1.

Introduction
2. Imidazothiazole derivatives
3. Chalcone derivatives
4. Imidazothiazole--chalcone
conjugates
5. Expert opinion
Review
The design and development
of imidazothiazole--chalcone
derivatives as potential
anticancer drugs
Ahmed Kamal

, Methuku Kashi Reddy & Arutla Viswanath

CSIR -- Indian Institute of Chemical Technology, Division of Organic Chemistry,
Hyderabad, India
Introduction: Imidazothiazole derivatives have long been therapeutically
used for the treatment of various diseases. In recent years, the imidazothia-
zole and chalcone moieties have emerged as important pharmacophores in
the development of antitumor agents. Imidazothiazole--chalcone conjugates
can be accessed by covalently binding these two powerful pharamacophore
units. These conjugates are known to exhibit a wide range of biological
properties, including anticancer, antimicrobial, anti-inflammatory and
immunosuppressive activities. Their promising biological profile and easy syn-
thetic accessibility have triggered investigations directed at the design and
development of new imidazothiazole--chalcone conjugate derivatives as
potential chemotherapeutics.
Areas covered: The present review focuses on recent reports of the syntheses
and anticancer properties of various imidazothiazoles, chalcones and
imidazothiazole-linked chalcone conjugates. Furthermore, the authors discuss
the structure--activity relationships (SAR) of imidazothiazoles and chalcones
and their conjugates as new antitumor agents, as well as in vitro and in vivo
evaluation, clinical use and their future therapeutic applications.
Expert opinion: A large number of imidazothiazoles, chalcones and a new
series of imidazothiazole--chalcone conjugates possess potent anticancer activ-
ity that could be further developed as drug candidates. Imidazothiazole-based
conjugates could also display synergistic effect, and still there is a need to use
the drug combinations permitting lower dose and development of new
generation of drugs. Despite encouraging observed results for their response
to tumors in clinical studies, full characterization of their toxicity is further
required for their clinical usage as safe drugs for the treatment of cancer.
Keywords: anticancer activity, chalcones and imidazothiazole--chalcone conjugates and
chemotherapeutic agents, imidazothiazoles
Expert Opin. Drug Discov. (2013) 8(3):289-304
1. Introduction
Despite decades of continual effort, cancer is a leading cause of death worldwide,
claiming more than 20% of affected patients annually [1]. The Roll Back Cancer ini-
tiative, recently established by WHO, aims to combat the disease through effective
global partnership and cooperation. It is estimated that there will be more than
13 million deaths caused by cancer around the world in 2030 [2]. The past century
has demonstrated that cancer can be effectively treated with surgery, chemotherapy
and radiotherapy. These treatment strategies, when used either alone or in combina-
tion, can significantly impact tumor growth and even produce cures. For many solid
tumors, as in colon cancer, improved methods for early diagnosis and combination
10.1517/17460441.2013.758630 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X 289
All rights reserved: reproduction in whole or in part not permitted
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therapies have had an important impact on survival rate.
However, once the tumor has metastasized, treatment
becomes more complicated. Even in such cases, current treat-
ment strategies can relegate cancer to more of a chronic dis-
ease. Still, significant challenges remain for specific cancer
types, such as glioblastoma, in which a combination of early
detection, surgery, chemotherapy and radiotherapy cannot
extend the survival for more than couple of years [3].
Currently, combination chemotherapy with drugs of
different mechanisms of action is one of the methods that is
adopted to treat cancer. Alternatively, a single drug which
incorporates two pharmacophores with different modes of
action may be employed for treatment. In recent years there
has been growing interest in the design of ligands that could
act in a specific manner on more than one target. The devel-
opment of such hybrid molecules not only lowers the risk of
drug--drug interaction in comparison to cocktails but also
could enhance the efficacy as well as improve the safety aspects
in relation to the drugs that interact on a single target [4-6] and
one such example is of bleomycin [7].
2. Imidazothiazole derivatives
The chemistry as well as the biological activity of imidazo
[2,1-b]thiazoles and their derivatives has recently attracted
considerable attention. The imidazo[2,1-b]thiazole system
constitutes the core unit of the well-known antihelminthic
and immunomodulatory agent levamisole which is 2,3,5,6-
tetrahydro-6-phenylimidazo[2,1-b]thiazole [8]. Levamisole
(marketed as the hydrochloride salt under the trade name
Ergamisol

