aminergic GPCRs is located
within the transmembrane (TM) region of the receptor and D3.32 is common as an anchoring point
throughout the entire biogenic amine family.[1-3] Aspartic acid acting as the counterion for the charged
amine, forming the interaction responsible for a correct ligand orientation.[4] Theoretical study
indicated that D3.32 is directly involved in agonist and antagonist binding for the aminergic GPCRs.[5]
Considering the above, it was reasonable to undertake advanced theoretical study on the nature of
salt bridge, which are exactly the double charge-assisted hydrogen bond (+/-CAHB). For this
purpose, the ETS-NOCV (the natural orbitals for chemical valence (NOCV) combined with extended-
transition-state method (ETS), [6]) calculations were performed for the model systems representing
the all possible scenarios in biological interactions.
E1=-27.3 kcal/mol E2=-3.6 kcal/mol E3=-2.8 kcal/mol
Figure: N-methyl-piperidinum – aspartate.
The results indicated that the main force of +/-CAHB is the charge transfer from an oxygen atom of
aspartic acid. The binding is enhanced by the flow of electron density between the oxygen atoms of
D, as illustrated by the third -type orbital NOCV.
[1]
R.P. Bywater, J. Mol. Recognit. 2005, 18, 60.
[2]
A.J. Kooistra, S.Kuhne, I.J.P. de Esch, R. Leurs, C. de Graaf, British J. Pharmacol., 2013, 170, 101.
[3]
K. Kristiansen, W.K. Kroeze, D.L. Willins, E.I. Gelber, J.E. Savage, R.A. Glennon, B.L. Roth, J. Pharmacol.
Exp. Ther., 2000, 293, 735.
[4]
M. Sencanski, V. Sukalovic, K. Shakib, V. Soskic, L. Dosen-Micovic, S. Kostic-Rajacic, Chem. Biol. Drug.
Des., 2014, 83, 462.
[5]
A. Ranganathan, R.O. Dror, J. Carlsson, Biochemistry, 2014, 53, 7283.
[6]
M. Mitoraj, A. Michalak, J. Mol. Model., 2007, 13, 347.
213
P-138
STEROID RECEPTOR BINDING AFFINITIES OF SELECTED MODIFIED

STEROIDS- A SCREENING TOOL FOR IDENTIFICATION OF POTENTIAL
THERAPEUTICS
Sofija S. Bekić,[a] Marija N. Sakač,[a] Suzana S. Jovanović-Šanta,[a]

Edward T. Petri[b] and Andjelka S. Ćelić[b],*
[a] Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of
Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
[b] Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića
2, 21000 Novi Sad, Serbia
* andjelka.celic@dbe.uns.ac.rs
Identification of compounds for treatment of prostate and breast cancer remains a major goal of
biomedical research, since these diseases are leading causes of death among men and women
worldwide. Currently the most effective treatment strategies include blocking the proliferative effects
of steroid hormones by binding structurally similar synthetic analogues to steroid receptors. Intensive
research has been focused on the synthesis of structurally modified steroid hormones with high
affinity for these receptors, in order to obtain potential drug candidates. Modified androstane and
estrane derivatives are an especially interesting class of compounds in the treatment of receptor-
mediated diseases.
There are numerous steroid receptor binding assays described in the literature. Muddana and
Peterson developed fluorescent cellular biosensor by expressing the ligand binding domain (LBD)
of some steroid receptors marked with yellow fluorescent protein (YFP) in Sacharomyces cerevisiae
for identification of steroid receptor ligands and quantification of their binding affinity.[1] Our goal was
to improve the sensitivity and selectivity of this assay and to test binding affinities of some selected
modified steroids. This simple, economical and sensitive assay can be applied as a preliminary
screen for libraries of steroid receptor ligands. Further examination of steroid derivative binding
affinities was performed using docking or in vitro studies.
[1]
S.S. Muddana, B.R.Peterson, ChemBioChem, 2003,4, 848.
214
P-139
DEVELOPMENT OF BIOORTHOGONAL 2-NITROIMIDAZOLE BASED

HYPOXIA SENSITIVE PROBES
Barbara Sohr,[a],# Christoph Denk,[a] Thomas Wanek[b] and Hannes Mikula[a],*

[a] Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Vienna, Austria
[b] Health and Environment Department, Biomedical Systems, Austrian Institute of Technology, Seibersdorf,
Austria
#
Recipient of a DOC Fellowship of the Austrian Academy of Sciences
* hannes.mikula@tuwien.ac.at
Hypoxia is a low oxygen condition often observed in a variety of solid tumors and associated with
high therapy resistance, invasiveness and metastasis. To properly plan and adjust cancer treatment,
it is of vital importance to identify, measure and localize hypoxic regions. Current methods, e.g. PET
imaging using 18F-labeled hypoxia sensitive probes such as 18F-FAZA, lack satisfactory tumor-to-
background ratios attributed to slow tumoral retention, unspecific accumulation in normal (normoxic)
tissue and washout of the probe.[1]
In this work, we focused on the development of novel hypoxia sensitive probes that enable two-step
pretargeting strategies based on bioorthogonal chemistry. The inverse electron demand Diels-Alder
(IEDDA)-initiated conjugation between 1,2,4,5-tetrazines and strained dienophiles (e.g. trans-
cyclooctenes, TCOs) has been proven to be a highly efficient and fast bioorthogonal ligation[2] and
was therefore used within this study.
The above-mentioned two-step process will
consist of (1) administration of a TCO-tagged
hypoxia sensitive probe that is specifically
trapped in hypoxic cells and (2) administration of
a tetrazine-modified compound, e.g. as pull down
reagent (PDR) that selectively binds to the probe
through bioorthogonal ligation. Depending on the
nature of the tetrazine-modified agent the
pretargeted hypoxia probe can be used for a wide
range of applications (Figure 1) making it a
remarkably versatile chemical tool for biomedical
research.
Figure 1: Possible applications for hypoxia
To achieve hypoxia probes.
sensitivity a 2-
nitroimidazole (NIM) moiety was incorporated in our target compounds
(as shown exemplarily in Figure 2). NIM is known to specfically
Figure 2: TCO-tagged
hypoxia probe. accumulate in hypoxic cells after intracellular reduction of the NO2
moiety.[3]
IEDDA ligation of the prepared probes was investigated using already available PDRs to acquire
kinetic data and facilitate characterization of conjugation products. Furthermore, in vitro stability, cell
permeability and accumulation in hypoxic cells were studied.
Results on the synthesis and in vitro evaluation of TCO-tagged NIM derivatives as bioorthogonal
hypoxia probes will be presented.
[1]
S. Carlin, J.L. Humm, J. Nucl. Med., 2012, 53, 1171.
[2]
M.L. Blackman, M. Royzen, J.M. Fox, J. Am. Chem. Soc., 2008, 130,13518.
[3]
J.D. Chapman, A.J. Franko, J. Sharplin, Br. J. Cancer, 1981, 43, 546.
215
P-140
NEUROPROTECTIVE POTENTIAL OF LINEZOLID: A QUANTITATIVE

AND DISTRIBUTION STUDY VIA MASS SPECTROMETRY
Sooraj Baijnath,[a],* Chivonne Moodley,[b] Bongani Ngcobo,[b] Sanil D. Singh,[c]

Gert Kruger,[1] Per I. Arvidsson,[a,d] Tricia Naicker,[a] Alexander Pym[b] and Thavendran
Govender[a]
[a] Catalysis and Peptide Research Unit, School of Pharmacy and Pharmacology, University of KwaZulu-
Natal, Westville Campus, Durban, South Africa
[b] Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal,
Durban, South Africa
[c] Biomedical Resource Unit, University of KwaZulu-Natal, Westville Campus, Durban, South Africa
[d] Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational Medicine
and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
Stockholm, Sweden
* baijnath.sooraj@gmail.com
Tuberculosis (TB) has been the scourge of the human race for many years, claiming countless
numbers of lives along the way. This is further complicated by the ability of Mycobacterium
tuberculosis (M.tb) infect extra-pulmonary sites, more specifically the brain. These forms of TB are
difficult to treat due to the problems associated with drug delivery across the blood brain barrier
(BBB). Linezolid (LIN) and clofazimine (CFZ) are two of the more promising anti-TB antibiotics in
recent times, with proven ability to penetrate the BBB. In this study Balb/c mice were aerosol infected
with M.tb H37Rv and treated for four weeks with both LIN (100 mg/kg.b.w) and CFZ (100 mg/kg.b.w).
Concurrently, we investigated if an aerosol TB infection would lead to the dissemination of TB bacilli
into the brain. Post-treatment brain and lung CFU’s were determined together with serum, lung and
brain drug concentrations. CFZ displayed a strong bactericidal effect in the lung, while LIN had a
bacteriostatic effect. M.tb appeared after one week post-infection in the untreated group (2.38 ± 0.43
log10CFU) and more surprisingly after two weeks post-infection in the LIN (1.14 ± 0.99 log10CFU).
TB bacilli could not be detected in the brains of the CFZ group. To the best of our knowledge, this is
the first study to show the appearance of M.tb in the brain after an aerosol TB infection in a mouse.
This study also demonstrates the potential of CFZ to protect against the development of extra-
pulmonary TB of the CNS.
[1]
S. Baijnath, S. Naiker, A. Shobo, C. Moodley, J. Adamson, B. Ngcobo, L.A. Bester, S.D. Singh, H.G. Kruger,
T. Naicker, T. Govender, J. Mol. Hist., 2015, 46, 439.
[2]
S. Baijnath, A. Shobo, L.A. Bester, S.D. Singh, H.G. Kruger, T. Naicker, P.I. Arvidsson, T. Govender, J. Mol.
Hist., 2016, 47, 429.
216
P-141
SYNTHESIS, ANTITUMOR AND ANTIOXIDATIVE ACTIVITY OF NITRO

AND AMINO SUBSTITUTED BENZIMIDAZOLE AND BENZOTHIAZOLE 2-
CARBOXAMIDES
Irena Sović,[a] Ida Boček,[a] Petra Roškarić,[a] Marijeta Kralj,[b] Irena Martin Kleiner,[b]
Kristina Starčević[c] and Marijana Hranjec[a],*
[a] Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20,
Zagreb, Croatia
[b] Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia
[c] Faculty of Veterinary Medicine, Heinzelova 55, Zagreb, Croatia
* mhranjec@fkit.hr
Heterocyclic compounds containing benzimidazole and benzothiazole have been found very
interesting to medicinal and organic chemists and are extensively studied due to their well known
and wide biological activities. Over the past several years we have become interested in antitumor
activity of different derivatives of benzimidazole and benzothiazole carboxamides, and recently in
their antioxidative activity.[1,2] Oxidative stress, as a result of excessive production and accumulation
of free radicals, is one of the leading causes of many degenerative diseases such as Alzheimer's
and Parkinson's disease, inflammatory processes and DNA damage leading to carcinogenesis.
In this report we present synthesis, antitumor and antioxidative activity of novel nitro and amino
substituted benzimidazole and benzothiazole carboxamides. For the synthesis of novel compounds
we have used methods of classical linear organic synthesis starting from aromatic acyl halogenides
which gave in the reaction with substituted 2-aminobenzimidazoles or 2-aminobenzothiazoles
corresponding carboxamides. Antiproliferative activity in vitro of selected compounds was tested on
several human tumor cell lines and the antioxidant properties were determined by DPPH and FRAP
methods.[3]
[1]
M. Hranjec, I. Sović, I. Ratkaj, G. Pavlović, N. Ilić, L. Valjalo, K. Pavelić, S. Kraljević Pavelić, G. Karminski-
Zamola, Eur. J. Med. Chem., 2013, 59, 111.
[2]
L. Racane, R. Stojković, V. Tralić- Kulenović, H. Cerić, M. Đaković, K. Ester, A. Mišir Krpan, M. Radić
Stojković, Eur. J. Med. Chem., 2014, 86, 406.
[3]
M. Tireli, K. Starčević, T. Martinović, S. Kraljević Pavelić, G. Karminski- Zamola, M. Hranjec, Mol. Divers.,
2017, 21, 201.
217
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ESTIMATION OF BINDING AFFINITY FOR SOME SYNTHESIZED

COUMARIN DERIVATIVES WITH RECEPTORS IMPORTANT FOR
BACTERIAL GROWTH AND DEVELOPMENT
Selma Špirtović-Halilović,[a],* Elma Veljović,[a] Mirsada Salihović,[b]

Aida Šapčanin,[b] Amar Osmanović,[a] Nihada Škrijelj[a] and Davorka Završnik[a]
[a] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sarajevo, Bosnia and
Herzegovina
[b] Department of Natural Sciences in Pharmacy, Faculty of Pharmacy, University of Sarajevo, Bosnia and
Herzegovina
* selmaspirtovic@yahoo.com
In silico methods have been used to estimate possible ways of binding for selected coumarin
derivatives with two receptors, amylase and gyrase (PDB: 1BAG and 1KZN), which are known to be
important in life process of some bacteria.[1,2] Docking analyses provided comparison of binding
energies, inhibitory constants, number of hydrogen bonds, as well as amino acids involved in the
interaction of analyzed compounds.
Binding energies of tested compounds and amylase were between -4.78 and -3.9 kcal mol-1, while
binding energies of tested compounds with gyrase were between -6.99 and -4.63 kcal mol-1.
Obtained results revealed possible hydrophobic interactions between ligands and receptors.
Moreover, correlation between in silico calculated parameters and in vitro biological testing of
antimicrobial activity has been examined.
[1]
L.W. Tari, M. Trzoss, D.C. Bensen, X. Li, Z. Chen, T. Lam, J. Zhang, C.J. Creighton, M.L. Cunningham, B.
Kwan, M. Stidham, K.J. Shaw, F.C. Lightstone, S.E. Wong, T.B. Nguyen, J. Nix, J. Finn, Bioorg. Med. Chem.
Lett., 2013, 23, 1529.
[2]
C. Anderle, M. Stieger, M. Burrell, S. Reinelt, A. Maxwell, M. Page, L. Heide, Antimicrob. Agents Chemother.,
2008, 52, 1982.
218
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ANTIBACTERIAL THIAZOLIN-4-ONES AS POTENTIAL DNA GYRASE

AND TOPOISOMERASE IV INHIBITORS
Anca Stana,[a],* Radu Tamaian,[b,c] Dan C. Vodnar,[d] Ovidiu Oniga[a] and

Brîndușa Tiperciuc[a]
[a] Department of Pharmaceutical Chemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy, 41
Victor Babeș Street, RO-400012 Cluj-Napoca, Romania
[b] National Institute for Research and Development for Cryogenic and Isotopic Technologies, 4th Uzinei
Street, RO-240050 Râmnicu Vâlcea, Romania
[c] SC Biotech Corp SRL, 4th Uzinei Street, RO-240050 Râmnicu Vâlcea, Romania
[d] Department of Food Science and Technology, University of Agricultural Sciences and Veterinary
Medicine, 3-5 Manăştur Street, RO-400372 Cluj-Napoca, Romania
* teodora_anca@yahoo.com
Despite the numerous antimicrobial agents approved for the treatment of infections, the emergence
of infectious diseases and the dramatically increasing number of pathogens resistant to different
classes of currently available anti-infective agents resulted in the acute need to implement new
strategies for developing new antimicrobial chemotherapeutics towards which there is little
antimicrobial resistance or no cross-resistance. [1]
The type IIA topoisomerases, DNA topoisomerase IV subunit A and DNA gyrase subunit A, are both
involved in supercoiled DNA relaxation and play a crucial role in the bacterial transcription and
replication process. Therefore, dual targeting of these enzymes is a good strategy in the research of
new antibacterial compounds.[2]
23 previously synthesized thiazolin-4-ones [3] were prospected for their antibacterial activity.
Minimum inhibitory concentrations and minimum bactericidal concentrations were determined,
employing the broth microdilution method. All the synthesized compounds were tested against
Staphylococcus aureus ATCC 49444 and Escherichia coli ATCC 25922. Moxifloxacin (Mox) was
used as positive control. All the synthesized thiazolin-4-ones presented good antibacterial
properties. Overall, the compounds were more active against S. aureus ATCC 49444 than against
E. coli ATCC 25922. The most active compounds were the thiazolin-4-one derivatives 10 and 9b,
displaying better antibacterial activities than moxifloxacin.
All the investigated molecules (the thiazolin-4-one derivatives and reference compound) were
virtually subjected to docking, against the generated homology models of bacterial DNA
topoisomerase IV subunit A and DNA gyrase subunit A in order to investigate their potential binding
mode and binding affinity. The docking results against DNA topoisomerase IV subunit A indicated
that six thiazolin-4-ones derivatives (6e and 9a-e) are more potent inhibitors than Mox against DNA
topoisomerase IV subunit A. Eight thiazolin-4-one derivatives (6d-e, 8 and 9a-e) are more potent
inhibitors than the reference compound against DNA gyrase subunit A.
The results of compounds’ docking towards the bacterial type IIA topoisomerases indicated that
derivative 6c had a medium inhibitory activity and could be used for dual targeting of these
topoisomerases, while compound 8 had a promising behavior (medium inhibitor of topoisomerase
and strong inhibitor of gyrase).
[1]
I. Chopra, C. Schofield, M. Everett, A. O’Neill, K. Miller, M. Wilcox, et al., Lancet Infect. Dis., 2008, 8, 133.
[2]
M.A. Azam, J. Thathan, S. Jubie, Bioorg. Chem., 2015, 62, 41.
[3]
A. Stana, D.C. Vodnar, R. Tamaian, A. Pîrnău, L. Vlase, I. Ionuț, O. Oniga, B. Tiperciuc, Int. J. Mol. Sci.,
2017, 18(1), 177.
219
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DESIGN, SYNTHESIS, X-RAY STUDIES AND BIOLOGICAL EVALUATION

OF NOVEL CHALCONE DERIVATIVES – POTENTIAL MICROTUBULE
TARGETING AGENTS
Tomasz Stefanski,[a] Rafał Kurczab,[b] Artur Korzanski,[a] Katarzyna Skonieczka,[c] Barbara

