WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Kothari* et al. World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 5.210

Volume 4, Issue 06, 1062-1073. Research Article ISSN 2278 4357

SYNTHESIS, SPECTROSCOPIC CHARACTERIZATION AND

BIOLOGICAL EVALUATION OF CIPROFLOXACIN MACROCYCLIC
COPPER (II) COMPLEXES

Richa Kothari*1 and Anurag Agrawal2

1
School of Sciences, Department of Chemistry, ITM University, Gwalior (M.P.) India.
2
School of Pharmacy, ITM University, Gwalior (M.P.) India.

ABSTRACT
Article Received on
13 April 2015, Ciprofloxacin macrocyclic Cu (II) complexes were synthesized by
Revised on 04 May 2015, refluxing of carbohydrazone, ciprofloxacin antibiotic and copper salts.
Accepted on 25 May 2015
All these synthesized compounds were characterized by various
physicochemical techniques like melting point, TLC, elemental
*Correspondence for analysis, molar conductance analysis, FT-IR, H1NMR, LC-MS, and
Author
electronic spectra. The geometry of Cu (II) complexes were octahedral
Dr. Richa Kothari
& distorted in nature which is confirmed by the electronic spectra. All
School of Sciences,
Department of Chemistry, compounds were subjected to antimicrobial & antioxidant activity
ITM University, Gwalior screening using broth serial dilution & H2O2 method. The investigated
(M.P.) India compounds were tested against various strains of bacteria like E.Coli,
S.aureus, Pseudomonas auruginosa and B.subtilus. Copper complexes
showed greater antimicrobial activity as compared to standard drug. All compounds showed
potent antioxidant activity in the range of 80%-90%.

KEYWORDS: Ciprofloxacin, fluoroquinolone, copper salts, antimicrobial, antioxidant

activity.

INTRODUCTION
The development of sensitive chemosensors is an active field of research in recent years
because of their potential applications in clinical biochemistry as well as analytical chemistry
and environmental science.[1-3] The chemistry of metal drug coordination compound is more
popular now than before in importance particularly in the designing of more biological active
drugs.[4] Metal ions are known to affect the action of many drugs. The efficacy of the drugs

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on coordination with a metal is enhanced in many cases.[5] Ciprofloxacin [1- cyclopro-pyl-6-

fluoro-1,4- dihydro-4-oxo-7- ( 1- piperaz- inil)- 3- quinolone carboxylic acid] is a second
generation fluoroquinolone that was synthesized for first time in 1987.[6] A well known
antibacterial drug with a wide spectrum of activity, it is extremely useful for the treatment of
a variety of infections.[7-8] Quinolones are a group of synthetic antibacterial agents now in
clinical use already for over thirty years and ciprofloxacin is one of the widely used
representatives.[9-10] The interactions of quinolones and metal ions have been thoroughly
studied especially due to the interacting biological and chemical properties. Ciprofloxacin can
usually act as a bidentate ligand through the pyridone oxygen and one carboxylate oxygen. It
is well known that metal ions present in complexes accelerate the drug action and the efficacy
of the organic therapeutic agents.[11] The pharmacological efficiencies of metal complexes
depend on the nature of the metal ions and the ligands.[12] It is reported in the literature that
different ligands and different complexes synthesized from same ligands with different metal
ions possess different biological properties.[13, 14] So there is an increasing requirement for the
discovery of new compounds having antimicrobial and antioxidant activities. The newly
synthesized compounds may be more effective than known others in terms of their biological
activities and possibly display their efficiencies with a distinct mechanism from those of well
known. Ciprofloxacin (quinolone) has been suggested to be such novel agents that can be
complexed to metallic ions to enhance their efficacy. The antimicrobial activity of
ciprofloxacin complexes against the multi- resistant organism is very scanty. This study
therefore presents the Synthesis, Spectroscopic characterization, & Biological evaluation of
ciprofloxacin macrocyclic Cu (II) complexes.