Grolik,[c] Emilia Kania,[d] Barbara Bojko,[d] Zbigniew Dutkiewicz,[e]
Agnieszka Gielara-Korzańska,[e] Renata Mikstacka[f],
Adam Hogendorf[b] and Maciej Kubicki[a]
[a] Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89B, 61-
614 Poznan, Poland
31-343 Krakow, Poland
[c] Department of Clinical Genetics, Faculty of Medicine, Ludwig Rydgier Collegium Medicum in Bydgoszcz,
Nicolaus Copernicus University, A. Jurasza 2, 85-089 Bydgoszcz, Poland
[d] Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Ludwig Rydgier
Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, A. Jurasza 2, 85-089 Bydgoszcz,
Poland
[e] Department of Chemical Technology of Drugs, Faculty of Pharmacy, Poznan University of Medical
Sciences, Grunwaldzka 6, 60-780 Poznan, Poland
[f] Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Ludwig Rydgier Collegium
Medicum in Bydgoszcz, Nicolaus Copernicus University, A. Jurasza 2, 85-089 Bydgoszcz, Poland
* tomasz.stefanski@amu.edu.pl
The microtubular system with its dynamic nature characterized by the polymerization and
depolymerization of α,β-tubulin heterodimers, is essential in a variety of cellular processes, including
maintenance of cell shape, regulation of motility and cell division.[1] Because of the latter function
microtubules are one of the significant and more successful molecular target for designing of new
active molecules possessing anticancer activity. Among this group of compounds chalcones (1,3-
diphenylprop-2-en-1-on derivatives) represent a promising class of compounds with a simple
structure, taking the possibility of extensive structural modifications that improve their natural
anticancer properties.
Their mechanism of action including the inhibition of tubulin assembly by binding to the colchicine
binding domain resulting from their structural similarity to other active ligands that have the same
molecular target (e.g. combretastatin A-4, CA-4). Our successful investigation on novel potent
inhibitors of tubulin polymerization from group of CA-4 thioderivatives prompted us to extend our
research on chalcone scaffold.
Herein we present synthesis, molecular modelling studies, X-ray structural characteristics and
biological evaluation of novel chalcone thioderivatives. Their antiproliferative activity was determined
using panel of human cancer and normal cell lines, tubulin inhibition, cell cycle and pro-apoptotic
analyses.
The multidisciplinary research methodology supported by computer aided drug design methods,
standard and high-resolution X-ray structural analysis combined with modelling of the multipole
electron density distribution[2] enable to develop of a new, effective chemotherapeutics from the
group of chalcone derivatives and for the better understanding of their interaction with tubulin at the
molecular level.
Acknowledgments: The project was supported by research grant OPUS (UMO-

2015/17/B/ST4/03701) financed by Polish National Science Center.
[1]
R. Mikstacka, T. Stefański, J. Różański, Cell. Mol. Biol. Lett., 2013, 18, 368.
[2]
A. Poulain-Paul, A. Nassour, C. Jelsch, B. Guillot, M. Kubicki, C. Lecomte, Acta Cryst. A, 2012, 68, 715.
220
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NOVEL DPDPE ANALOGUES INCORPORATING A XYLENE BRIDGE:

SYNTHESIS AND BIOLOGICAL PROFILE
Azzurra Stefanucci,[a],* Giorgia Macedonio,[a] Stefano Pieretti,[b] Ferenc Zador,[c] Sandor

Benyhe[c] and Mollica Adriano[a]
[a] Dipartimento di Farmacia, Università di Chieti-Pescara “G. D’Annunzio”, Via dei Vestini 31, 66100
Chieti, Italy
[b] Istituto Superiore di Sanità, Dipartimento del Farmaco, Viale Regina Elena 299, 00161, Rome, Italy
[c] Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726,
Szeged, Hungary.
* a.stefanucci@unich.it
Three cyclic analogues of DPDPE containing xylene bridge regioisomers (7a-c) have been
synthesized and fully characterized as mixed δ/µ/κ-opioid receptors agonists.[1,2]
The in vitro activity has been investigated showing a good affinity of 7a-c for both of them. In vivo
biological assays revealed that 7b is the most potent cyclic analogue with the ability to maintain high
level of analgesia after 60 and 90 minutes following i.c.v. and i.t. administrations respectively in Tail
Flick test and long lasting analgesia after subcutaneous administration.
7b: kim = 34.9 nM

ki = 292.2 nM
[1]
A. Mollica, G. Guardiani, P. Davis, S.-W. Ma, F. Porreca, J. Lai, L. Mannina, A.P. Sobolev, V.J. Hruby, J.
Med. Chem., 2007, 50, 3138.
[2]
C. Marculescu, H. Kossen, R. E. Morgan, P. Mayer, S. A. Fletcher, B. Tolner, K. A. Chester, L. H. Jones, J.
R. Baker, Chem. Comm., 2014, 50, 7139.
221
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IDENTIFICATION OF NOVEL STAT3 INHIBITORS AND SYNTHESIS-

ASSISTED ELUCIDATION OF MOLECULAR MECHANISM
Seungbeom Lee,[b] Changjin Lim,[a] Joonseong Hur[b] and Young-Ger Suh[a,b],*

[a] College of Pharmacy, Cha University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-Do,
Republic of Korea
[b] College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, Republic of
Korea
* ygsuh@cha.ac.kr
A series of novel STAT3 inhibitors consisting of Michael acceptor as a typical electrophilic moiety
has been identified through assays of the focused in-house library, which consist of a variety of
scaffolds derived through a long-term medicinal chemistry program.[1] In addition, mode of action
and structural feature of the identified STAT3 inhibitors responsible for the inhibitory activity were
investigated.
In particular, the enone analogs revealed promising inhibitory activities in the STAT3-driven
luciferase expression in HeLa cells. We confirmed that enone moiety of the selected analogs,
which possesses a less-hindered exo-olefin, is essential for direct interaction with the nucleophilic
cysteine residue of STAT3 via Michael addition. The analogs also exhibited selective inhibition of
STAT3 phosphorylation without affecting STAT1 phosphorylation.[2] It also exhibited cytostatic
effect in human breast epithelial cells (MCF10A-ras), which supports the cancer cell-specific
inhibitory properties.
In order to investigate the mode of action for the selected analogs, STAT3 phosphorylation was
confirmed by Western blot analysis using H-ras transformed MCF10A (MCF10A-ras), which
seemed to serve as an adequate model for studies on mammary carcinogenesis. Intensive studies
on the selected analogs including elucidation of their detailed inhibitory activities and development
of more potent STAT3 inhibitors based on the preliminary SAR will be reported.
[1]
D. Chang, H. An, K. Kim, H. H. Kim, J. Jung, J. M. Lee, N. Kim, Y. T. Han, H. Yun, S. Lee, G. Lee, S. Lee,
J. S. Lee, J. Cha, J. Park, J. W. Park, S. Lee, S. G. Kim, J. H. Kim, H. Lee, K. Kim, and Y.-G. Suh, J. Med.
Chem., 2012, 55, 10863.
[2]
K. Kim, S. Kim, Y. T. Han, S. Hong, H. An, D. Chang, T. Kim, B. Lim, J. Lee, Y. Surh, Y.-G. Suh, Bioorg.
Med. Chem. Lett., 2015, 25, 5444.
222
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HIGHLY REACTIVE DIENOPHILES FOR BIOORTHOGONAL TETRAZINE

LIGATIONS
Dennis Svatunek, Maximilian Haider and Hannes Mikula*

Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Vienna, Austria
* hannes.mikula@tuwien.ac.at
The tetrazine-TCO ligation, the reaction between 1,2,4,5-tetrazines and trans-cyclooctenes (TCO),
is the fastest bioorthogonal reaction reported so far with second order rate constants of up to 3 300
000 M-1s-1.[1] High reactivity is of significance for reactions intended to be used in biological
environments, which are commonly performed at very low concentration.
The two-step reaction of an electron deficient tetrazine and TCO is initiated by an inverse electron
demand Diels-Alder cycloaddition followed by a retro-Diels-Alder reaction under the loss of nitrogen.
Highly reactivity TCOs are the conformationally strained trans-cyclooctenes s-TCO (1) and d-TCO
(2) introduced by Fox and coworkers (Figure 1a).[1,2] They show incredibly high reaction rates,
however, in vivo stability is limited.
Within this work we aimed to improve the reactivity and stability of known trans-cyclooctene
derivatives and to develop new TCOs with improved properties.
Reactivity of proposed structures are first evaluated in silico using established DFT methods (M06-
2X/6-311+G(d,p)).[3,4] Most promising structures are selected and further investigated experimentally
regarding their stability and reactivity. Explored structures include derivatives of known TCOs, for
example bis-methylated s-TCO (3) and d-TCO (4) (Figure 1b), and trans-cyclooctenes with new
structural features such as the bridged TCO 5 (Figure 1c).
Figure 1: a) Chemical structure of s-TCO (1) and d-TCO (2); b) Bis-methylated TCOs; c) Bridged TCO
DFT calculations show lowered free energies of activation for bis-methylated derivatives 3 and 4 in
comparison to their parent compounds 1 and 2. The additional methyl groups are furthermore
expected to be beneficial for stability. Computational investigation of the novel TCO 5 and similar
structures suggests reactivities comparable to s-TCO (1).
Results on quantum chemical calculations, the synthesis and evaluation of novel TCOs will be
presented.
[1]
A. Darko, S. Wallace, O. Dmitrenko, M. M. Machovina, R. a. Mehl, J. W. Chin, J. M. Fox, Chem. Sci.,
2014, 5, 3770.
[2]
M. T. Taylor, M. L. Blackman, O. Dmitrenko, J. M. Fox, J. Am. Chem. Soc., 2011, 133, 9646.
[3]
C. Denk, D. Svatunek, S. Mairinger, J. Stanek, T. Filip, D. Matscheko, C. Kuntner, T. Wanek, H. Mikula,
Bioconjug. Chem., 2016, 27, 1707.
[4]
C. Denk, D. Svatunek, T. Filip, T. Wanek, D. Lumpi, J. Fröhlich, C. Kuntner, H. Mikula, Angew. Chemie Int.
Ed., 2014, 53, 9655.
223
P-148
SYNTHESIS AND CYTOTOXIC ACTIVITY OF NEW DERIVATIVE OF

ISOTHIAZOLOPYRIDINE
Piotr Świątek,[a],* Agnieszka Matera-Witkiewicz,[b] Karolina Królewska-Golińska,

Julia Kaźmierczak-Barańska, Marcin Cieślak and Barbara Nawrot[c]
[a] Department of Chemistry of Drugs, Faculty of Pharmacy, Wroclaw Medical University, Borowska
211, 50-556 Wrocław, Poland
[b] Screening Laboratory of Biological Activity Tests and Collection of Biological Material Wroclaw
Medical University, Borowska 211A, 50-556 Wroclaw, Poland
[c] Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112,
90-363 Lodz, Poland
* piotr.swiatek@umed.wroc.pl
A series of isothiazolopyridines of Mannich base type was synthesized. The structures of

heterocycles were assigned on the bases of IR and 1H NMR data. The cytotoxicity of new
compounds was determined on three neoplastic cell lines: HeLa (human cervix carcinoma), K562
(leukemia) and CFPAC (human pancreatic cancer cell line) by MTT assay as described in literature.[1]
In the present screening program compound PS8 schowed the best cytotoxic activity.
O
N O
N S N
O
N
Figure: PS8
In the screening test following survival rates were obtained:
HeLa K562 CFPAC

48H 72H 48H 72H 48H 72H
12% 8% 0% 0% - 1%
Because of high cytotoxic activity of PS8 on all three neoplastic cells lines, further cytotoxicity tests
were performed using 6 different concentrations of the compound: 1mM, 1x10-1mM, 1x10-2mM, 1x10-
3
mM, 1x10-4mM, 1x10-5mM. After 72 hours a survival of the cancer cells was measured and IC50
values were calculated, yielding the following results: HeLa 30µM, K562 40µM and CFPAC 25µM.
The cytotoxicity in HUVEC (human umbilical vein endothelial cells) as a reference/normal line was
also determined. The IC50 = 6µM was obtained after 48 hours of incubation of HUVECs with PS8.
[1]
M. Maszewska, J. Leclaire, M. Cieslak, B. Nawrot, A. Okruszek, A.-M. Caminade, J.-P. Majoral,
Oligonucleotides, 2003, 13, 193.
224
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STUDIES ON ARYL-SUBSTITUTED PHENYLALANINES: SYNTHESIS,

ACTIVITY AND DIFFERENT BINDING MODES AT AMPA RECEPTORS
Ewa Szymańska,[a],* Birgitte Nielsen,[b] Darryl S. Pickering[b] and

Tommy N. Johansen[b]
[a] Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy Jagiellonian University
Medical College, Medyczna 9, 30-688 Kraków, Poland
[b] Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen,
Universitetsparken 2, DK-2100 Copenhagen, Denmark
* ewa.szymanska@uj.edu.pl
Glutamate- and GABA-releasing neurons form two basic, excitatory and inhibitory systems
responsible for neurotransmission in the mammalian central nervous system. Fast excitatory
synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its
family of ion ligand-gated channel receptors (iGluRs). The family of iGluRs is divided into three
functionally distinct subclasses: NMDA, AMPA and kainate receptors. Structurally, AMPA-receptors
are cation-selective tetrameric heterooligomers formed by combinations of the highly homologous
subunits GluA1-4, while kainate receptors are tetrameric assemblies of GluK1-5 subunits.
The present project is a continuation of earlier studies on potent and selective competitive AMPA
and/or KA receptors ligands among phenylalanine derivatives.[1-3] In order to map out molecular
determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-
substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native
rat ionotropic glutamate receptors. The individual stereoisomers of selected compounds were further
evaluated in radioligand binding assays at recombinant homomeric rat GluA2 and GluA3 receptors
as well as in a TEVC electrophysiology assay at homomeric rat GluA2(Q)i receptor.
In the process of molecular modeling and docking to recently published X-ray structures of the
glutamate ionotropic receptors binding sites,[2] two alternative antagonist binding modes at the GluA2
binding core were compare for the synthesized compounds. Structural factors important for
pharmacological activity of individual enenantiomers were analyzed.
Acknowledgments: The financial support of the National Science Centre Poland

(2014/15/B/NZ7/00908) is gratefully acknowledged.
[1]
E. Szymanska, D. Pickering, B. Nielsen, T. Johansen, Bioorg. Med. Chem. 2009, 17, 6390.
[2]
E. Szymanska, K. Frydenvang, D.S. Pickering, C. Krintel, B. Nielsen, A. Kooshki, L.G. Zachariassen, L.
Olsen, J.S. Kastrup, T.N. Johansen, J. Med. Chem., 2016, 59, 448.
[3]
E. Szymanska, P. Chalupnik, K. Szczepanska, A.M.C. Moral, D.S. Pickering, B. Nielsen, T.N. Johansen, K.
Kiec-Kononowicz, Bioorg. Med. Chem. Lett., 2016, 26, 5568.
225
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NOVEL AND EFFICIENT BICYCLIC GUANIDINE CATALYST FOR THE

CYCLOTRIMERIZATION OF ISOCYANATES. A QUANTUM CHEMICAL
STUDY.
Tana Tandarić and Robert Vianello

Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Zagreb, Croatia.
* Tana.Tandaric@irb.hr, Robert.Vianello@irb.hr
Polyurethane foams are widely used polymers composed of organic units joined by carbamate
(urethane) linkers.[1] Management of their physical properties represents significant challenge in the
creation of new materials with desired properties. Since the cyclotrimerisation of organic isocyanates
is one of the most sensitive steps in the whole process, identifying efficient catalysts for this chemical
transformation represents an important and needed research goal.
In this work we considered triazabicyclodecene (TBD) as a potential catalyst for the
cyclotrimerization of isocyanates. We have investigated the reaction pathway involving a sequential
addition of metyl-isocyanate (MIC) using well established quantum chemistry methods at the MP2/6–
311++G(2df,2pd)//M062X/6–31+G(d) level.[2] Our results show that the first MIC molecule is
activated by the TBD catalyst through the nucleophilic attack of its imino nitrogen atom to strongly
electrophilic carbon on MIC followed by the intramolecular MIC–TBD proton transfer, thus opening
the possibility for the activation of another MIC molecule on the second nitrogen atom on TBD. After
that, the two MIC systems combine to give a dimer, to be followed by the analogous formation of an
open-chain trimer chemically bonded to TBD. The last step involves the cyclization of the trimer and
the liberation of the final hexacyclic product concomitant with the regeneration of the TBD catalyst.
The overall reaction pathway reveals that the investigated trimerization is thermodinamically a very
favorable process (ΔrG = –34.3 kcal/mol) with reasonable reaction barrier (ΔG‡ = 27.7 kcal/mol) in
the THF solution. In addition, it provides a convincing insight to why dimerization is not favorable
from both thermodynamic and kinetic points of view, being strongly in line with experimental
observations. Compared to the uncatalyzed reaction, TBD lowers the activation barrier by 8.4
kcal/mol, thus increasing the reaction rate by the factor of 106. These significant results suggest TBD
as a much efficient catalyst than some other systems proposed in the literature based on
proazaphosphatranes.[3]
Figure: Schematic representation of a reaction involving three methyl-isocyanates (MIC) with the TBD
catalyst.
[1]
D. Heift, Z. Benkő, H. Grützmacher, A. R. Jupp, J. M. Goicoechea, Chem. Sci., 2015, 6, 4017.
[2]
I. Picek, R. Vianello, P. Šket, J. Plavec, B. Foretić, J. Org. Chem., 2015, 80, 2165.
[3]
J. N. Gibb, J. M. Goodman, Org. Biomol. Chem., 2013, 11, 90.
226
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DESIGN AND SYNTHESIS OF DUAL G9A METHYLTRANSFERASE/LSD1

DEMETHYLASE OR SELECTIVE LSD1 INHIBITORS BY STRUCTURAL
MANIPULATION OF THE QUINAZOLINE SCAFFOLD
Daniela Tomaselli,[a],* Alessia Lucidi,[a] Mariantonietta Forgione,[a]

Gebremedhin Solomon Hailu,[a] Valentina Speranzini,[b] Biagina Marrocco,[b]
Simona Pilotto,[b] Andrea Mattevi,[b] Dante Rotili[a] and Antonello Mai[a]
[a] Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5,
00185 Rome, Italy
[b] Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
* daniela.tomaselli@uniroma1.it
In humans, histone methylation pattern results from the balance between lysine methylation and
demethylation. The removal of methyl unit(s) is performed by two families of demethylases (KDMs)
that differ for the reaction mechanism: LSD1/2 are FAD-dependent amine oxidases, while JmJC are
iron/α-ketoglutarate dependent proteins.[1] LSD1 is able to catalyze demethylation of H3K4me1/2
and, in association with the co-repressor protein Co-REST, takes part in a multicomponent
repressive complex including also REST and HDAC1/2.[2] LSD1 plays a crucial role in the epigenetic
modulation of gene expression and represents a valuable target in cancer chemotherapy, since it is
overexpressed in several types of tumors.[3] Our investigation of quinazolines as H3K9
methyltransferase/demethylase or DNMT inhibitors led us to identify MC3774, a Lys-mimicking
derivative displaying dual G9a methyltransferase/LSD1 inhibition. In particular, MC3774 showed IC50
values of 1205 nM and 440 nM on G9a and LSD1 respectively. In MV4-11 leukemia cells, MC3774
showed antiproliferative activity with IC50 = 894 nM. The most interesting aspect of this investigation
is about the inhibition mechanism. We designed MC3774 supposing that the insertion of the
propanamine moiety could mimic the H3K4me2 moiety of the substrate bound within the active site.
Surprisingly, the compound does not enter into the accessory pocket but binds the enzyme disposed
with five copies in a stacked way obstructing the active site. The orientation of the molecules can be
“face to face” or “head to tail”, and in both modes they interact with a cluster of negatively charged
amino acidic residues.[4] This kind of non-covalent and reversible inhibition is typical for the
interaction between quinazoline scaffold and the catalytic cleft of LSD1, in fact MC3774 does not
inhibit G9a using the same stacking mode. Considering these observation, we worked on the
synthesis of several analogs of the lead compound MC3774, modifying the quinazoline scaffold in
position 2 with alkylamino functions of different length, variously substituted at omega position, and
replacing the NH in position 4 with an oxygen atom or with N-CH3, or modifying the N-benzyl moiety
with other aryl-alkyl functions, with the aim to increase the selectivity towards LSD1 and to improve
the potency in AML cells of the compounds. The results are consistent with the inhibition mechanism.
In fact, the insertion, on different position, of electron-rich functions, increase the potency on LSD1
and the disguise of proton donor groups determines the loss of the inhibitory activity on G9a.
[1]
D. Rotili, A.Mai, Genes & Cancer, 2011, 2, 633.
[2]
S. Saleque, J. Kim, H. M Rooke, Mol. Cell., 2007, 27, 562.
[3]
J. W. Hojfeldt, K. Agger, K. Helin, Nat. Rev Drug Discov., 2013, 12, 917.
[4]
V. Speranzini et al., Sci. Adv., 2016, 2, 1.
227
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HOMOLOGY MODELLING, STRUCTURE- AND LIGAND-BASED DRUG

DESIGN OF NOVEL CALCIUM CHANNEL BLOCKERS WITH
LEISHMANICIDAL ACTIVITIES
Carlos Henrique Tomich de Paula da Silva,[a],* Leonardo Bruno Federico,[a]

Laura M. Alcântara,[b] Carolina B. Moraes,[b] Lucio H. Freitas-Júnior[b] and
Joaquín M. Campos Rosa[c]
[a] School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São
Paulo, Brazil.
[b] Laboratório Nacional de Biociências (LNBio) – Centro Nacional de Pesquisa em Energia e
Materiais (CNPEM) – Campinas, Brazil.
[c] Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de
Granada, Spain
* tomich@fcfrp.usp.br
Nowadays, the biggest challenge for the chemotherapeutic treatments and which is responsible for
many cases of failures in the leishmaniasis treatments is called multidrug resistance (MDR). MDR is
not only related to a class of medication or to a specific target, but it can also be related to the multiple
factors involved in this process. The pathways that affect the decrease of drug concentration in the
intracellular environment are related to the decrease associated with the inflow of the carriers, e.g.
a diminution via the ABC superfamily (ATP-binding cassette) through the efflux caused by the action
of P-glycoprotein (MDR1). Within the ABC superfamily, the P-glycoprotein (P-gp) is the most widely
studied class and the calcium channel blockers class is the first generation of P-gp modulators.
Moreover, they interfere with the adhesion of the parasite to macrophages and this could be an
important strategy to control the initial phase of leishmaniasis.
In this work, we carried out the design of drug candidates addressed to a leishmanicidal activity
through a potential calcium channel blockage, and not suffering the MDR phenomenon. We have
used Ligand-Based Drug Design (LBDD), Structure-Based Drug Design (SBDD), pharmacokinetic
and toxicological (ADME/Tox) predictions, as well as homology modeling of a L-type calcium
channel. Resulting model was well evaluated as the top-ranked amongst three other models based
on two other structures detected in a previous Blastp search. The two drug design approaches above
mentioned were then used to perform virtual screening in different commercial compounds
databases, totalizing up to 15 compounds selected for purchase. In silico validations of the
approaches here used were initially performed using small “contaminated” (with known active ones)
databases, and our drug candidates were then validated in vitro, showing interesting leishmanicidal
activity as well as efficacy.
228
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NOVEL D- GLUCOSAMINE N- PEPTIDYL DERIVATIVES ENDOWED WITH

SELECTIVE ACTIVITY TOWARDS IKK alpha
V. Tudino,[a],* V. N. Madia,[a] F. Saccoliti,[a] G. Pupo,[a] R. Cocchiola,[b]

A. Scotto D’Abusco,[b] R. Scandurra,[b] R. Costi[a] and R. Di Santo[a]
[a] Pasteur Institute – Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del
Farmaco, “Sapienza” University of Rome, p.le Aldo Moro 5, 00185, Rome, Italy
[b] Dipartimento di Scienze biochimiche “Alessandro Rossi Fanelli”, “Sapienza” University of Rome,
p.le Aldo Moro 5, 00185, Rome, Italy
* valeria.tudino@uniroma1.it
Osteoarthritis (OA) is a rheumatic disease which represents the major cause of disability in the adult
population as well as a severe health burden with a significant economic impact. OA is the result of
abnormal biomechanics and cell-derived and tissue-derived factors.[1] The NF-kB family of nuclear
transcription factors is involved in the induction of inflammatory disorders, representing a potential
therapeutic target in OA. It comprehends ubiquitously expressed proteins responsible for the
regulation of a considerable number of genes. These transcription factors are sequestered in the
unstimulated cell cytoplasm by inhibitor proteins called IkBs, forming inactive complexes. As a result
of specific stimuli IkB is phosphorylated by IkB kinase (IKK) complex, leading to the dissociation of
IkB from NF-kB which can migrate into the nucleus, activating the gene transcription. IKK includes
three components: IKK, IKK and NF-Kb essential modulator (NEMO). IKK and IKK are
implicated in the regulation of the expression of genes involved in the extracellular matrix remodeling
and terminal differentiation of chondrocytes.[2,3] From a random screening of our in house library the
compound RC510 (already known as substrate analog inhibitors of papain and cathepsin-B),[4] a D-
glucosamine N-peptidyl derivative, showed selective activity towards IKK.[5] Following this result we
decided to investigate the interactions of this compound with the target by conducting molecular
docking studies, in order to speculate about the mechanisms by which it binds to IKK kinase
domain. As docking molecular target we used a three-dimensional model of IKK, built by homology
modelling. Docking experiment showed that RC510 interacts with ATP binding pocket mainly by the
establishment of hydrogen bonds (with backbone atoms of Thr15 and Glu140 and with side chains
of Thr15 and Asp94) and of hydrophobic interactions. From these results we decided to design and
synthesize a novel series of D-glucosamine N-peptidyl derivatives in order to obtain compounds
having an inhibitory activity towards IKK.
[1]
L.J. Sandell, Nat. Rev. Rheumatol., 2012, 8, 77.
[2]
E. Zandi, D. M. Rothwarf, M. Delhase, M. Hayakawa, M. Karin, Cell, 1997, 91, 243.
[3]
S. Ghosh, M. Karin, N. Haven Cell, 2002, 109, S81.
[4]
C. Giordano, C. Gallina, V. Consalvi, R. Scandurra, E. J. Med. Chem., 1991, 26, 753.
[5]
A. Scotto D’Abusco, L. Politi, C. Giordano, R. Scandurra, Arthritis Res. Ther., 2010, 12, R18.
229
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MEMANTINE ANALOGUES WITH ACTIVITY AS GLUTAMATE N-METHYL

D-ASPARTATE RECEPTOR ANTAGONISTS
Andreea L. Turcu,[a] Daina Martínez-Falguera,[b] Francesc X. Sureda[b] and

Santiago Vázquez[a],*
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institute of
Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, Spain
[b] Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, C/St.
Llorenç 21, Reus, 43201, Spain
* svazquez@ub.edu
Current treatments for Alzheimer’s disease (AD), the most common form of dementia, neither
prevent nor reduce the progression of the disease.[1] Thus, new therapies are urgently needed.
The N-Methyl-D-aspartate (NMDA) receptor antagonists act by protecting neurons from excessive
pathological calcium influx, which leads to neuronal damage and finally to neuronal cell death,
common features in neurodegenerative disorders such as AD. So far, memantine is the only NMDA
uncompetitive receptor antagonist that has been approved for the treatment of AD.[2]
In the last few years, our research group has synthesized and carried out the pharmacological
evaluation of new memantine analogues with general structure 1. We found that this polycyclic
amines were active as NMDA receptor antagonists, some of them with IC50 values similar to that of
memantine (IC50 = 1.5 µM) (Figure 1).[3]
Figure 1: Compounds 1a-d and their activity as NMDA receptor antagonists
These results and the simplicity of the route led us to design and synthesize new derivatives with
general structure 2, which pharmacological activities will be presented here (Figure 2).
Figure 2: Compounds 2a-h, new NMDA receptor antagonists

[1]
J. Korabecny, F. Zemek, O. Soukup, K. Spilovska, K. Musilek, D. Jun, E. Nepovimova, K. Kuca, in Drug
Design and discovery in Alzheimer’s Disease, Atta-ur-Rahman and Choudhary, M. I., ed.; Elsevier 2014, 3.
[2]
a) L. Devi, M. Ohno, Pharmacol. Biochem. Behav., 2016, 144, 60. b) W. Danysz, C. G. Parsons, British J.
Phamacol., 2012, 167, 324.
[3]
E. Valverde, F. X. Sureda, S. Vázquez, Bioorg. Med. Chem., 2014, 22, 2678.
230
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NOVEL THIAZOLES AS TRYPANOCIDAL AGENTS
Santiago Vázquez,[a],* Rosana Leiva,[a] Jèssica Rubí,[a] Martin C. Taylor,[b]

Belén Pérez[c] and John M. Kelly[b]
[a] Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of
Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, Spain
[b] London School of Hygiene and Tropical Medicina, Department of Infectious and Tropical Diseases,
Keppel Street, London WC1E 7HT, United Kingdom
[c] Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, E-
08193, Bellaterra, Barcelona, Spain
* svazquez@ub.edu
The Trypanosoma protozoa infect humans and many domestic mammals causing severe mortality
and significant economic burden. The human diseases related to these parasites are Human African
trypanosomiasis (HAT, Sleeping sickness) caused by Trypanosoma brucei ssp. and Chagas disease
caused by Trypanosoma cruzi. The existing therapies for both diseases exhibit serious side effects,
require long treatment schedules and often fail to eliminate parasitemia.[1,2]
Both diseases present clinically relevant neurological disorders. The second phase of the HAT –the
neurological phase, is characterized by the presence of the parasite in the central nervous system
(CNS).[3] In the case of Chagas disease, neurological alterations such as dementia are common in
the chronic phase.[4] For these reasons, the design of new trypanocidal agents able to cross the
blood-brain barrier (BBB) is of interest.
Previous investigations have identified novel hydrazinylthiazoles as promising scaffolds having a low
micromolar activity against T. cruzi.[5] Furthermore, adamantyl derivatives with submicromolar
activity against T. brucei have been identified.[6]
In light of these findings, we have combined both scaffolds to achieve potent, CNS-penetrant
trypanocidal agents and to establish structure-activity relationships in a novel family of promising
anti-Trypanosoma compounds. Preliminary results on the synthesis, structure-activity relationships
of their trypanocidal activity and ability for BBB permeability will be presented.
[1]
R. Brun, J. Blum, F. Chappuis, C. Burri, Lancet, 2010, 375, 148.
[2]
B. Perry, K. Sones, Science, 2007, 315, 333.
[3]
http://www.who.int/trypanosomiasis_african/en/ (accessed on 15th Feb 2017).
[4]
http://www.who.int/chagas/en/ (accessed on 15th Feb 2017).
[5]
M.V.O. Cardoso, L.R.P. de Siqueira, E.B. da Silva, L.B. Costa, M.Z. Hernandes, M.M. Rabello, R.S. Ferreira,
L.F. da Cruz, D.R.M. Moreira, V.R.A. Pereira, M.C.A.B. de Castro, P.V. Bernhardt, A.C.L. Leite, Eur. J. Med.
Chem., 2014, 86, 48.
[6]
I. Papanastasiou, A. Tsotinis, N. Kolocouris, S.R. Prathalingam, J.M. Kelly, J. Med. Chem., 2008, 51,
1496.
231
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FLUORINATED PHENYLALANINE DERIVATIVES: VERSATILE

BIOLOGICAL ACTIVITY
Martin Krátký,[a] Jarmila Vinšová,[a],* Šárka Štěpánková[b] and Jiřina Stolaříková [c]
[b] Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of
Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
[c] Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava,
Partyzánské námĕstí 7, 702 00 Ostrava, Czech Republic
* jarmila.vinsova@faf.cuni.cz
Unnatural amino acids are useful building blocks in medicinal chemistry. Replacement of the
hydrogen atom with a hydrophobic and highly electronegative fluorine atom often results in
significant changes in the properties of the parent molecule. Presence of a fluorine atom changes
proteinogenic α-amino acids to unnatural (non-proteinogenic) species, thus influencing their
biological behaviour. Phenylalanine with fluorine atom in the positions 2, 3 or 4 of the phenyl ring
have affected activity of a wide range of proteins and enzyme with many potential medicinal
applications including antiviral[1] or anti-cancer agents.[2] Inspired by these data, we designed and
synthesized a novel series of aromatic esters and amides of ortho/meta/para DL-phenylalanine.
A series of thirty novel N-acetylated fluorophenylalanine-based aromatic amides and esters was
synthesized using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide or phosphorus trichloride in
pyridine. They were characterized by spectral methods and underwent a screening of their potential
biological activity against Mycobacterium tuberculosis and three non-tuberculous mycobacterial
strains, other bacteria (G+, G-), fungi and for their cytotoxicity (HepG2 cells). In general, the amidic
derivatives avoided any significant antibacterial, antimycobacterial and antifungal properties. The
majority of the esters exhibited a mild antimycobacterial activity against both tuberculous and non-
tuberculous mycobacteria and several of them inhibited the growth of Gram-positive bacteria and a
fungal strain (Trichophyton mentagrophytes). All prepared derivatives were evaluated on
acetylcholinesterase and butyrylcholinesterase activity with IC50 values for AChE and BChE of 57.88-
130.75 µM and 8.25 to 289.0 µM, respectively. Some derivatives were comparable or superior to
rivastigmine, an established drug. The modification of parent acids offers more active inhibitors of
BChE but not AChE. IC50 values for BChE were within a broader concentration range when
compared to AChE. One derivative produced a selective inhibition of BChE otherwise the inhibition
is non-selective. With respect to the substitution of ester/amidic benzene nuclei, the introduction of
NO2 and CH3 groups into aniline ring and CF3 moiety into phenol enhanced activity.
Focusing on cytotoxicity, IC50 values for eukaryotic cell line were not sharply different from MIC
obtained for prokaryotes. Contrarily, a range of investiPPgated derivatives provided a sufficient
selectivity for butyrylcholinesterase.[3]
27514Y.
[1]
S.E. Webber, J.T. Marakovits, P.S. Dragovich, T.J. Prins, R. Zhou, S.A. Fuhrman, A.K. Patick, D.A.
Matthews, C.A. Lee, B. Srinivasan, T. Moran, C.E. Ford, M.A. Brothers, J.E.V. Harr, J.W. Meador, R.A.
Ferre, S.T. Worland, Bioorg. Med. Chem. Lett., 2001, 11, 2683.
[2]
X. Li, J. Wang, L. Zhang, W. Xu, Arch. Pharm. Chem. Life Sci. ,2011, 344, 494.
[3]
. M. Krátký, J Vinšová, Š. Štěpánková, K. Vorčáková, L. Navrátilová, F. Trejtnar, J. Stolaříková, Bioorg.
Chem., 2017, accepted.
232
P-157
DISCOVERY OF THE FIRST-IN-CLASS CHEMICAL PROBES FOR THE

SPINDLIN1 METHYL-LYSINE READER DOMAIN
M. Viviano,[a],* S. Castellano,[a,b] M. T. Bedford,[c] H. Li[d] and G. Sbardella[a]