2. EXPERIMENTAL SECTION
2.1 Chemistry
All the reagents were of analytical grade purchased commercially from Merck and used
without further purification. Solvents employed were distilled, purified and dried by standard
procedure prior to use.[14] The carbon, hydrogen and nitrogen content in each sample were
performed at RSIC, CDRI Lucknow. The UV-vis. Spectra of the complexes were recorded on
a Perkin-Elmer UV lambda spectrophotometer using KBr in PC Ray research center ITM
University, Gwalior. The molar conductivity of copper complexes was measured on a
systronic conductivity bridge with a dip type cell, using 10-3M solution. Copper contents of
the complexes were estimated by the EDTA method. The H1 NMR spectrum of the
synthesized compounds was recorded in DMSO-d6, using Bruker Avance II 400 NMR

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spectrometer, SAIF, Punjab University, Chandigarh. using m-nitro benzyl alcohol as the
matrix. Melting point of the ligands and Cu complexes were measured by open capillary tube
method which are uncorrected. The bacterial strains used were two Gram- negative
(Escherichia Coli & Pseudomonas auruginosa) & two Gram- positive (Bacillus subtilis,
Staphylococcus aureus) which were obtained from the department of microbiology of ITM
University, Gwalior.

2.2 Synthesis of ethyl-3- [(4-methylphenyl) amino] -3-oxopropanoate

A mixture of 4- methyl aniline and diethylmalonate (1:2) was refluxed for 30 minutes in a
round bottom flask fitted with air condenser of such a length (18 inch) that ethanol formed
escaped and diethylmalonate followed back into the flask. The contents were cooled and
ethanol was added when malondianilide separated as light yellow solid. It was filtered under
suction and filtrate containing ethyl malonianiliate was slowly added with constant stirring on
ice. The ester which precipitated as a white solid was filtrate, dried and re-crystallized from
petroleum ether. (Scheme 1)

Yield: 45%; melting point- 70-72oC, IR (KBr) Cm-1: 3345, 2983, 1726, 1685, 1537, 1HNMR
(): 1.27, 2.3, 7-7.4, 8.1 and 9.98, max = 450 nm, ESI MS m/z: 222.2 a.m.u.

CH3
H3C

O O
CH2
+ Reflux
O
H2C O HN CH3
O

CH2 ethyl-3- [(4-methylphenyl) amino] -3-oxopropanoate

NH2 O
CH3
Para methyl aniline Diethyl malonate

Scheme 1: Synthesis of ethyl-3- [(4-methylphenyl) amino] -3-oxopropanoate

2.3 Synthesis of 3- hydrazinyl-N-(4- methyl phenyl)-3-oxopropanamide

To a solution of compound (1) in ethanol hydrazine hydrate was added. The mixture was
stirred for about 10 minutes when the acid hydrazide separated and the contents were left
overnight. The solid was filtered and re-crystallized twice from hot ethanol when the acid
hydrazide was obtained as white crystals. (Scheme 2).

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Yield: 45%; melting point- 145oC, IR (KBr) Cm-1: 3301, 3053, 1680, 1634, 1512., 1HNMR
(): 1.2, 2.2-2.5, 7.0-7.46, 8.2 and 9.94, max = 410 nm, ESI MS m/z: 265 a.m.u.

NH2
O Stirring
H2N H
N NH
+ NH2
O HN CH3
hydrazine hydrate
O O
ethyl-2-(4-methylanilino)ethanoate
H3C 3- hydrazinyl-N-(4- methyl
phenyl)-3-oxopropanamide

Scheme 2: Synthesis of 3- hydrazinyl-N-(4- methyl phenyl)-3-oxopropanamide

2.4 Synthesis of 3-{2-[1-(4-chlorophenyl) ethylidene] hydrazinyl}-N-(4-methyl)-3-

oxopropanamide
To a methanolic solution of compound (2), salicyaldehyde and glacial acetic acid were added.
The mixture was stirred for about 10 minutes and then refluxed for 5 hours and contents were
left overnight. The colored solid was filtrated and re-crystallized twice from hot ethanol.
(Scheme 3)

Yield: 75-90%; melting point- 220- 260oC, IR (KBr) Cm-1: 3073, 2960, 1686, 1652, 1606,
and 1404 (m), 1HNMR (): 2.2, 2.52-2.54, 3.7-3.8, 6.8-6.9, 7.4-7.9, 10 and 11.33, max = 344
n.m, ESI MS m/z: 326.2 a.m.u

HO

NH2

H
N NH
O
orthohydroxybenzaldehyde

O O

H3C CH3
malonanilic acid hydrazide O O

N
HC N N
H
HO H
3-{2-[1-(4-
chlorophenyl)ethylidene]hydrazinyl}-N-(4-
methyl)-3-oxopropanamide