[a] Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno,
Italy
[b] Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, I-84081 Baronissi,
Salerno, Italy
[c] The University of Texas, MD Anderson Cancer Center, Smithville, TX 78957, USA
[d] Tsinghua University, Center for Structural Biology, Beijing 100084, P.R. China
* mviviano@unisa.it
Histone post-translational modifications (PTMs) have been proposed to constitute a “histone code”,
which helps to organize genetic information at the chromatin level, and play a pivotal role in gene
expression, cell differentiation, and development.[1]
During the past decade, a wealth of “reader” modules have been characterized for histone PTM
recognition, that function in a histone type- and site-specific manner.[2] In particular, the detection
of methylated histone tail lysine residues by Tudor domains plays important roles in epigenetic
control of gene expression and DNA damage response. Among them, Spindlin1 (SPIN1) is a
protein of the SPIN/SSTY family implicated in the regulation of gametogenesis.[3] Furthermore, its
overexpression perturbs the cell cycle, induces chromosome instability, and leads to
tumorigenesis,[4-6] even if the molecular mechanisms remain poorly understood.
Being interested in the development of novel small molecule modulators of epigenetic targets, here
we report the identification of a compound (EML405) that acquired a novel interaction with the
Tudor domain-containing protein Spindlin1. Structural studies revealed that the symmetric nature
of EML405 allows it to simultaneously engage two of SPIN1’s Tudor domains (Figure), and also
facilitated the rational synthesis of more selective SPIN1 inhibitors (EML631-633, Figure). The
EML631-633 compounds engage SPIN1 in cells, block its ability to “read” H3K4me3 marks, and
inhibit its transcriptional coactivator activity, paving the way for future progress in Spindlin1 biology
and its therapeutic applications.
N N N
NH O NH O
N N NH O
N N N
N N N
N
O O
N N O
N
EML631 EML632 EML633
Figure: From structural studies of EML405 to new potent Spindlin1 inhibitors EML631-633.
[1]
T. Jenuwein, C.D. Allis, Science, 2001, 293, 1074.
[2]
C. A. Musselman, M.E. Lalonde, J. Cote, T. G. Kutateladze, Nat. Struct. Mol. Biol., 2012, 19, 1218.
[3]
E. Staub, D. Mennerich, A. Rosenthal, Genome Biol., 2002, 3, 1.
[4]
P. Zhang, B. Cong, H. Yuan, L. Chen, Y. Lv, C. Bai, X. Nan, S. Shi, W. Yue, X. Pei, J. Cell. Physiol., 2008,
217, 400.
[5]
X. Su, G. Zhu, X. Ding, S. Y. Lee, Y. Dou, B. Zhu, W. Wu, H. Li, Genes. Dev., 2014, 28, 622.
[6]
H. Franz, H. Greschik, D.Willmann, L. Ozretic, C. A. Jilg, E. Wardelmann, M. Jung, R. Buettner, R. Schüle,
Oncotarget, 2015, 6, 4773.
233
P-158
HYDRAZINO PEPTIDOMIMETICS AS MODULATORS OF

PROTEIN-PROTEIN INTERACTIONS
Kristina Vlahoviček-Kahlina,[a] Luka Kavčič,[b] Marija Marković,[a] Janez Plavec,[b]

Ivo Piantanida[a] and Ivanka Jerić[a],*
[a] Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
[b] National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
* ivanka.jeric@irb.hr
Design and synthesis of peptidomimetics represent an important field in chemistry, pharmacology

and material science, as they circumvent the numerous limitations of natural peptides. We aimed to
develop solid-phase methodology for smooth incorporation of hydrazido derivatives of natural alpha-
amino acids into peptide chain and study interaction of designed peptidomimetics with biomolecules.
Modulation of protein–protein interactions (PPIs) have emerged as one of the main challenges in
chemical biology and drug discovery.[1] Therefore, as a biological target, we chose a well-described
p53-mDM2 model. Disruption of the p53-mDM2 interaction is an important goal for cancer therapy.
To explore the utility of hydrazino-based peptidomimetics to interfere with these interaction, we
designed a small library of compounds based on the biologically active octapeptide fragment of p53
protein (Figure). Three amino acids, Phe, Trp and Leu, directly participate in interaction, so we
decided to replace two of them (Phe and Leu) and Tyr adjacent to Trp, with their hydrazino
analogues. Prepared peptides were characterized by NMR spectroscopy. Detailed NMR analysis
revealed presence of multiple conformations in D2O/DMSO solution, depending on number and
position of hydrazino acids in a peptide sequence. Interaction between mDM2 protein and prepared
peptides was assayed by fluorimetric titrations based on intrinsic fluorescence of both, mDM2 and
peptides. For some peptides titration with mDM2 yielded non-additive change of fluorescence,
allowing estimation of binding constants by multivariate least square analysis of complete titration
spectra in HyperQuad programme.[2] For all peptide/mDM2 complexes similar, micromolar affinity
was determined, pointing out that various introductions of hydrazine-moiety do not interfere
significantly with binding.
Figure: Hydrazino-peptidomimetics for p53-mDM2 interaction inhibition study.
[1]
P. Chene, ChemMedChem, 2006, 1, 400.
[2]
P. Gans, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739.; L. Alderighi, P. Gans, A. Lenco, D. Peters, A.
Sabatini, A. Vacca, Coord. Chem. Rev., 1999, 184, 311.
234
P-159
SALICYLANILIDE MUTUAL PRODRUGS: SYNTHESIS AND BIOLOGICAL

ACTIVITY
R. Vosátka,* M. Krátký, J. Vinšová

Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles
* vosatkar@faf.cuni.cz
Tuberculosis (TB), particularly the development of drug-resistant forms (multidrug-resistant TB,

extensively drug-resistant TB and recently reported totally drug-resistant TB), represents a serious
global problem currently. According to the WHO report, about 1/3 of the world population is infected
by latent TB. These alarming facts are reflected in an intensive search for new antimycobacterial
drugs. Contemporary development is focused, e.g., on the unique steps in the biosynthesis of cell
wall, the mapping of metabolic pathways or the identification of specific genes affecting virulence
and latent state of Mycobacterium tuberculosis.[1]
Salicylanilide (2-hydroxy-N-phenylbenzamide) derivatives belong to the promising agents. It has
been reported that esterification of phenolic group to form its prodrugs with improved properties. This
modification is able to enhance bioavailability, which is often a limiting factor for their activity, improve
physicochemical properties (lipophilicity etc.) or reduce toxicity.[2] Salicylanilide-based esters have
shown a high in vitro activity against both drug-sensitive and resistant TB strains with minimum
inhibitory concentrations ≥0.125 µM.[3]
In this study, salicylanilides were esterified by isonicotinic and pyrazine-2-carboxylic acids to obtain
novel mutual prodrugs. Based on previous results, the design was focused on the compound with
electron-withdrawing substituents (especially CF3 group) at aniline ring. This substitution pattern
contributes to an increased efficacy against both M. tuberculosis and nontuberculous mycobacteria
(Mycobacterium avium and Mycobacterium kansasii).[3]
The synthesis of these esters involves two steps. The first step is the preparation of salicylanilides,
which are obtained routinely by the reaction of appropriate salicylic acids with various anilines in the
presence of PCl3 under microwave irradiation. The second step consists in a reaction with
appropriate acyl chlorides in the presence of a tertiary base or Steglich esterification.
Synthesized derivatives undergo in vitro evaluation against drug-sensitive M. tuberculosis H37Rv and
atypical strains of M. avium and M. kansasii currently. The most active derivatives will be assayed
against one extensively drug-resistant TB and five multidrug-resistant TB strains with different
resistance patterns and for their cytotoxicity.
27514Y.
[1]
WORLD HEALTH ORGANIZATION. Global tuberculosis report 2016.
http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1 (4.2.2017)
[2]
J. M. Ferriz, J. Vinšová, Curr. Pharm. Des., 2010, 16, 2033.
[3]
M. Krátký, J. Vinšová, Curr. Pharm. Des., 2011, 17, 3494.
235
P-160
SYNTHESIS AND PHARMACOLOGICAL ACTIVITY IN A GROUP OF

PHENOXYALKYL DERIVATIVES OF PIPERAZINE
Anna M. Waszkielewicz,[a],* Katarzyna Pańczyk,[a] Karolina Pytka,[b] Anna Rapacz,[b]

Monika Głuch-Lutwin,[c] Agata Siwek,[c] Adam Bucki,[d] Marcin Kołaczkowski[d] and Henryk
Marona[a]
[a] Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy,
Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland
[b] Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College,
Medyczna 9, 30-688 Krakow, Poland
[c] Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College,
Medyczna 9, 30-688 Krakow, Poland
[d] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical
College, Medyczna 9, 30-688 Krakow, Poland
* awaszkie@cm-uj.krakow.pl
Central nervous system disorders such as anxiety, depression or epilepsy are important health
challenges, and they are comorbid. Coexistence and common etiology include factors such as
trauma or neurodegeneration.[2] The aim of our study was to design new phenoxyalkyl derivatives of
piperazine for their potential anxiolytic, antidepressant and possibly anticonvulsant activity and to
evaluate coexistence of observed activities in the group of compounds. The structure design was
based on our former findings in a group of derivatives of 1- phenoxyalkyl-4-(2-
methoxyphenyl)piperazine.[2] Ten new compounds have been designed and they were synthesized
by aminolysis of appropriate phenoxyalkyl bromides, according to formerly published procedures.
The final compounds were achieved in the form of hydrochlorides.[2]
The compounds were evaluated for their affinities towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2, and α1
receptors, and in functional assays, and they were subject to in vivo tests in mice, i.p. for their
antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as
– at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). The most active
compound was 1-(2-(2,5-dimethylphenoxy)ethyl)-4-phenylpiperazine dihydrochloride. It exhibits
affinity and/or activity towards 5-HT1A receptor (Ki=35 nM, weak antagonist), 5-HT2A receptor (Ki=121
nM), 5-HT7 (Ki=130 nM, weak antagonist), and α1 (Ki=82 nM). Its anxiolytic-like properties were
observed at 1.25 mg/kg and it is inactive in MES at 100 mg/kg. It was also subject to molecular
modeling (docking), and mutagenicity (Ames test) and was found safe until 50 μg/plate. Within the
title group of compounds an example of anticonvulsant agent was 1-(2,6-dimethylphenoxybutyl)-4-
phenethylpiperazine hydrochloride (MES ED50 = 17.05 mg/kg, TD50 = 37.25 mg/kg). Among all tested
compounds, anticonvulsant and anxiolytic activities have been observed, however, with no
coexistence of both activities, since the active dose ranges did not cover.
The research was financed by the Polish National Science Centre, grant no. DEC-
2013/11/B/NZ7/04834.
[1]
S. D. Silberstein, Headache, 2001, 41 S1, S11.
[2]
A. M. Waszkielewicz, K. Pytka, A. Rapacz, E. Wełna, M. Jarzyna, G. Satała, A. Bojarski, J. Sapa, P.
Zmudzki, B. Filipek, H. Marona, Chem. Biol. Drug Des., 2014, 85, 326.
236
P-161
STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF INTERVENOLIN, A

NATURAL QUINOLONE WITH ANTI-TUMOR AND ANTI-HELICOBACTER
PYLORI ACTIVITIES
Takumi Watanabe,[a],* Hikaru Abe,[a] Manabu Kawada,[b,c] Chiharu Sakashita,[a]

Shun-ichi Ohba,[c] Hiroyuki Inoue,[c] Tomokazu Ohishi,[c] Tohru Masuda,[c]
Chigusa Hayashi,[d] Masayuki Igarashi[d] and Masakatsu Shibasaki[a]
[a] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Synthetic Organic Chemistry, 3-14-23
Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
[b] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, 3-14-23 Kamiosaki, Shinagawa-ku,
Tokyo 141-0021, Japan
[c] Institute of Microbial Chemistry (BIKAKEN), Numazu, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301,
Japan
[d] Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, 3-14-23 Kamiosaki, Shinagawa-
ku, Tokyo 141-0021, Japan
* twatanabe@bikaken.or.jp
Targeted therapy is one of the most active research subjects for treatment of cancer, which utilizes
the chemotherapeutic agents that can modulate the growth signal of tumor cells. As long as the
target is tumor relevant, the compounds are expected to be inert to normal tissues and display low
toxicity. However, proteinous key players in the growth signal of tumor cells are more prone to mutate
compared to those of normal cells, which is frequently causative of resistance. Therefore, we have
been interested in the growth signal to affect tumor tissue transmitted from the adjacent stromal cells
as a target of screening for anticancer agents; a novel natural product of microorganism origin,
intervenolin, has been discovered.[1]
Intervenolin has a 4-quinolone skeleton substituted with an iminodithiocarbonate moiety at the 1-
position and a geranyl side chain at the 2-position; they are unusual substituents for 4-quinolones.
In the present SAR study, various intervenolin analogs were prepared according to the synthetic
procedure reported previously[2] to clarify that long aliphatic side chain at the 2-position was favorable
for antiproliferative activity, and the substituent at the 1-position was able to alleviate the acute
toxicity in many cases.[3]
Intriguingly, several intervenolin derivatives exhibited potent anti-Helicobacter pylori activity
comparable to that of clarithromycin with remarkable selectivity over other microorganisms.[3]
[1]
M. Kawada, H. Inoue, S.-i. Ohba, M. Hatano, M. Amemiya, C. Hayashi, I. Usami, H. Abe, T. Watanabe, N.
Kinoshita, M. Igarashi, T. Masuda, D. Ikeda, A. Nomoto, J. Antibiot., 2013, 66, 543.
[2]
H. Abe, M. Kawada, H. Inoue, S.-i. Ohba, A. Nomoto, T. Watanabe, M. Shibasaki, Org. Lett., 2013, 15,
2124.
[3]
H. Abe, Kawada, H. Inoue, S.-i. Ohba, T. Masuda, C. Hayashi, M. Igarashi, A. Nomoto, T. Watanabe, M.
Shibasaki, Tetrahedron, 2013, 69, 7608.
237
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DISCOVERY OF ISOQUINOLINOQUINAZOLINONES AS A NOVEL PPAR

GAMMA ANTAGONISTS
Yifeng Jin,Younho Han, Daulat B. Khadka, Kwang Youl Lee and Won-Jea Cho*
College of Pharmacy, Chonnam National University, South Korea
* wjcho@jnu.ac.kr
Metabolic syndrome has undergone extensive investigation as it is an increasing medical problem

worldwide. It is characterized by insulin resistance, hyperglycemia, dyslipidemia, obesity, fatty liver,
and atherosclerosis. The peroxisome proliferator activated receptor γ (PPAR γ), a member of the
steroid-thyroid hormone superfamily of ligand-activated transcription factors, has an important role
in several metabolic diseases including adipocyte differentiation, lipogenesis, and glucose
metabolism. Similar to other nuclear receptors, PPARγ shares a conserved modular domain
structure, including a N-terminal activation function-1 (AF-1) and central DNA-binding domain (DBD).
On the basis of helix 12 alteration, ligands can be divided into agonists and antagonists. Usually, the
agonist of PPARγ such as rosiglitazone (an insulin-sensitizing agent) can stabilize H12 by interacting
directly with Tyr473. While the antagonist of PPARγ, GW9662, forms covalent bond with Cys285
sulfur of PPARγ but lacks interaction with H12. To design novel inhibitors of PPARγ, GW9662 and
berberine with PPARγ inhibitory activities were hybridized into isoquinolinoquinazolinones. We
performed docking study in ligand binding domain (LBD) of the GW9662-PPARγ complex (PDB ID:
3B0R), and the designed molecule interacted in similar manner as GW9662 at the Y-shaped pocket
of PPARγ. The designed molecule had H-bond with Cys285 and located away from H12.
Isoquinolinoquinazolinones were simply synthesized by 2-step intermolecular cyclization reactions.
The biological evaluation suggests that this new series of PPARγ antagonists may become effective
agents for metabolic disorders.
[1]
Y. Jin, Y. Han, D.B. Khadka, C. Zhao, K. Youl Lee, W.-J. Cho, Scientific Report 2016, 6, 34661.
238
P-163
SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW

S-TRIAZOLE DERIVATIVES
M. Wujec,[a],* A. Paneth,[a] Ł. Popiołek,[a] T. Plech,[a] Sz. Kosiek,[a]

E. Kędzierska[b] and J. Kotlińska[b]
[a] Department of Organic Chemistry, Medical University, 4a Chodźki St., 20-093 Lublin, Poland
[b] Department of Pharmacology and Pharmacodynamics, Medical University, 4a Chodźki St., 20-093 Lublin,
Poland
* monika.wujec@umlub.pl
Nowadays CNS disorders are among the most common. We have a various range of drugs but the
treatment of central nervous system diseases, such as anxiety, analgesic, depression and epilepsy
is still non satysfied. There is a need to search for new terapies; more effective and less toxic.
Our erlier work showed that a large group of triazole derivatives showed very good anticonvulsant
activity.[1-3] Additionally, some s-triazoles produced significant antinociceptive effect in the writhing
syndrome test and in the hot plate test.[4-6]
It is important to note, that all tested s-triazoles were devoid of neurotoxicity as they did not impair
the mouse motor coordination and they did not affect the body temperature of mice.
Considering the above, we have decided to obtain some new s-triazole with fluoro sustituted phenyl
ring in position 3 of triazole scaffold with promissing CNS activity.
First part of our experiments included: synthesis of nine s-triazoles with 2-fluorophenyl-, 3-
fluorophenyl- and 4-fluorophenyl substituent in position 3 of triazole. The second one: the acute
toxicity evaluation, motor coordination test, body temperature measurement, the thiopental induced
sleeping time test and L-5-hydroxytryptophan-induced head-twitch test, which are generally
accepted as basic in central activity investigations of new agents. Finnally, we were focused on
potential antinociceptive, anticonvulsant, antidepressant and anxiolytic activity of title compounds.
[1]
T. Plech, B. Kaproń, J. Łuszczki, A. Paneth, A. Siwek, M. Kołaczkowski, M. Żołnierek, G. Nowak, Eur. J.
Med. Chem., 2014, 86, 690.
[2]
T. Plech, J. Łuszczki, M. Wujec, J. Flieger, M. Pizoń, Eur. J. Med. Chem., 2013, 60, 208.
[3]
J. Łuszczki, T. Plech, M. Wujec, Pharmacol. Rep., 2012, 64, 970.
[4]
A. Siwek, M. Wujec, M. Dobosz, E. Jagiełło-Wójtowicz, A. Kleinrok, A. Chodkowska, P. Paneth,
Phosphorus Sulfur Silicon Relat. Elem., 2008, 183, 2669.
[5]
A. Siwek, M. Wujec, M. Dobosz, E. Jagiełło-Wójtowicz, A. Chodkowska, A. Kleinrok, P. Paneth, Centr Eur.
J. Chem., 2008, 6, 47.
[6]
J. Listos, S. Talarek, J. Orzelska, S. Fidecka, M. Wujec, T. Plech, Naunyn-Schmiedeberg’s Arch.
Pharmacol., 2014, 387, 367.
239
P-164
DEVELOPMENT OF THE METHOD FOR HPLC ASSAY OF THE

LIMОNIUM GMЕLINII DRY EXTRACT
G. Е. Zhussupova, D. T. Kassymova and A. I. Zhussupova*

Al-Farabi Kazakh National University
* aizhan.zhusupova@gmail.com
Phаrmасеutiсаl prоduсt whеn intrоduсed into mеdiсinе must mееt аll thе rеquirеmеnts аnd еnsurе
thе sаfеty аnd еffiсiеnсy оf its usе, and validation is one of the basic parts of GMP rules enabling
the production of consistently high-quality medicinal products.
Thе substаnсе оbtаinеd frоm thе grass оf Limоnium gmеlinii contains epigallocatechin gallate in the
free form and in the form of monomer units of condensed tannins. It is known that epigallocatechin
gallate is superior to other forms of monomeric flavan-3-ols for the antioxidant activity, which
decreases in the series: epigallocatechin, epicatechin gallate and epicatechin. High antitumor activity
of epigallocatechin gallate has been shown as well.
That is why the epigallocatechin gallate was selected as an active substance for the assay of
Limоnium gmеlinii dry extract by HPLC. The method has to be designed and validated firstly. The
use of gradient elution, where the stationary phase (A) was diluted acid – 0.5-0.2% trifluoroacetic
acid (method 1), acetic acid (method 2) and phosphoric (method 3) acid, and as a mobile phase B
was acetonitrile, did not lead to satisfactory results. The best separation of the components was
achieved with isocratic elution, where mobile phase consists of water: acetonitrile: acetic acid in a
ratio of 89:10:1. A retention time equal to 5.109 minutes was obtained for a standard of
epigallocatechin gallate, while 5.100 minute retention for the studied plant extract.
By calculation based on peaks areas the content of epigallocatechin gallate in isolated extract was
estimated as 35.89%.
It is supposed that the contribution to a high content of epigallocatechin gallate cannot be simply
connected to its monomeric form, but is also due to the polymeric forms of condensed tannins.
Designed by HPLC analysis conditions in the long term can be used to standardize the test dry
extract and drugs obtained on its basis.
240
P-165
STRUCTURE-ACTIVITY AND MECHANISTIC STUDY OF

INHIBITORY EFFECTS OF POLYSUBSTITUTED PYRIMIDINES
ON PROSTAGLANDIN E2 PRODUCTION
Zdeněk Zídek,[a],* Zlatko Janeba,[b] Petr Jansa,[b] Miloslav Kverka,[a]

Eva Kmoníčková,[a] Filip Kalčic[b] and Viktor Kolman[b]
[a] Department of Pharmacology, Institute of Experimental Medicine, The Czech Academy of Sciences,
Vídeňská 1083, 14220 Prague 4, Czech Republic
[b] Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2,
16610 Prague 6, Czech Republic
* zidekz@biomed.cas.cz
Pyrimidines possess multiple biological activities and thus have become an important source of
drugs used for the treatment of diseases, such as viral, bacterial and fungal infections, cancer and
Parkinson disease.[1] The aim of our studies was to examine possible beneficial effects of pyrimidine
derivatives on inflammation. We have synthesized a series of novel polysubstituted pyrimidines and
analysed their interaction with production of prostaglandin E2 (PGE2) implicated in etiology of various
inflammatory processes.
The test compounds differed at combinations of distinct substituents at the positions C2, C4, C5 and
C6 of the pyrimidine ring (Table). Effects of compounds on production of PGE2 were determined
under the in vitro conditions using mouse peritoneal cells. They were cultured (2x106/ml) in the
presence of bacterial lipopolysaccharide (LPS; 10 ng/ml) and pyrimidines. Supernatant
concentration of PGE2 was assayed by ELISA after 5 h of culture.
We have found that pyrimidines are the structure-dependent inhibitors of PGE2 production. The C4,6-
(bis)chloro compounds with hydrogen or methyl substituents at the C5 position (groups I-III) are
devoid of the inhibitory effects. The intrinsic PGE2-inhibitory activity has only been acquired by the
replacement of the C5-hydrogen and C5-methyl with C5-butyl. Irrespective of the length of aliphatic
substituent at the C5 position, all compounds with phenyl, p-methylphenyl or p-methoxyphenyl
(instead of chlorine) at both or just one of the C4 and C6 positions (groups IV-VIII) are strong
inhibitors of PGE2 production. Their IC50s range between 1 to 5 µM.
The tested pyrimidines do not interfere with the transductional (MAP kinases p38, ERK1/2, JNK) and
transcriptional (mRNA expression of cyclooxygenases COX-1 and COX-2) pathways of PGE2
production. Pharmacodynamic profile of PGE2 inhibition has indicated post-translational mechanism
of pyrimidine action. However, they do not suppress the enzyme activity of COX-1 and COX-2.
Mechanism of action of pyrimidines thus differs from that of the non-steroidal anti-inflammatory drugs
(NSAIDs) such as indomethacin, aspirin and celecoxib, recognized and clinically used PGE2
inhibitors that bind to the active centre of COX enzymes.
gr. positions: C2 C4 C6 C5
I amino chlorine chlorine hydrogen/ methyl/ butyl
II dimethylamino(methylenamino) chlorine chlorine hydrogen/ methyl/ butyl
III formylamino chlorine chlorine hydrogen/ methyl/ butyl
IV amino phenyl phenyl hydrogen/ methyl/ butyl
V amino methylphenyl methylphenyl hydrogen/ methyl/ butyl
VI amino methylphenyl chlorine hydrogen/ methyl/ butyl
VII amino methoxyhenyl methoxyhenyl hydrogen/ methyl/ butyl
VIII amino methoxyhenyl chlorine hydrogen/ methyl/ butyl
Acknowledgments: The research was supported by grant TE01020028.

[1]
T.P. Selvam, C.R. James, P.V. Dniandev, S.K. Valzita, Res. Pharm., 2012, 2, 1.
241
P-166
DESIGN AND ANTIMYCOBACTERIAL EVALUATION OF COMPOUNDS

COMBINING PYRAZINAMIDE AND PARA-AMINOBENZOIC ACID
Jan Zitko[a],* and Martin Doležal[a]

[a] Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové, 500 05,
Czech Republic
* jan.zitko@faf.cuni.cz
According to the latest WHO Global Tuberculosis Report, estimated 10.4 million people worldwide
developed active tuberculosis (TB) in 2015. In 2015, TB was the causative agent of 1.4 million
deaths, including 0.4 million deaths in people with HIV/TB co-infection. This ranks TB the second
leading cause of death from infectious diseases, following HIV. On contrary to positive trends in
global epidemiology of TB, the widespread of drug-resistant TB is threatening the TB control policy.
The basic regimen for non-complicated, non-resistant TB is a cocktail of first-line antituberculars
(rifampicin, isoniazid, ethambutol and pyrazinamide) administered for six months. Such prolonged
administration is a draw-back with the respect to side effects and compliance. Therefore, there is an
urgent need for the development of new TB drugs, preferably with not yet exploited mechanism of
action.
Pyrazinamide (PZA) exerts synergistic effects with rifampicin and is active against dormant
subpopulation of mycobacteria. The draw-backs of PZA are its narrow spectrum of activity (M.
tuberculosis only), frequent resistance, and hepatotoxicity. However, the aforementioned valuable
clinical properties of PZA, its simple structure as well as supposed multi-target activity, make PZA a
good starting point for the development of new antituberculars. In recent years, the perception of
PZA and its metabolite pyrazinoic acid (POA) has changed from a non-specific cytosol acidifier to a
multi-target inhibitor of specific mycobacterial enzymes and processes. Although p-aminosalicylic
acid (PAS) as an antitubercular drug was considered obsolete and was used only in developing
countries, it has experienced resurrection due to its usability in combination therapy of resistant TB.
Recent studies indicate that PAS interferes with folate pathway in mycobacteria. [1]
Compound 1 combining PZA and PAS fragments, exerted a micromolar in vitro activity against M.
tuberculosis H37Rv and was non-toxic against several mammalian cell lines.[2] In this study, we took
1 as a reference compound and designed and prepared derivatives with modified substitution on the
phenyl ring and/or esterification of the carboxylic group. The series showed quite tight SAR which
pointed out the necessity of the p-aminosalicylic fragment for substantial antimycobacterial activity.
Acknowledgments: The research was supported Czech Science Foundation project No. 17-
27514Y.
[1]
J. Zheng, E. J. Rubin, P. Bifani, V. Mathys, V. Lim, M. Au, J. Jang, J. Nam, T. Dick, J. R. Walker, K. Pethe,
L. R. Camacho, J. Biol. Chem., 2013, 288, 23447.
[2]
J. Zitko, B. Servusova, P. Paterova, J. Mandikova, V. Kubicek, R. Kucera, V. Hrabcova, J. Kunes, O. Soukup,
M. Dolezal, Molecules, 2013, 18, 14807.
242
P-167
BIOLOGICAL ACTIVITY OF NOVEL PRIMAQUINE-CINNAMIC ACID

CONJUGATES OF THE ACYLSEMICARBAZIDE TYPE
K. Pavić,[a] K. Ester,[b] M. Kralj,[b] D. Schols,[c] D. Hadjipavlou-Litina,[d]

E. Pontiki[d] and B. Zorc[a],*
[a] Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, Zagreb, Croatia
[b] Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia
[c] Rega Institute for Medical Research, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium
[d] Faculty of Health Sciences, School of Pharmacy, Aristotles University of Thessaloniki, Thessaloniki,
Greece
* bzorc@pharma.hr
Considering the individual biological and medicinal importance of primaquine (PQ) and cinnamic-
acid derivatives (CADs), we wanted to explore biological significance of novel conjugates combining
both moieties in single entities. Here we report the results of antiproliferative, antiviral and
antioxidative evaluation of new PQ-CAD hybrids 1a-k in which PQ and CADs were connected by
acylsemicarbazide groups, built from the PQ amino group, CONHNH spacer and the carbonyl group
originating from the CADs.[1]
Their antiproliferative activity was evaluated in vitro on five types of human tumor cell lines:
lymphoblastic leukemia (CEM), cervical carcinoma (HeLa), lung carcinoma (NCI-H460), colon
carcinoma (SW 620), breast carcinoma (MCF-7) and murine lymphocytic leukemia (L1210), and
compared with the standard anticancer drugs and PQ. All new hybrids were more or less active
against all the tested cell lines in low micromolar concentrations and very active against MCF-7.
Compounds bearing methoxy, chloro or benzodioxole substituents showed high selectivity and
activity against MCF-7 in micromolar scale and p-CF3 in nanomolar concentration. Most of them bear
substituents in para position.
Compounds 1a–k were evaluated against a broad variety of viruses (herpes simplex virus type 1
(KOS), herpes simplex virus 2 (G), herpes simplex virus 1 TK–(KOS) ACVr, vaccinia virus, adeno
virus 2 and human coronavirus (229E) in HEL cell cultures) and their activities were compared with
reference drugs. CF3 derivatives showed selective antiviral activity against human coronavirus at
concentrations which did not alter normal cell morphology.
Two different antioxidant assays were used to evaluate antioxidant potentials of PQ-CADs:
interaction with DPPH free radical and AAPH. For the majority of derivatives, DPPH-reducing ability
was concentration and time dependent. CF3, dimethoxy and chloro derivatives showed the highest
DPPH-reducing ability, while unsubstituted, methoxy, benzodioxole, p-Cl and m-CF3 derivatives
exerted the highest anti-lipid peroxidation activity (83–89%). Dimethoxy derivative was the most
potent LOX inhibitor.
[1]
K. Pavić, I. Perković, P. Gilja, F. Kozlina, K. Ester, M. Kralj, D. Schols, D. Hadjipavlou-Litina, E. Pontiki, B.
Zorc, Molecules, 2016, 21, 1629.
243
P-168
ANTIMYCOBACTERIAL SCREENING OF FOUR SERIES OF PRIMAQUINE

DERIVATIVES
Josef Jampílek,[a] Sarka Pospíšilová,[a,b] H. Michnová,[a,b] Kristina Pavić,[c]

Ivana Perković[c] and Branka Zorc[c],*
[a] Faculty of Pharmacy, Comenius University, Odbojárov 10, Bratislava, Slovakia
[b] Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Palackého
1, Brno, Czech Republic
[c] Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, Zagreb, Croatia
* bzorc@pharma.hr
Primaquine (PQ) is a well known antimalarial drug active against all species of parasite causing
human malaria, including multi-resistant P. falciparum strains. Primaquine has been also identified
as orally administrated drug capable of inhibiting M. tuberculosis growth.[1] In several papers, we
have described preparation of almost hundred various PQ derivatives and their evaluation as
potential antiproliferative, antioxidative, antimalarial, antimicrobial and antiviral agents.[2-7] Here we
report the results of antimycobacterial screening of four groups of PQ derivatives: amides 1a-k, ureas
2a-s, semicarbazides 3a-c and bis-ureas 4a-u.
Antimycobacterial evaluation was performed in vitro against three different Mycobacterium species:
M. tuberculosis H37Ra ATCC 25177 (MTB), well characterised clinical isolates of M. avium complex
CIT19/06 (MAC), and M. avium subsp. paratuberculosis CIT03 (MAP). The results were compared
with PQ diphosphate and the standard antitubercular drugs isoniazid (INH), rifampicin (RIF) and
ciprofloxacin (CPX).
Most of the compounds of series 1 and 2 showed high activity against MAP, comparable or even
higher than the relevant drug CPX, and weak or no activity against the other two bacteria. Cinnamic
acid amide 1a and bis-CF3 cinnamic acid amide 1k were active against all three Mycobacterium
species comparable or slightly higher than the reference drugs. PQ urea derivatives 2f-p with
hydroxyl, halogen and particularly trifluoromethyl substituted benzene ring exerted very strong
antimycobacterial activity towards all three tested bacteria, stronger than PQ and the reference
drugs. In general, meta substituted derivatives were more active than analogues para derivatives.
The benzene substituted ureas were also more active than urea derivatives with cycloalkyl or
hydroxyalkyl moieties. Semicarbazide 3a showed similar activity as PQ, while the other two
semicarbazides were inactive. In general, bis-urea derivatives were less active than the analogues
urea derivatives sharing the same scaffold, differing only in the spacer type. Out of 21 evaluated bis-
urea derivatives only p-Cl, m-CF3 phenyl derivative 4p, benzhydryl derivatives 4t and 4u and bis-PQ
derivative 4s showed high activity, higher than the all three reference drugs.
This work has been fully supported by the Croatian Science Foundation under the project number
IP-09-2014-1501 and by the Slovak Research and Development Agency, Grant No. APVV-0516-
12.
[1]
K. E. A. Lougheed et al., Tuberculosis (Edinb.), 2009, 89, 364.
[2]
G. Džimbeg et al., Eur. J. Med. Chem., 2008, 43, 1180.
[3]
M. Šimunović et al., Bioorg. Med. Chem., 2009, 17, 5605.
[4]
I. Perković et al., J. Enzyme Inhib. Med. Chem., 2013, 28, 601.
[5]
K. Pavić et al., Eur. J. Med. Chem., 2014, 86, 502.
[6]
I. Perković et al., Eur. J. Med. Chem., 2016, 124, 622.
[7]
K. Pavić et al., Molecules, 2016, 21, 1629.
244
P-169
INSIGHTS INTO ANTIOXIDANT AND CYTOSTATIC ACTIVITY OF THE

NOVEL PRIMAQUINE UREIDOAMIDES
Branka Zorc,[a],* Kristina Pavić,[a] Dimitra Hadjipavlou-Litina,[b] Eleni Pontiki,[b]

Marijeta Kralj[c] and Katja Ester[c]
[a] Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacica 1, Zagreb, Croatia
[b] Faculty of Health Sciences, School of Pharmacy, Faculty of Health Sciences, Aristotle University of
Thessaloniki, Thessaloniki, Greece
[c] Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia
* bzorc@pharma.hr
In the last decade our research group has designed and prepared almost a hundred of various
primaquine (PQ) derivatives and evaluated their cytostatic and antioxidant activity. Many compounds
from the different series of PQ derivatives showed prominent cytostatic and/or antioxidant activity.[1–
6]
The latest series of compounds synthesized by our group are PQ hybrids of ureidoamide type
bearing amino acid moiety in the central part of the structure.[7] Although they were primarily designed
as potential antimalarial drugs, we wanted to explore their cytostatic and antioxidant activities as
well.
The antioxidant properties of novel PQ hybrids 1a-g were investigated using two different assays:
interaction with DPPH free radical and AAPH. DPPH-reducing ability of the ureidoamide derivatives
1a-g was very low possibly due to stereochemical reasons. However, all derivatives significantly
inhibited lipid peroxidation (77–99%) with the exception of the compound 1a (15%), the only
derivative of an aliphatic amino acid. In the latter experiment AAPH was used as a free radical
initiator to follow oxidative changes of linoleic acid to conjugated diene hydroperoxide. Compound
1c was the most potent (99%). Furthermore, all tested compounds, except of 1a again, appeared to
be potent LOX inhibitors (40–71 μΜ). Derivative 1c was the most potent LOX inhibitor with an IC50
value of 40 μΜ followed by 1e and 1f. It seems that the presence of the chloride atom in the molecule,
and not its position, influence the inhibition.
The antiproliferative activity of the compounds 1a-g was evaluated in vitro on three types of human
tumor cell lines: NCI-H460, MCF-7 and SW620. In general, most of the compounds displayed weak,
and only several compounds, along with PQ, showed moderate antiproliferative activity on all tested
cell lines. Compound 1e showed the strongest activity against SW620, and moderate against other
tested cell lines. Compounds 1d and 1e were generally the most active. The weak antiproliferative
activity of the novel PQ hybrids 1a-g favours the hypothesis that the general cytotoxicity is not the
reason for their prominent antimalarial activity against erythrocytic stages of P. falciparum.[8]
[1]
G. Džimbeg et al., Eur. J. Med. Chem., 2008, 43, 1180.
[2]
M. Šimunović et al., Bioorg. Med. Chem., 2009, 17, 5605.
[3]
I. Perković et al., J. Enzyme Inhib. Med. Chem., 2013, 28, 601.
[4]
K. Pavić et al., Eur. J. Med. Chem., 2014, 86, 502.
[5]
I. Perković et al., Eur. J. Med. Chem. 2016, 124, 622.
[6]
K. Pavić et al., Molecules, 2016, 21, 1629.
[7]
K. Pavić et al., 25th Croatian Meeting of Chemists and Chemical Engineers, Poreč, 2017.
[8]
B. Zorc et al., 10th Joint Meeting on Medicinal Chemistry, Dubrovnik, 2017.
245
INDEX
A Beloglazkina, E. K. ..................... 19, 73, 86, 148, 158, 197