Scheme 3: Synthesis of 3-{2-[1-(4-chlorophenyl)ethylidene]hydrazinyl}-N-(4-methyl)-3-

oxopropanamide

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2.5 Synthesis of Ciprofloxacin macrocyclic copper (II) complexes

An aqueous solution of Cu salts (10mMol) was added into ethanolic solution of compound 3
(10mMol) and subsequently an ethanolic solution of ciprofloxacin (10mMol) was added with
continuous stirring. The pH was adjusted in between 4.5-6.0 by addition of diluted
ammonium hydroxide solution. The resulting solution was refluxed for 5 hours and then
heated over a steam bath to evaporate up to half of the volume of the solution. The reaction
mixture was kept overnight at room temperature. A fine brown colored crystalline product
was obtained. The obtained product was washed with ether and dried over vacuum
desiccator. (Scheme 4).

O O
O O
CH3 F
N N HO
HC H N
HO H
+ N N + CuX2.2H2O
NH

3- hydrazinyl-N-(4- Ciprofloxacin
methyl phenyl)-3-
oxopropanamide Template
Synthesis Methanol, Reflux 6-8 hrs

CH3
OH2
O O

HN C O O
C
Cu 2X
HN O N
N
HC
OH2 N
OH
NH

Where X= Cl, NO3, SO4

Scheme-4: Synthesis of ciprofloxacin macrocyclic copper (II) complexes.

3. IN-VITRO ANTIBACTERIAL ACTIVITY

The synthesized ligands and corresponding copper (II) complexes were screened in vitro for
their antibacterial activity against two Gram- negative bacteria (Escherichia Coli &
Pseudomonas auruginosa) & two Gram- positive bacteria (Bacillus subtilis, Staphylococcus
aureus) bacterial strains using Muller-Hinton agar media.[15] The sterilized (autoclaved at
1210C) for 15 minutes) at (40-500C) temperature was poured into petriplates to give a depth
of 3-4mm and allowed to solidify. The suspension of the microorganism streaked on plates.
The paper discs were placed on the solidified medium. The plates were incubated for 1 hour
at room temperature and incubated at 370C for 24 hrs.[16]

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4. INVITRO ANTIOXIDANT ACTIVITY

A solution of hydrogen peroxide (40 mm) was prepared in phosphate buffer (pH 7.4).
Samples of ligand and copper complexes in distilled water were added to a hydrogen
peroxide solution (0.6 ml, 40mm). Absorbance of hydrogen peroxide at 230 nm was
determined 10 minutes later against a blank solution containing the phosphate buffer without
hydrogen peroxide. Ascorbic acid used as a standard in evaluation of antioxidant activity of
samples. The % of hydrogen peroxide scavenging by compounds was calculated as follows:
% Scavenged [H2O2] = AC-ASX100/ AC
Where AC is the absorbance of control & AS is the absorbance in the presence of the copper
samples.[17-18]

5. RESULT AND DISCUSSION

All the copper chelates of ciprofloxacin antibiotics are brown colored. All of them are stable
towards the air and moisture. They decompose at higher temperature. Ligands and copper
chelates are soluble in common organic solvents like DMSO, DMF, Ethanol, Methanol, but
insoluble in water. The analytical data (table 1) of ligand and copper complexes showed that
all copper chelates have 1:2 copper to ligand stoichiometry. Molar conductance values of
copper complexes in 10 -3 M DMF solution at room temperature suggested their non-
electrolytic nature. The tests of the anions were negative for copper complexes indicating
their presence outside the coordination sphere. The analytical data revealed that the copper
complexes have general formula [Cu (C34H39FN6 O8) (H2O)2]X2 Where X= Cl, NO3 & SO4
ions.

Infrared Spectral Studies: The infrared spectra of fluoroquinolones are quite complex due
to the presence of the numerous functional groups in the molecules, therefore their
interpretation is based on the most typical vibrations being the most important region in the
IR spectra of fluoroquinolones between 1800 Cm-1 and 1300 Cm-1. The IR of ligands
shows a band in the region 3073, 2960, 1686, 1652, 1606, 1440 (m), 1725-1730 and 1248-
1254 Cm-1 assignable to the COOH group. Spectra of ligands reveals that a broad band in the
region 3420-3460 Cm-1 due to stretching vibration of OH group. The (C=O) stretching
vibration band appears at 1708 Cm-1 in the spectra of ciprofloxacin and the complex show
this band at 1628 Cm-1; this band shifted towards lower energy, suggesting that
coordination occurs through the pyridone oxygen atom. The strong absorption bands obtained
at 1624 and 1382 Cm-1 in ciprofloxacin were observed at 1572-1584 and 1346-1376
cm-1 in its copper complexes, respectively.