Abad, Paloma ........................................................... 178 Benaki, D. ............................................................. 18, 53
Abakumova, T. O. ................................................. 19, 73 Benedec, Daniela........................................................ 91
Abe, Hikaru ................................................... 18, 60, 237 Benedetto Tiz, Davide........................................... 19, 63
Adriano, Mollica ....................................................... 221 Benyhe, Sandor ........................................................ 221
Albarghouti, Ghassan............................................ 19, 65 Ber, A. P. .................................................................. 158
Alcalde, E. ................................................................ 109 Beus, Maja ............................................................... 205
Alcântara, Laura M. .................................................. 228 Biała, Grażyna .......................................................... 132
Alencar, Nelson ........................................................ 178 Bidon-Chanal, Axel ............................................... 19, 74
Alente, S................................................................... 172 Binnie, Margaret .................................................. 19, 74
Aligiannis, N. ........................................................ 18, 53 Birkus, Gabriel ...................................................... 18, 47
Allu, Senkara Rao.................................................. 17, 44 Bist, Ganesh ............................................................. 111
Altomare, Cosimo................................................. 19, 75 Blank, Michael ...................................................... 19, 67
Altucci, L. ............................................................83, 172 Bobanović, Kristina ................................................... 147
Amić, Ana............................................................. 77, 78 Bochicchio, Anna ...................................................... 104
Amić, Dragan........................................................ 77, 78 Boček, Ida ................................................................ 217
Anderluh, Marko ...................................................... 141 Boháč, Andrej ...................................................... 17, 42
Andreadou, Ioanna ................................................... 152 Bojarski, Andrzej J.................................68, 117, 155, 213
Angeli, A............................................................... 18, 62 Bojko, Barbara.......................................................... 220
Angiulli, G................................................................. 210 Boka, V. I. ............................................................. 18, 53
Anna, Munder .......................................................... 177 Borcea, Anca-Maria .................................................... 89
Annunziato, G............................................................. 62 Bősze, Szilvia ............................................................ 146
Argyros, Orestis ........................................................ 165 Boura, Evzen .............................................................. 47
Arie, Gruzman .......................................................... 177 Brea, J. Manuel....................................................99, 100
Arvidsson, Per I.......................................... 116, 179, 216 Brea, José............................................................. 19, 75
Aytemir, M. D. ............................................................ 79 Brennan, Paul ............................................................. 37
Azoulay-Ginsburg, Salome .......................................... 80 Brkljača, Zlatko ......................................................... 145
Azuaje, Jhonny ..................................................... 19, 75 Bronner, Christian ................................................ 19, 70
Azzam, Amina........................................................... 135 Bruno, A. .............................................................. 18, 62
Brus, Boris ............................................................ 17, 39
B Bucki, Adam ............................................................. 236
Babić, Maja Stipković ................................................ 113
Bacsa, Ildikó ............................................................. 173 C
Baek, Seung Yeop ..................................................... 190 Cadavid, María I. .................................................. 19, 75
Baijnath, Sooraj ................................................. 202, 216 Cahard, Dominique................................................... 139
Baiocco, P................................................................. 210 Campos Rosa, Joaquín M. ......................................... 228
Baji, Ádám...........................................................81, 112 Cannalire, Rolando ............................................... 19, 64
Balabasquer, M. ....................................................... 156 Capasso, C. ........................................................... 18, 62
Ballekova, Jana .............................................. 18, 56, 201 Car, Željka ................................................................ 119
Balogh, Balázs ............................................................ 82 Carbajales, Carlos ................................................. 19, 75
Balzano, A. L. .............................................................. 83 Carev, Ivana ......................................................... 85, 90
Bampali, Konstantina.......................... 17, 19, 38, 72, 124 Carloni, Paolo ........................................................... 104
Ban, Nenad ................................................................ 31 Carlsen, Peter N.................................................... 17, 44
Barančoková, Michaela......................................... 19, 63 Casey, P.J. ................................................................ 156
Baranyai, Zsuzsa ............................................ 17, 32, 146 Castellano, S. ........................................83, 175, 207, 233
Barashkin, A. A. .......................................................... 86 Castro, Marian.......................................................... 132
Barbaraci, Carla ........................................................ 178 Cecchetti, Violetta ................................................ 19, 64
Barreca, Maria Letizia ........................................... 19, 64 Cellamare, Saverio................................................ 19, 75
Bartenschlager, Ralf.................................................. 115 Çetin Atalay, Rengül ................................................. 102
Bartolini, Manuela .................................................... 206 Chalupská, Dominika ............................................ 18, 47
Basarić, Nikola............................................. 97, 121, 144 Chang, Minsun ......................................................... 136
Baumlová, Adriana ............................................... 18, 47 Chatzisideri, Theodora ................................................ 93
Bautista, José M. ...................................................... 178 Chinthakindi, Praveen K. ........................................... 179
Bazina, Linda .............................................................. 84 Chmielewska, Ewa ....................................... 94, 133, 192
Bedford, M. T. .......................................................... 233 Cho, Won-Jea ........................................................... 238
Bekić, Sofija S. .......................................................... 214 Choi, Ji Won ............................................................. 125
Bektašević, Mejra ....................................................... 85 Choi, Sun.................................................................... 95
Beloglazkina, A. A. ...............................................86, 148 Christoffels, Alan ...................................................... 162
246
Chudzik, Mariola....................................................... 193 Dziuk, Błażej ............................................................. 192

Cieślak, Marcin J. .............................. 19, 66, 96, 180, 224
Cindrić, Maja ............................................................ 120 E
Cindrić, Matej............................................................. 97 Edward, Korshin ....................................................... 177
Cintulova, Daniela ...................................................... 98 Efentakis, Panagiotis................................................. 152
Cirrincione, Girolamo.................................................. 35 Efrat, Shtriker ........................................................... 177
Cocchiola, R.............................................................. 229 Egieyeh, Samuel ....................................................... 162
Codony, Sandra ...................................................99, 100 Ejiri, Hiromi .............................................................. 118
Cokarić Brdovčak, Maja ........................................ 18, 61 Eraković Haber, Vesna ................................................ 58
Colotti, G. ................................................................. 210 Ercan, A...................................................................... 79
Coluccia, A......................................................... 191, 203 Erdoğan, Merve................................................. 105, 110
Coluccia, Addolorata Maria Luce ............................... 153 Ernst, Margot ................................................ 38, 72, 124
Coluccia, Antonio .............................................. 153, 154 Esposito, F. ............................................................... 161
Condakes, Matthew L. .......................................... 17, 44 Esquena, J. ............................................................... 109
Contu, Michela ........................................................... 82 Estè, J. A. .................................................................. 191
Corona, A. ................................................................ 161 Ester, Katja ........................................................ 243, 245
Costantino, G. ............................................................ 62
Costi, R. .............................................. 161, 203, 210, 229 F
Cotman, Andrej Emanuel .......................................... 139 Fallon, I. ................................................................... 109
Crespan, E. ............................................................... 203 Famiglini, V............................................................... 191
Crespo, Abel ......................................................... 19, 75 Famiglini, Valeria ...................................................... 154
Cummins, Carolyn .................................................... 176 Federico, Leonardo Bruno......................................... 228
Cushman, I. .............................................................. 156 Felicetti, Tommaso ............................................... 19, 64
Cvetanović, Aleksandra...................................... 182, 183 Felici, Antonio ...................................................... 19, 63
Čipčić Paljetak, Hana.......................................... 120, 195 Feoli, A. .................................................................... 175
Ćelić, Andjelka S. ...................................................... 214 Filatov, V. E. ............................................................. 148
Fiorillo, A. ................................................................. 210
D Forgione, Mariantonietta.......................................... 227
D’Abusco, A. Scotto .................................................. 229 Forné, I....................................................................... 83
D’Alba, F............................................................... 18, 62 Frakolaki, Efseveia .................................................... 115
Dahmoune, Amina.................................................... 135 Franci, G. .................................................................... 83
Damjanović, Ana ...................................................... 182 Frank, Éva ........................................ 17, 36, 81, 112, 114
Damjanović-Vratnica, Biljana ............................. 101, 196 Fraser, Paul E............................................................ 206
Dawidowski, Maciej.................................................... 51 Freitas-Júnior, Lucio H. ............................................. 228
de Andrade Ramos, Giselle ....................................... 206 Fukuzaki, Takehiro................................................ 17, 44
de Melo, Eduardo B. .......................................... 168, 169 Furač, Lidija .............................................................. 147
de Oliveira Miranda, Camila...................................... 176
Dejmek, Milan ...................................................... 18, 47 G
Demirci, Aslı ............................................................. 102 García-Celma, M. J. ................................................... 109
Denk, Christoph................................................. 103, 215 Garrido, Vanesa.................................................... 19, 63
Denya, Ireen............................................................. 129 Gaurina Srček, Višnja ................................................ 182
Desantis, Jenny......................................................... 104 Gavriil, Efthymios-Spyridon....................................... 157
Di Muccio, T. ............................................................ 210 Gazivoda Kraljević, Tatjana ....................................... 113
Di Santo, R................................................. 161, 210, 229 Gelmi, M. L. .............................................................. 159
Diallinas, George ...................................................... 157 Gerasi, Maria............................................................ 200
Dimitrakis, Spyridon ................................................. 157 Getter, Tamar............................................................. 80
Dimitrić Marković, Jasmina M. .............................. 77, 78 Giannakopoulou, Erofili ............................................ 115
Dinarès, I. ................................................................. 109 Giannouli, Vasiliki ..................................................... 165
Djaković, Lara ....................................................... 18, 61 Gielara-Korzańska, Agnieszka.................................... 220
Dobiaš, Juraj ........................................................ 17, 42 Gikas, E. ............................................................... 18, 53
Doğruer, Deniz S. ............................................... 105, 110 Gil, A. ....................................................................... 156
Doležal, Martin......................................................... 242 Ginalska, Grazyna ..................................................... 199
Dorocka-Bockowska, B................................................ 87 Ginex, Tiziana ........................................................... 100
Downs, Jessica Ann............................................... 19, 70 Glamočlija, Una ........................................................ 186
Drabczyk, Anna................................... 106, 107, 149, 163 Glavaš-Obrovac, Ljubica............................................ 113
Drabczyk, Anna K. ..................................................... 126 Głuch-Lutwin, Monika .............................................. 236
Dreier, D................................................................... 108 Gobec, Martina ........................................................ 211
Drenjančević, Domagoj ............................................. 113 Gobec, Stanislav ...................................... 18, 39, 48, 211
Drynda, Angelika ...................................................... 160 Gobin, Ivana ......................................................... 18, 61
Durmaz, İrem ........................................................... 102 Golemac, Anja ............................................................ 90
Duszkiewicz, Roksana ........................................... 19, 69 Gopal, Nirmala D. ..................................................... 202
Dutkiewicz, Zbigniew ................................................ 220 Góra, Małgorzata...................................................... 184
Dzamova, Pavlina ................................................. 17, 46 Govender, Kimberleigh B. ......................................... 179
247
Govender, Thavendran ................. 71, 116, 179, 202, 216 Jaśkowska, Jolanta....... 106, 107, 126, 127, 149, 163, 212
Gramiccia, M. ........................................................... 210 Jeong, Hui Rak ................................................... 128, 138
Grandi, N.................................................................. 161 Jeremić, Svetlana........................................................ 78
Grbčić, Petra ..................................................... 164, 204 Jerić, Ivanka....................................................... 145, 234
Gredičak, Matija ....................................................... 145 Jin, ........................................................................... 238
Green, William D. ................................................. 17, 44 Johansen, Tommy N. ................................................ 225
Grolik, Barbara ......................................................... 220 Jójárt, Rebeka........................................................... 173
Gruzman, Arie ................................................. 19, 67, 80 Joubert, Jacques ................................................ 129, 134
Jovanović-Šanta, Suzana S......................................... 214
H Juárez-Jiménez, Jordi ................................................ 178
Ha, Jae Du ................................................................ 122 Jukić, Marijana ......................................................... 113
Hadian, Kamyar ........................................................ 104 Jung, Da Woon .................................................. 130, 137
Hadjipavlou-Litina, Dimitra ................................ 243, 245 Jung, U.-K. .................................................................. 88
Haider, Maximilian ................................................... 223 Jung, Y.-S. ................................................................... 88
Hailu, Gebremedhin Solomon ................................... 227 Jung, Young Hoon..................................................... 190
Hamel, Ernest ........................................................... 153 Jurak, Igor ............................................................ 18, 61
Han, S. B..................................................................... 88 Jurić, Snježana .......................................................... 131
Han, Younho ............................................................ 238 Jurin, Mladenka.......................................................... 85
Handzlik, Jadwiga .............................................. 117, 155
Hanquet, Gilles ........................................................... 42 K
Hapko, V. V. ......................................................... 19, 73 Kaczor, Agnieszka A. .......................................... 132, 199
Harej, Anja ............................................ 18, 61, 174, 186 Kafarski, Paweł ............................................ 94, 133, 192
Hayashi, Chigusa............................................ 18, 60, 237 Kalčic, Filip ............................................................... 241
Hayashi, Yuko ........................................................... 118 Kamiński, Krzysztof ..............................................52, 184
Herman, Bianka Edina............................................... 173 Kang, Chung Hyo ...................................................... 122
Hirai, Yoshiro............................................................ 118 Kang, Yong Gu .......................................................... 125
Hiscott, John ............................................................ 154 Kania, Emilia............................................................. 220
Hlaváč, Matúš ...................................................... 17, 42 Kapp, Erika ............................................................... 134
Hog, Daniel T. ....................................................... 17, 44 Karagiannis, Dimitrios ............................................... 152
Hogendorf, Adam ..................................................... 220 Karakaya, G. ............................................................... 79
Holy, M. ................................................................... 108 Karczmarzyk, Zbigniew ............................................. 199
Horak, Ema............................................................... 147 Karminski-Zamola, Grace ........................... 120, 195, 204
Hranjec, Marijana ...................................... 120, 195, 217 Karpov, N. A. .............................................................. 86
Hu, X. ....................................................................... 159 Kassymova, D. T........................................................ 240
Humpa, Otakar ......................................................... 170 Katila, Pramila .......................................................... 111
Hur, Joonseong ........................................................ 222 Katirtzi, Anastasia ................................................. 17, 46
Husak, Antonija ........................................................ 121 Katsamakas, Sotirios ................................................... 93
Husnjak, Koraljka ...................................................... 131 Kavčič, Luka.............................................................. 234
Hwang, Jong Yeon ...............................................92, 122 Kawada, Manabu........................................... 18, 60, 237
Hyeon, Changbong ..................................................... 95 Kaźmierczak-Barańska, Julia.............. 19, 66, 96, 180, 224
Kędzierska, E. ........................................................... 239
I Kelavić, Ana................................................................ 90
Igarashi, Masayuki ......................................... 18, 60, 237 Kelly, John M. .................................................... 189, 231
Ihmof, A. .................................................................... 83 Kessal, Fetta ............................................................. 135
Ilari, A. ..................................................................... 210 Khadka, Daulat B. ..................................................... 238
Ilaš, Janez ............................................................. 19, 63 Kieć-Kononowicz, Katarzyna .............................. 117, 155
Inoue, Hiroyuki .............................................. 18, 60, 237 Kijkowska-Murak, Urszula ......................................... 209
Inoue, Motomu ........................................................ 185 Kikelj, Danijel.............................................................. 63
Ionuţ, Ioana................................................. 91, 123, 167 Kılıç, Burcu ........................................................ 105, 110
Iorio, Maria Teresa ................................................... 124 Kim, C......................................................................... 88
Ivanković, Siniša ....................................................... 166 Kim, Hee-Doo ........................................................... 136
Kim, Hyeon Jeong ..................................................... 125
J Kim, Hyeon Ji ............................................................ 125
Jakas, Andreja .......................................................... 145 Kim, Hyoung Rae ........................................................ 92
Jakimov, Dimitar....................................................... 151 Kim, J. W. ................................................................... 88
Jakubec, Pavol ...................................................... 17, 44 Kim, Jin Han ...................................................... 130, 137
Jampílek, Josef ......................................................... 244 Kim, Pilho ................................................................... 92
Jandourek, Ondrej ................................................ 17, 46 Kim, Si Won.............................................................. 125
Janeba, Zlatko .......................................................... 241 Kim, Sun Yeung......................................................... 128
Jang, Bo Ko............................................................... 125 Kim, Sun Young ........................................................ 138
Janowska, Dominika ................................................. 188 Kiricsi, Mónika ............................................................ 81
Jansa, Petr................................................................ 241 Kiss, Anita ................................................................ 140
Jäntsch, K. ................................................................ 108 Kiss-Faludy, Réka ...................................................... 114
248
Kišić, Andrea ............................................................ 139 Lazarides, Theodore ................................................... 93