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Table 1: Analytical and physical characterization of synthesized compounds

Molar
Molecular Melting
S.N. Molecular Formula Color Yield conductance %C %H %N % Cu
Weight Point
(-1Cm-1mol-1)
Reddis
C12H15NO3 50.16 4.89
1 221 h 63.5% 80oC 2.1 3.75 (3.86) 7.45 (7.60)
(L1) (50.21) (5.02)
White
C9H12N3O2
50.40 4.87
2 (L2) 122 White 65% 175oC 2.2 3.74 (3.88) 6.96 (7.06)
(50.53) (5.05)
C17H17N3O3 50.42 5.86
3 311 White 53.9% 178oC 2.3 3.78 (3.88) 6.98(7.08)
(L3) (50.46) (5.06)
51.6 5.90
4 [Cu(C34H39FN6O8) (H2O)2]Cl2 777 Green 58% 198oC 2.5 3.72 (3.70) 7.46 (7.5)
(51.4) (5.1)
[Cu(C34H39FN6O8) 50.78 6.1
5 839 Brown 62% 210 oC 2.3 3.74 (3.73) 7.49 (7.45)
(H2O)2]NO3 (51.0) (5.98)
[Cu(C34H39FN6O8) 52.1 5.7
6 873 White 65% 218 oC 2.1 3.79 (3.77) 7.40 (7.39)
(H2O)2]SO4 (51.9) (5.65)

The IR spectra of the coumarin derivatives shows 1614 Cm-1 and 1746 Cm-1 bands corresponding to , unsaturated ketone and lactone
carbonyl ketone respectively. On the complexation these peaks shifted to a lower frequency 1600 Cm -1 and 1738 Cm-1 due to complex
formation. In Cu (II) complex, a new band appeared in the region 536-548 Cm-1, which is probably due to the formation of the weak band
observed in the 432-456 Cm-1 range can be attributed to frequency for (M-O).

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H1-NMR Spectra
The 1HNMR spectra of the ligands and their macrocyclic Cu (II) complexes in DMSO-d6
exhibit a multiplet at 7.1- 7.4 assigned to C6H5- and at 2.7, which can be attributed to the -
CH2 group. The peak in the down field region at 10.7- 11.2 in the spectra of the ligand can
be assigned to the proton of the OH group. Comparison of chemical shift of the
uncomplexed ligand with their Cu (II) complex showed that all the signals are in the expected
range except for that of the OH group. The absence of this signal suggested the deprotonation
of the hydroxyl group and the involvement of the oxygen atoms in complexation. The
1
HNMR spectrum of Cu (II) complexes of ciprofloxacin shows signals corresponding to
CH3, -NH2, NH (hydrozone) and at 2.28 (5, 3H), 7.40- 7.48 (m, 3H), 8.059-8.38 (2H), and
10.09 (5, 1H), 9.0593 (aldehydic proton) 11.1205 (carboxylic proton), 8.95-8.21 (Aromatic
proton), 7.641- 7.36 (pyridone proton), 3.83 (aryl amine), 2.50 (acidic proton). The electronic
spectra of the copper complexes are compared with those of the ligands, two bands appeared
at 270-275 nm and 310-315 nm which can be assigned to * and n * transition,
respectively in ligand. The complex of Cu (II) shows less intense bands in the region 560-
640 nm, which can be assigned to d-d transition of Cu (II) ions. The Cu (II) complexes
display these prominent bands. Low intensity broad band in the region 16800- 17910 Cm-1
was assigned as 10 Dq band corresponding to 2 Eg 2T2g transition.[24] In addition, these
were a high intensity band in the region 22900-27200 Cm-1. This band is due to symmetry
forbidden ligand metal charge transfer transition.[25] Therefore distorted octahedral
geometry around Cu (II) ion was suggested on the basis of electronic spectra.[26]

Antimicrobial Bioassay
The ligands and their Cu complexes were screened for their antibacterial activities according
to the respective literature protocol[27] and the results obtained as represented in table 2. The
results were compared with those of the standard drug, streptomycin. Cu complexes were
more potent bactericidal than the ligands. The increased activity of Cu (II) complexes can be
explained on the basis of chelation theory.[28] On chelation the polarity of the Cu ion is
reduced largely due to the overlap of the ligand orbital and the partial sharing of the positive
charge of the Cu ion with the donor group.[29]

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Table 2: Antibacterial activity of ligands and their macrocyclic copper complexes

Ligand/
S.N. Zone of inhibition in (mm) after 24 hr
Compounds
E.coli B. Subtilis S. aureus P.aurogenosa
1 L1 20 15 10 16
2 L2 22 15 11 17
3 L3 26 22 21 10
4 [Cu(C34H39FN6O8) (H2O)2]Cl2 20 15 10 12
5 [Cu(C34H39FN6O8) (H2O)2]NO3 36 32 34 10
6 [Cu(C34H39FN6O8) (H2O)2]SO4 30 31 34 13
Streptomycin
7 38 33 32 20
(Standard)
Antioxidant activity
Schiff base ligands and their transition metal complexes have been suggested as promising
agents for the diagnosis and treatment of different disease. All the newly synthesized ligands
and Cu complex were tested for their radical scavenging activity (RSA) using H2O2. The
results were compared with the standard compound ascorbic acid (30, 31) in table 3.

Table 3- Invitro antioxidant activity of ligands and their copper (II) complexes
S.N. Ligand/ Percentage Radical Scavenging activity (RSA) of ligands and
Compounds their macrocyclic Cu(II) complexes
200 g/ml 400 g/ml 600 g/ml 800 g/ml 1000 g/ml
1 L1 24.26 62.84 68.80 70.1 72.2
2 L2 24.22 60.24 68.82 69.1 69.9
3 L3 70.4 69.71 68.80 68.9 70.3
4 [Cu(C34H39FN6O8) (H2O)2]Cl2 74.02 73.01 74.02 74.04 74.9

5 [Cu(C34H39FN6O8) (H2O)2]NO3 76.24 76.26 76.9 77.1 77.9

6 [Cu(C34H39FN6O8) (H2O)2]SO4 77.1 77.9 78.1 78.6 79
7 Ascorbic Acid 81 81.2 81.5 82.2 83
(Standard)
The RSA of all copper complexes may be due to the presence of NH groups and thio group
which may donate an electron or hydrogen atom to hydrogen peroxide and form a stable free
radical. This radical can be stabilized by delocalization. This fact confirm their good electron
and a hydrogen atom donating ability and to act as radical scavenger. However none of the
compounds exhibited radical scavenging activity better than the standard ascorbic acid. All
these compounds showed significant free radicals at different concentrations 200g/ml,
400g/ml, 600g/ml, 800g/ml, 1000g/ml. In this investigation, ascorbic acid is used as a
standard compound.

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6. CONCLUSION
This paper presents Synthesis, Spectroscopic characterization and biological evaluation of
ciprofloxacin macrocyclic copper (II) complexes derived from carbohydrazone,
thiosemicarbazide and Cu (II) salts. All these compounds were characterized in detail by FT-
IR, H1NMR, LCMS and electronic spectra. The geometry of all copper complexes was
distorted octahedral in nature which is confirmed by the electronic spectra. The determined
Invitro antibacterial activities indicate that the copper chelates of ciprofloxacin antibiotic
show a greater inhibitory effect than the parent ligands. It is also concluded that concentration
plays a important role in increasing degree of inhibition, as the concentration increases, the
antibacterial activity also increases. Analysis of invitro antioxidant activity results revealed
that all compounds exhibited good radical scavenging activity. More detailed studies are
needed to understand the mechanism of action at the cellular level and the role of various
metal ions in the treatment of diseases in human.

ACKNOWLEDGEMENT
The authors are thankful to the chancellor, ITM University, Gwalior for providing laboratory
facilities and to the Director of sophisticated analytical instrumentations facility, Chandigarh
for providing spectral data. Richa Kothari is thankful to MPCST, Bhopal (Council order No.
4566/ CST/R & D/2010) for providing financial support through research fellowship in
science.

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