Kitamura, Yoshiaki ................................................ 17, 44 Łażewska, Dorota .............................................. 117, 155
Klebe, Gerhard ........................................................... 33 Lee, Chong Ock....................................................92, 122
Klimek, Katarzyna ..................................................... 199 Lee, Dong Ho............................................................ 122
Klisuric, Olivera......................................................... 151 Lee, Eung-Seok ......................................................... 111
Kliza, Katarzyna ........................................................ 131 Lee, Gary.............................................................. 18, 47
Kmoníčková, Eva ...................................................... 241 Lee, J. Y. ..................................................................... 88
Knapp, Stefan ....................................................... 19, 70 Lee, Jae Yeol ....................................... 128, 130, 137, 138
Knez, Damijan ........................................... 17, 18, 39, 48 Lee, Jin-Ching ........................................................... 154
Koczurkiewicz, Paulina.............................................. 187 Lee, Seungbeom ....................................................... 222
Kohyama, Aki ........................................................... 171 Lee, Sun Young ......................................................... 136
Kołaczkowski, Marcin ............................................... 236 Lee, Yerim ................................................................ 125
Kolarič, Anja ............................................................. 141 Lee, Yoonji ................................................................. 95
Kolb, Peter ............................................................... 132 Leiva, Rosana ................................... 19, 74, 99, 100, 231
Kolcarkova, Lucie.................................................. 17, 46 Lešnik, Samo ........................................................ 18, 48
Kolman, Viktor ......................................................... 241 Li, H.......................................................................... 233
Konc, Janez .......................................................... 18, 48 Li, Quan.................................................................... 171
Konecna, Klara ..................................................... 17, 46 Lim, Changjin............................................................ 222
Korshin, Edward ......................................................... 80 Linares, María .......................................................... 178
Korzanski, Artur........................................................ 220 Login, Cezar................................................................ 91
Kosiek, Szymon.................................................. 188, 239 López-Rodríguez, M.L. .............................................. 156
Kossakowski, Jerzy........................................... 19, 66, 96 Lougiakis, Nikolaos .................................... 157, 165, 200
Kostakis, Ioannis K. ................................................... 165 Loza, María Isabel .................................... 19, 75, 99, 100
Košak, Urban ........................................................ 17, 39 Luca, V. De ........................................................... 18, 62
Koteliansky, V. E. ................................... 19, 73, 158, 197 Lucidi, Alessia ........................................................... 227
Kotlińska, J. .............................................................. 239 Lučić, Bono........................................................... 77, 78
Kotovskii, G. A. ........................................................... 86 Lukaszewska-Kuska, M................................................ 87
Kovačević, Tatjana .................................................... 142 Luque, F. Javier...................................... 19, 74, 100, 178
Kovarik, Zrinka.......................................................... 143
Kralj, Damir .............................................................. 145 M
Kralj, Marijeta ............... 97, 120, 144, 147, 217, 243, 245 Macchia, Marco.......................................................... 54
Kraljević Pavelić, Sandra ............... 61, 164, 174, 186, 204 Maccioni, Elias............................................................ 82
Krátký, Martin ................................ 17, 32, 146, 232, 235 Macedonio, Giorgia .................................................. 221
Krauss, Sybille .......................................................... 104 Machulkin, A. E......................................................... 158
Krištafor, Svjetlana ................................................... 147 Maciążek-Jurczyk, Małgorzata............................ 193, 194
Krivokapić, Slađana................................................... 101 Macut, H. ................................................................. 159
Królewska, Karolina ................................. 19, 66, 96, 180 Mączyński, Marcin.................................................... 160
Królewska-Golińska, Karolina .................................... 224 Maček-Hrvat, Nikolina .............................................. 143
Kruger, Gert ............................................................. 216 Madia, V. N. ....................................... 161, 203, 210, 229
Kruger, Hendrik G. ..................................... 116, 179, 202 Maga, G. ........................................................... 191, 203
Kruk-Słomka, Marta.................................................. 132 Mai, Antonello .................................................. 172, 227
Kubicki, Maciej ......................................................... 220 Majchrowski, R. .......................................................... 87
Kucerova-Chlupacova, Marta ................................ 17, 46 Májeková, Magdaléna ................................... 18, 56, 201
Kucia, Urszula ....................................................... 19, 69 Majellaro, Maria................................................... 19, 75
Küçükgüzel, İlkay ...................................................... 102 Majka, Zbigniew ................................................ 126, 127
Kukushkin, M. E. ..................................................86, 148 Majouga, A. G................................. 73, 86, 148, 158, 197
Kułaga, Damian .......................... 106, 107, 126, 149, 163 Maklakova, S. Yu. .......................................... 19, 73, 197
Kumar, A. Sanjeeva................................................... 179 Malan, Sarel F............................................ 129, 134, 162
Kunin, M. A. ............................................................... 86 Malatesti, Nela ..................................................... 18, 61
Kuntner-Hannes, Claudia .......................................... 103 Malinowska, Magdalena ............. 106, 107, 126, 149, 163
Kuran, Bożena ................................................. 19, 66, 96 Manfroni, Giuseppe.............................................. 19, 64
Kurczab, Rafał...........19, 68, 117, 150, 155, 212, 213, 220 Manikoth Ayyathan, Dhanoop .............................. 19, 67
Kuzminac, Ivana ....................................................... 151 Maračić, Silvija ......................................................... 164
Kverka, Miloslav ....................................................... 241 Marakos, Panagiotis .................................. 157, 165, 200
Kwon, Youngjoo ....................................................... 111 Marasović, Maja ....................................................... 166
Marc, Gabriel .............................................. 89, 123, 167
L Marín-Ramos, N. ...................................................... 156
La Regina, G. ............................................................ 191 Marković, Marija ...................................................... 234
Lambrinidis, George .......................................... 152, 157 Marković, Snežana D. ............................................... 198
Lameira, Jerónimo .................................................... 178 Marković, Zoran ................................................... 77, 78
Lamut, Andraž ...................................................... 19, 63 Marona, Henryk ................................................ 187, 236
Langlois-Mercier, Audrey ...................................... 17, 44 Marrocco, Biagina .................................................... 227
Lankri, David ........................................................ 19, 65 Martin Kleiner, Irena ................................... 97, 120, 217
249
Martinet, Nadine .................................................. 19, 70 Naicker, Tricia .................................... 116, 179, 202, 216
Martínez-Falguera, Daina.......................................... 230 Napiórkowska, Mariola ............................ 19, 66, 96, 180
Martín-Fontecha, M. ................................................ 156 Nastasă, Cristina..................................................91, 181
Martins, João Paulo A. ....................................... 168, 169 Nastić, Nataša ................................................... 182, 183
Marvanová, Pavlína .................................................. 170 Nawrot, Barbara .................................... 66, 96, 180, 224
Masci, D. .................................................................. 191 Nebbioso, A.............................................................. 172
Masci, Domiziana ..................................................... 154 Nencka, Radim ..................................................... 18, 47
Massari, Serena ........................................................ 104 Ngcobo, Bongani ...................................................... 216
Masuda, Tohru ......................................................... 237 Nielsen, Birgitte........................................................ 225
Matera-Witkiewicz, Agnieszka .................................. 224 Nikolić, Andrea ......................................................... 151
Matić, Josipa ............................................................ 121 Novakov, Vesna........................................................ 183
Matijašić, Mario ................................................ 120, 195 Novaković, Irena....................................................... 186
Matosiuk, Dariusz ..................................................... 209 Novotortsev, V. K...................................................... 148
Matovina, Mihaela ................................................... 131 Nowakowska, Angelika ............................................. 117
Matsuura, Nobuyasu ................................................ 185 Nujić, Krunoslav........................................................ 142
Matsuya, Yuji............................................................ 171
Mattevi, Andrea ....................................................... 227 O
Matthes, Frank ......................................................... 104 Obmińska-Mrukowicz, Bożena .................................. 160
Mátyus, Péter............................................................. 82 Obniska, Jolanta ....................................................... 184
Mazzone, R............................................................... 172 Odehnalová, Klára .................................................... 170
McBride, Andrew ................................................. 19, 74 Odžak, Renata ............................................................ 84
Meglić, Karlo ............................................................ 119 Offermann, Nina....................................................... 104
Mejdrová, Ivana ................................................... 18, 47 Ohba, Shun-ichi ............................................. 18, 60, 237
Mernyák, Erzsébet......................................... 17, 36, 173 Ohishi, Tomokazu .......................................... 18, 60, 237
Mertlíková-Kaiserová, Helena ............................... 18, 47 Oikawa, Tsutomu ..................................................... 185
Mesić, Milan............................................................. 142 Olga, Viskind ............................................................ 177
Messore, A. .............................................................. 203 Öncül, S. ..................................................................... 79
Meščić, Andrijana ..................................................... 174 Ondar, E. E. .............................................................. 197
Miazga-Karska, Małgorzata ....................................... 199 Oniga, Ilioara .............................................................. 89
Michnová, H. ............................................................ 244 Oniga, Ovidiu...........................89, 91, 123, 167, 181, 219
Mihovilovic, Marko D............. 17, 19, 38, 72, 98, 108, 124 Opletalova, Veronika ............................................ 17, 46
Mihovilović, Moris .................................................... 113 Ortega, F.J. ............................................................... 156
Mikros, Emmanuel .............. 18, 19, 53, 70, 115, 152, 157 Ortega-Gutiérrez, S................................................... 156
Mikstacka, Renata .................................................... 220 Osada, Hiroyuki ........................................................ 185
Mikula, Hannes ....................................57, 103, 215, 223 Osmanović, Amar .............................................. 186, 218
Milite, C. ..................................................... 83, 175, 207 Oyarzábal, Julen ..................................................99, 100
Miloš, Mladen .......................................................... 166
Minovski, Nikola ....................................................... 141 P
Miošić, Mande.......................................................... 113 Padhye, Subhash ...................................................... 186
Miszczyk, Patrycja..................................................... 192 Padrtová, Tereza ...................................................... 170
Miyazawa, Masahiro................................................. 118 Pae, Ae Nim.............................................................. 125
Mlinarič-Raščan, Irena .............................................. 211 Palma, Luca Di .......................................................... 178
Mlinarić-Majerski, Kata............................................. 144 Pamreddy, Annapurna .............................................. 202
Młynarz, Piotr........................................................... 133 Pańczyk, Katarzyna ............................................ 187, 236
Mohar, Barbara ........................................................ 139 Paneth, A. ................................................................ 239
Mok, Hui Yeon.......................................................... 190 Paneth, Agata........................................................... 188
Mokrý, Petr .............................................................. 170 Pantović, Snežana.............................................. 101, 196
Moodley, Chivonne .................................................. 216 Papadakis, Georgios ................................................. 200
Moraes, Carolina B. .................................................. 228 Pardali, Vasiliki ......................................................... 189
Morawiak, Maja ....................................................... 199 Pardo, L. ................................................................... 156
Motojima, Atsuko..................................................... 185 Park, Chi Hoon............................................................ 92
Mótyán, Gergő .................................................. 112, 114 Park, Chi-Hoon ......................................................... 122
Müller, Christin..................................................... 18, 47 Park, Hyun-Ju ........................................................... 190
Müller, Susanne ................................................... 19, 70 Park, Jong-Hyun ....................................................... 125
Muñoz-Torrero, Diego .............................................. 178 Park, Ki Duk .............................................................. 125
Murár, Miroslav ................................................... 17, 42 Pârvu, Alina .............................................................. 181
Murković Steinberg, Ivana ........................................ 147 Passacantilli, S. ......................................................... 191
Myers, Andrew G........................................................ 44 Paurević, Marija ....................................................... 208
Myrianthopoulos, Vassilios ............................ 19, 70, 115 Pavić, Kristina ............................................ 243, 244, 245
Pawełczak, Bartosz ............................................ 193, 194
N Pedrys, Anna .............................................................. 69
Naccarato, Valentina ................................................ 153 Pękala, Elżbieta ........................................................ 187
Naesens, Lieve.......................................................... 115 Pellay, François-Xavier ................................................ 90
250
Pellegrino, S. ............................................................ 159 Roškarić, Petra ......................................................... 217

Pérez, Belén ................................................ 99, 100, 231 Rotili, Dante ............................................................. 227
Pérez-Benavente, Susana.......................................... 178 Rožman, Kaja........................................................ 18, 48
Perić, Mihaela ................................................... 120, 195 Rubí, Jèssica ............................................................. 231
Perin, Nataša............................................................ 195 Rybka, Sabina ........................................................... 184
Perković, Ivana ......................................................... 244 Ryng, Stanisław ........................................................ 160
Peroković, V. Petrović ............................................... 119
Perović, Andrej ......................................................... 196 S
Perović, Svetlana ............................................... 101, 196 Saccoliti, F. ......................................... 161, 203, 210, 229
Pescatori, L............................................................... 203 Sáez, Elena ..........................................................99, 100
Petri, Edward T. ........................................................ 214 Saito, Tomio ............................................................. 185
Petrov, R. A. .................................................. 19, 73, 197 Sakač, Marija N.................................................. 151, 214
Petrov, S. A............................................................... 197 Sakashita, Chiharu ......................................... 18, 60, 237
Petrović, Vladimir P. ................................................. 198 Salihović, Mirsada..................................................... 218
Petrović, Zorica D. .................................................... 198 Saltykova, I. V. ................................................... 158, 197
Philips, M.R. ............................................................. 156 Samia, Boualem........................................................ 135
Piantanida, Ivo ............................................ 41, 121, 234 Sampedro, Cristina ................................................... 178
Pickering, Darryl S..................................................... 225 Sampson, Samantha L............................................... 134
Pieretti, Stefano ....................................................... 221 Santo, R. Di............................................................... 203
Pieroni, M. ........................................................... 18, 62 Sarli, Vasiliki ......................................................... 49, 93
Pilotto, Simona ......................................................... 227 Sarno, F. ..................................................................... 83
Pîrnău, Adrian .....................................................89, 167 Satała, Grzegorz .......19, 68, 106, 107, 117, 126, 149, 155
Pitucha, Monika ....................................................... 199 Savić, Marina............................................................ 151
Pizarro, Javier ......................................................99, 100 Sbardella, G. ................................... 50, 83, 175, 207, 233
Plačková, Pavla ..................................................... 18, 47 Scandurra, R. ............................................................ 229
Plavec, Janez ............................................................ 234 Scherman, Daniel ..................................................... 181
Plech, T. ................................................................... 239 Schiffrer, Eva Shannon .............................................. 211
Plech, Tomasz........................................................... 188 Schilling, Judith......................................................... 104
Polanski, Jaroslaw................................................. 19, 69 Schmidt, Tuanny P. ................................................... 168
Politeo, Olivera..................................................... 85, 90 Schneider, Gyula ................................... 17, 36, 140, 173
Pont, Caterina .......................................................... 178 Schnürch, Michael ..................................... 17, 19, 38, 72
Pontiki, E. ................................................................. 243 Schols, Dominique ............................................. 174, 243
Pontiki, Eleni ............................................................ 245 Schorp, Kenji ............................................................ 104
Popiołek, Ł. .............................................................. 239 Scipione, L. ............................................................... 210
Poso, Antti ............................................................... 132 Sedić, Mirela ..................................................... 164, 204
Pospíšilová, Sarka ..................................................... 244 Seiple, Ian B.......................................................... 17, 44
Pouli, Nicole .............................................. 157, 165, 200 Seira, Constantí .................................................... 19, 74
Pricopie, Andreea ....................................................... 89 Sergeeva, O. V. ..................................................... 19, 73
Procházková, Eliška............................................... 18, 47 Shibasaki, Masakatsu..................................... 18, 60, 237
Prokopowicz, Monika ............................................... 133 Shin, Su Jeong .......................................................... 125
Ptiček, Lucija ............................................................ 204 Shokhen, Michael ................................................. 19, 67
Pujol, Eugènia......................................................99, 100 Shrestha, Aarajana ................................................... 111
Pupo, G. ............................................. 161, 203, 210, 229 Shubely, Moran .................................................... 19, 67
Pym, Alexander ........................................................ 216 Siebert, David Chan Bodin.......................... 17, 19, 38, 72
Pytka, Karolina ......................................................... 236 Silia, Boumrar........................................................... 135
Silva, Andrea G. ........................................................ 132
R Silvestri, R. ............................................................... 191
Racané, Livio ............................................................ 204 Silvestri, Romano............................................... 153, 154
Radošević, Kristina............................................. 182, 183 Simeone, Xenia..................................................... 19, 72
Raić, Sanda................................................................. 90 Simijonović, Dušica ................................................... 198
Raić-Malić, Silvana ..................................... 113, 164, 174 Singh, Sanil D............................................................ 216
Rajić Džolić, Zrinka.................................................... 205 Sitte, H. H. ................................................................ 108
Rapacz, Anna..................................................... 184, 236 Sitte, Harald H. ........................................................... 98
Ražić, Slavica ............................................................ 182 Siwek, Agata............................................................. 236
Regina, Giuseppe La .......................................... 153, 154 Skonieczka, Katarzyna............................................... 220
Rescigno, D. ...................................................... 175, 207 Skvortsov, D. A. ...................................................86, 148
Ribić, Rosana ..................................................... 119, 208 Slivac, Igor......................................................... 182, 183
Roca, Sunčica ........................................................... 186 Śliwa, Paweł .............................................. 126, 212, 213
Rodriguez, Yoel......................................................... 201 Słoczyńska, Karolina ................................................. 187
Roig, F. ..................................................................... 109 Smith, Ana Sunčana .................................................. 145
Roje, Marin ................................................................ 85 Smith, David ............................................................. 145
Rosińska, Agata ........................................................ 209 Smolíček, Maroš .................................................. 17, 42
Rossetti, Giulia ......................................................... 104 Soares Romeiro, Luiz A. ..................................... 176, 206
251
Sobczak, Milena .............................................. 19, 66, 96 Tammela, Päivi ..................................................... 19, 63

Sohr, Barbara ........................................................... 215 Tamvakopoulos, Constantin...................................... 165
Sola, Irene ................................................................ 178 Tandarić, Tana................................................... 119, 226
Soldo, Barbara............................................................ 84 Tarantino, D. ............................................................ 159
Soltesova Prnova, Marta................................ 18, 56, 201 Targowska-Duda, Katarzyna M. ................................. 132
Son, Han Pyo ............................................................ 190 Taylor, Martin C................................................. 189, 231
Song, Yun Seon......................................................... 136 Teklezgi, Belin G. ...................................................... 202
Sosič, Izidor .............................................................. 211 Terán, Hugo Gutiérrez de...................................... 19, 75
Sotelo, Eddy ............................................................... 75 Thapa Magar, Til Bahadur ......................................... 111
Sova, Matej .......................................................... 18, 48 Thysiadis, Savvas ........................................................ 93
Sović, Irena........................................................ 204, 217 Tiperciuc, Brîndușa ..................89, 91, 123, 167, 181, 219
Speranzini, Valentina ................................................ 227 Tir, Nora................................................................... 208
Srček, Višnja Gaurina ................................................ 183 Tkocz, Aleksandra................................................. 19, 69
Stana, Anca .........................................................91, 219 Tomaselli, Daniela .................................................... 227
Starčević, Kristina .............................................. 195, 217 Tomašič, Tihomir ........................................... 19, 63, 141
Stathopoulou, K.................................................... 18, 53 Tomich de Paula da Silva, Carlos Henrique ................ 228
Stefanachi, Angela ................................................ 19, 75 Tomić, Srđanka.................................................. 119, 208
Stefano, Sabatini .................................................. 19, 64 Torrecillas, I.R........................................................... 156
Stefanski, Tomasz ..................................................... 220 Tramontano, E.......................................................... 161
Stefanucci, Azzurra ................................................... 221 Trotsko, Nazar .......................................................... 188
Stefek, Milan .......................................................56, 201 Tschammer, Nuška ................................................... 141
Stelmasiński, Michał ................................................. 155 Tsvelikhovsky, Dmitry ................................................. 65
Stepanić, Višnja ................................................. 174, 195 Tudino, V................................................... 161, 210, 229
Stephan, Michel ....................................................... 139 Turcu, Andreea L. ..................................................... 230
Stepić, Robert........................................................... 145 Turło, Jadwiga ............................................................ 40
Stevaert, Annelies .................................................... 115
Steven, Chessler ....................................................... 177 U
Stojković, Ranko ....................................................... 166 Ueno, Yurie .............................................................. 185
Stolaříková, Jiřina ..................................................... 232 Ukrainczyk, Marko.................................................... 145
Strunin, Dmytro.................................................... 18, 47 Urbanczyk-Lipkowska, Zofia ...................................... 199
Sugimoto, Kenji ........................................................ 171 Uzelac, Lidija ............................................... 97, 144, 147
Suh, Young-Ger ........................................................ 222
Supuran, C. T. ............................................................. 62 V
Supuran, C.T. .............................................................. 18 Valverde, Elena ...................................................99, 100
Sureda, Francesc X.................................................... 230 Vassilaki, Niki ........................................................... 115
Svatunek, Dennis ............................................... 103, 223 Vázquez, Santiago .......................... 74, 99, 100, 230, 231
Świątek, Piotr ........................................................... 224 Vázquez-Carrera, Manuel ....................................99, 100
Syce, James .............................................................. 162 Veljović, Elma .................................................... 186, 218
Szabó, Nóra ................................................... 17, 32, 146 Verbanac, Donatella .......................................... 120, 195
Szczpinski, Filip ..................................................... 17, 44 Vianello, Robert........................................... 55, 119, 226
Szécsi, Mihály ................................................ 17, 36, 173 Vinšová, Jarmila.............................. 17, 32, 146, 232, 235
Szilvia, Bősze ........................................................ 17, 32 Viviano, M. ........................................................ 207, 233
Szkudlarek, Agnieszka ............................................... 194 Vlahoviček-Kahlina, Kristina ...................................... 234
Szymańska, Ewa ....................................................... 225 Vlase, Laurian ............................................................. 89
Šála, Michal .......................................................... 18, 47 Vodnar, Dan C. ............................................ 89, 167, 219
Šapčanin, Aida .......................................................... 218 Vorobyeva, N. A...................................................86, 148
Šarić, Maria ................................................................ 90 Vos, Margaretha de .................................................. 134
Šćepanović, Valentina............................................... 196 Vosátka, R. ............................................................... 235
Škalamera, Đani ....................................................... 144 Vullo, D. ............................................................... 18, 62
Škrijelj, Nihada ......................................................... 218
Špirtović-Halilović, Selma ................................... 186, 218 W
Šprung, Matilda .......................................................... 84 Wanek, Thomas................................................. 103, 215
Šramel, Peter ....................................................... 17, 42 Waszkielewicz, Anna M...................................... 187, 236
Štajner, Lara ............................................................. 145 Watanabe, Takumi ........................................ 18, 60, 237
Štěpánková, Šárka .................................................... 232 Weber, Jan ........................................................... 18, 47
Šuvak, Anđelo ...................................................... 18, 61 Weber, Stephanie..................................................... 104
Švajger, Urban............................................... 18, 48, 141 Webster, Scott P................................................... 19, 74
Švarc-Gajić, Jaroslava......................................... 182, 183 Więcek, Małgorzata........................................... 117, 155
Wietrzyk, Joanna ......................................... 94, 133, 192
T Wilkovitsch, Martin .................................................. 103
Tabarrini, Oriana ...................................................... 104 Wimmer, Laurin ..................................................98, 124
Tafani, M. ................................................................. 172 Wojtowicz, Natalia ................................................... 133
Tamaian, Radu ......................................................... 219 Wölfling, János ............................... 17, 36, 114, 140, 173
252
Woś, Maciej ............................................................. 199 Żelaszczyk, Dorota .................................................... 187

Wright, Peter M.................................................... 17, 44 Żesławska, Ewa......................................................... 187
Wu, Ling ................................................................... 206 Zhang, Ziyang ....................................................... 17, 44
Wujec, Monika .................................................. 188, 239 Zhou, Xiang .......................................................... 17, 44
Wybrańska, Iwona ................................................ 19, 66 Zhussupova, A. I. ...................................................... 240
Wysocki, Waldemar.................................................. 199 Zhussupova, G. Е. ..................................................... 240
Yabu, Kazuo.......................................................... 17, 44 Zidar, Nace ...................................................... 19, 45, 63
Yeon, Seul Ki............................................................. 125 Zídek, Zdeněk ........................................................... 241
Yin, Shuqiang............................................................ 171 Ziebuhr, John ....................................................... 18, 47
Yokoyama, Hajime.................................................... 118 Zitko, Jan.................................................................. 242
Yoon, Hong Bin.................................................. 130, 137 Zoidis, Grigoris ............................................ 34, 115, 189
Youl Lee, Kwang ....................................................... 238 Zorbaz, Tamara ........................................................ 143
Yun, Chang-Soo .......................................................... 92 Zorc, Branka ....................................... 205, 243, 244, 245
Zupkó, István.......................................................36, 112
Z Zwergel, C. ............................................................... 172
Zador, Ferenc ........................................................... 221 Zyk, N. V. .......................................... 19, 73, 86, 148, 158
Zaręba, Przemysław.................................................. 127 Žarković, Jelena .......................................................... 90
Zatsepin, T. S. ....................................................... 19, 73 Živanović, Marko N. .................................................. 198
Završnik, Davorka .............................................. 186, 218
253
PARTICIPANTS
Miroslava Radečić Yuji Matsuya Zdenek Zidek
Maria Majellaro Thavendran Govender Sooraj Baijnath
Pasquale Linciano Dariusz Matosiuk Matej Cindrić
Ciro Milite Tricia Naicker Antonija Husak
Jenny Desantis Maria Ermitas Alcalde Anita Bosak
Valeria Tudino Hendrik Gerhardus Kruger Marco Pieroni
Valentina Noemi Madia Ivana Kuzminac Marko Anderluh
Daniela Tomaselli Nirmala Gopal Stanislav Gobec
Vesna Gabelica Marković Byron Peters Maciej Dawidowski
Sanja Koštrun Tsutomu Oikawa Werner Embrechts
Ines Vujasinović Branka Zorc Jadwiga Turlo
Ivanka Jerić Zrinka Rajić Džolić Patrizia Diana
Ivana Perković Giuseppe La Regina Tomasz Stefanski
Silvana Raić-malić Piotr Świątek Girolamo Cirrincione
Danijel Namjesnik Marcin Mączyński Takumi Watanabe
Višnja Stepanić Pawel Śliwa Kristina Vlahoviček-kahlina
Gavin Logie Pawel Kafarski Marta Kučerová-chlupáčová
John Hogg Ewa Chmielewska Margot Ernst
Damir Bakoš Jolanta Jaskowska Balázs Balogh
Gabrielle Costantino Giannamaria Annunziato Michael Schnürch
Milan Mesić Antoni Torrens Jover Radim Nencka
Srđanka Tomić-Pisarović Agnieszka Kaczor Nataša Štefanac
Danijel Kikelj Monika Pitucha Magdaléna Májeková
Paul Brennan Amar Osmanović Young Hoon Jung
Gerhard Klebe Nace Zidar Grigorios Zoidis
Péter Mátyus Manabu Kawada Moran Shubely
Danielle Bradshaw Damian Kulaga Martin Doležal
Heather Lambert Jadwiga Handzlik Panagiotis Marakos
Emmanuel Mikros Dorota Lažewska Jarmila Vinšová
Nenad Ban Anna Karolina Drabczyk Istvan Borza
Davorka Završnik Vasiliki Pardali Martin Krátký
Irena Sović Ivo Piantanida Deniz S. Dogruer
Dragan Amić Matej Sova Anca-Maria Borcea
Ana Amić Helena Macut Gabriel Marc
Pavlina Marvanová Monika Wujec Eva Shannon Schiffrer
Tereza Padrtova Ewa Szymanska Svetlana Maklakova
Jolanta Obniska Agata Paneth Erzsébet Mernyák
Nataša Perin Yoshiro Hirai Michaela Barančoková
Andrijana Meščić Krzysztof Kaminski Grace Karminski-zamola
Marijana Hranjec Jaroslaw Polanski Marta Šoltésová Prnová
Livio Racané Heedoo Kim Jana Ballekova
Tatjana Gazivoda Kraljević Jin Han Kim Andrea Kišić
Silvija Maračić Sun Young Kim Andreea Larisa Turcu
Nela Malatesti Patrycja Miszczyk Merve Erdogan
Robert Vianello Barbara Dorocka Bobkowska João Paulo Ataide Martins
Svjetlana Krištafor Hui Rak Jeong Sandra Codony
Vladimir Petrović Dawoon Jung Agata Rosińska
Éva Frank Asli Demirci Maxim Kukushkin
Gergö Mótyán Vasiliki Sarli Rudolf Vosátka
Ádám Baji Maja Marasović Dominik Dreier
Anita Kiss Theodora Chatzisideri Santiago Vazquez
Nikola Basarić Rafal Kurczab Rosana Leiva
Sofija Bekić Zrinka Kovarik Barbara Sohr
254
Dennis Svatunek Ioana Andrada Ionut Snježana Jurić

Christoph Denk Florian Montel David Peralta
Maria Luz Lopez Rodriguez Brindusa Georgeta Tiperciuc Azzurra Stefanucci
Christopher Graham Cristina Mariana Nastasa Roberta Mazzone
Eugènia Pujol Won Jea Cho Marco Macchia
Ana Gil Ordoñez Shouming Wang Giuseppe Saccomanni
Magdalena Malinowska Gianluca Sbardella Marko Mihovilovic
Pavol Jakubec Marijeta Kralj Tommaso Felicetti
Maria-Teresa Iorio Svetlana Perović Monica Viviano
Daniela Cintulova Snežana Pantović Aizhan Zhussupova
Hannes Mikula Damir Kralj Jong Yeon Hwang
Nicole Pouli David Chan Bodin Siebert Chang Soo Yun
Nikolaos Lougiakis Barbara Nawrot Soo Bong Han
Aleksei Machulkin Marcin Cieślak Sun Choi
Vesna Eraković Haber Karolina Królewska-golińska Giselle Ramos De Andrade
Rostislav Petrov Victoria Coulthard Camila Miranda Oliveira
Paola Barraja Julia Kaźmierczak-barańska Cynthia Leigh Schreiber
Konstantina Bampali Natasa Nastic Emily Ann Shangle
Cristian Cezar Login Diego Muñoz Torrero George Lamprinidis
Stana Anca-daniela Jacques Joubert Boko Jang
Salome Emma Azoulay Sarel Malan Mutlu Aytemir
Ginsburg Erika Kapp Vasileios Myrianthopoulos
Youngger Suh Mario Varasi Roberto Di Santo
Erofili Giannakopoulou Dmitry Tsvelikhovsky János Wölfling
Rosana Ribić Katarzyna Pańczyk Eung Seok Lee
Linda Bazina Anna Waszkielewicz Matea Kovač
Tana Tandarić Sara Passacantilli Raimund Maier
Denise Harding Anja Kolarič Aligiannis Nektarios
Ivana Carev Mariola Napiórkowska Ksenija Markešić
Ovidiu Oniga Carlos Silva Branka Ergović
255

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BOOK OF

ISBN 978-953- 55232-8- 4

Section of Medicinal/Pharmaceutical Chemistry

Vesna Gabelica Marković

NATIONAL ORGANIZING COMMITTEE

Vesna Gabelica Marković (Chair)

Vesna Gabelica Marković (Chair)

Nenad Ban (ETH Zürich, CH)

Gerhard Klebe (University of Marburg, DE)

Paul Brennan (University of Oxford, UK)

Margot Ernst (Medical University Vienna, AT)

Ivo Piantanida (Ruđer Bošković Institute, HR)

Martin Krátký (Charles University, CZ)

Grigoris Zoidis (National and Kapodistrian University of Athens, GR)

János Wölfling (University of Szeged, HU)

Girolamo Cirrincione (University of Palermo, IT)

Jadwiga Turlo (Medical University of Warsaw, PL)

Stanislav Gobec (University of Ljubljana, SI)

Hannes Mikula (Technical University Vienna, AT)

Vesna Eraković Haber (Fidelta Ltd., HR)

Robert Vianello (Ruđer Bošković Institute, HR)

Marta Kučerová-Chlupáčová (Charles University, CZ)

Radim Nencka (Czech Academy of Sciences, CZ)

Nektarios Aligiannis (National and Kapodistrian University of Athens, GR)

Vasiliki Sarli (Aristotle University of Thessaloniki, GR)

Marco Macchia (University of Pisa, IT)

Gianluca Sbardella (University of Salerno, IT)

Krzysztof Kaminski (Jagiellonian University, PL)

Maciej Dawidowski (Medical University of Warsaw, PL)

Magdaléna Májeková (Slovak Academy of Sciences, SK)

Pavol Jakubec (Slovak University of Technology, SK; Harward University, USA)

Matej Sova (University of Ljubljana, SI)

Nace Zidar (University of Ljubljana, SI)

ORAL PRESENTATIONS – section II

12:15-12:45 WINNING POSTERS FLASH PRESENTATIONS

KL-4 RATIONAL DESIGN OF PI4KB INHIBITORS AS POTENTIAL BROAD-SPECTRUM ANTIVIRAL AGENTS

OP-5 FIGHTING ANTIMICROBIAL RESISTANCE BY BREAKING RESISTANCE MECHANISMS

P-5 MULTICOMPONENT SYNTHESIS OF NOVEL ANDROSTANO-PYRIMIDINES AND THEIR PHARMACOLOGICAL

P-23 NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FEATURING A 2-OXAADAMANTANE MOIETY I:

P-40 ORGANOCATALYSIS MEETS BETA LACTAMS

P-57 DIRECT PHOSPHONYLATION OF HETEROAROMATIC COMPOUNDS AS A MEAN TO SYNTHESIZE CYTOTOXIC

P-74 DIFFERENT ROLES OF HALOGEN SUBSTITUENTS IN LIGAND-RECEPTOR INTERACTIONS –

P-89 DESIGN, SYNTHESIS AND CYTOTOXIC ACTIVITY EVALUATION OF NEW AMINOSUBSTITUTED

P-90 IN VITRO CITOTOXITY AND ANTI-TUMOR INVESTIGATION OF PHENYLBORONIC ACID

P-107 IN VITRO SCREENING OF ANTICARCINOGENIC PROPERTIES OF CHERRY STEM EXTRACTS OBTAINED BY

P-159 SALICYLANILIDE MUTUAL PRODRUGS: SYNTHESIS AND BIOLOGICAL ACTIVITY

BEYOND THE PROKARYOTIC RIBOSOME: STRUCTURAL AND

OLIGOTUFTSIN-BASED CARRIERS FOR NOVEL ANTIMYCO-

Krátký Martin,[a],* Baranyai Zsuzsa,[b] Szilvia Bősze,[b] Szabó Nóra[c] and

The global tuberculosis epidemic and increasing emergence of drug-resistant Mycobacterium

WHAT THERMODYNAMICS CAN HELP TO UNDERSTAND

Small-molecule drug discovery involves the optimization of various physicochemical properties of a

METAL CHELATING AGENTS AGAINST VIRUSES AND PARASITES

MARINE ENVIRONMENT INSPIRES KINASES INHIBITORS

OLD SCAFFOLDS IN NEW ROLE: STEROIDS AS ANTIPROLIFERATIVE

János Wölfling,[a],* Éva Frank,[a] Erzsébet Mernyák,[a] Gyula Schneider,[a]

CHEMICAL PROBES IN TARGET DISCOVERY

GABAA RECEPTOR SUBTYPES: A STRUCTURE GUIDED PATH TO

Konstantina Bampali,[a] David Siebert,[b] Marko D. Mihovilovic,[b] Michael Schnürch,[b] and

NEW HITS AND LEADS FOR NEURODEGENERATIVE DISORDERS

Urban Košak, Damijan Knez, Boris Brus, Stanislav Gobec*

POLYSACCHARIDES AS BIOLOGICAL RESPONSE MODIFIERS:

Acknowledgements: Investigation of structure-activity relationship in Se-enriched polysaccharides