) is an antihelminthic and immunomodulator

belonging to a class of synthetic imidazothiazole derivatives,
discovered at Janssen Pharmaceutica in 1966. Levamisole has
been used in humans to treat parasitic worm infections and
has been studied in combination with other forms of
chemotherapy for colon cancer, melanoma and head and
neck cancer [9,10].
Andreani et al. studied a series of imidazo[2,1-b]thiazole
and benzimidazo[2,1-b]thiazole guanyl hydrazones that are
active against various cancer cell lines. Besides, imidazo
[2,1-b]thiazoles are well-known compounds and many deriv-
atives of this fused ring system have been evaluated for poten-
tial biological activity. The 6-substituted imidazothiazole and
benzimidazothiazole guanylhydrazones (1) have been reported
to exhibit an antiproliferative effect on the cell cycle, apoptosis
and mitochondria [11]. Moreover, 3-(5-imidazo[2,1-b]thiazo-
lylmethylene)-2-indolinones (2) are potent antitumor agents
and their ability to inhibit cellular proliferation was mediated
by cell cycle arrest at the G2/M phase, accompanied by inhi-
bition of ornithine decarboxylase (ODC), the limiting
enzyme of polyamine synthesis, and followed by induction
of apoptosis [12]. The effect of the guanyl hydrazone
of 2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]-
thiazole-5-carbaldehyde (3) was investigated, and it was found
to be an inhibitor of Complex III of the mitochondrial respi-
ratory chain and could induce apoptosis in the cell lines
HT29 and HL60 [13]. Later the same group reported a series
of imidazothiazole guanylhydrazones by varying the substitu-
tions on the thiazole ring of the imidazothiazole skeleton. The
antiproliferative effect of compound 4 was associated with a
Article highlights.
.
The advantage of conjugates/hybrids derived from two
or more pharmacophore moieties over conventional
approaches in cancer chemotherapy are highlighted. The
recent reports on imidazothiazoles, chalcones and
imidazothiazole--chalcone conjugates as potential
anticancer agents are described.
.
Imidazothiazoles are well-known compounds and many
derivatives of this fused ring system have been
evaluated for potential biological activity particularly for
antitumor activity. Moreover, structurally modified
imidazothiazole scaffold is an important core unit of
well-known antihelminthic and
immunomodulatory agents.
. Chalcone constitute an important building block for a
large number of clinical drugs that possess a variety of
biological activities, including anticancer, anti-
inflammatory, immunomodulatory and antibacterial
activities. In addition they also exhibit antiprotozoan,
trypanocidal, leishmanicidal, antimalarial activities and
modulation of P-gp-mediated multidrug resistance.
Chalcone-based analogues are the most effective
compounds exhibiting tubulin-binding activity in human
breast, ovarian and gastric cancer HGC-27 cell lines and
also show considerable antiproliferative effects.
. Biaryl-based chalcones synthesized by sequential
Knoevenagel reaction and microwave-assisted Suzuki
coupling showed good anticancer and NF-kB nuclear
translocation inhibition activities. Anticancer activities of
chalcone-based compounds may be a result of its
inhibitory activities against the NF-kB signaling pathways.
. It focuses on the structural modifications of the
imidazothiazoles and chalcones, including the design
and synthesis of imidazothiazole--chalcone conjugates as
antitumor agents. SAR of imidazothiazoles, chalcones
and their conjugates their in vitro and in vivo screening
results and their future therapeutic applications
are discussed.
.
Imidazothiazole--chalcone conjugates were accessible via
Claisen--Schmidt condensation of appropriately
substituted acetophenones by treatment with
imidazothiazole aldehydes in basic media. All the
conjugates showed significant anticancer activity and
G0/G1-phase cell cycle arrest, downregulation of
G1-phase cell cycle regulatory proteins, such as cyclin D1
and cyclin E1, and upregulation of CDK4. Moreover,
these compounds elicit the characteristic features of
apoptosis such as enhancement in the levels of p53,
p21 and p27, suppression of NF-kB and upregulation
of caspase-9.
. Future applications and scope of such imidazothiazoles,
chalcones and imidazothiazole--chalcone conjugates
toward the treatment and prevention of cancer are
brought out.
This box summarizes key points contained in the article.
A. Kamal et al.
290 Expert Opin. Drug Discov. (2013) 8(3)
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block in cell cycle progression, with accumulation of cells in
the G2/M phase and with a marked reduction in the mito-
chondrial transmembrane potential DY
m
and a decrease in
the intracellular ATP content [14]. However, the most active
compound (5) of this series follows a different mechanism
which is not known. A series of 6-nitrophenyl-substituted
imidazothiazole guanylhydrazone derivatives have also been
examined for the anticancer activity. Compounds 6, 7 and 8
exhibited significant antitumor activity; however, compound 8
showed cytotoxicity by acting as a CDK-1 inhibitor [10].
Among the synthesized compounds 9, 10 and 11 have also
showed significant growth inhibition against a broad range
of cancer cell lines and the cytotoxicity of these compounds
is associated with early damage to mitochondria (Figure 1).
Recently a new series of substituted 3-(5-imidazo[2,1-b]-
thiazolylmethylene)-2-indolinones have been reported as anti-
cancer agents. Among these, compounds 12, 13 and 14 exhibit
growth inhibition in submicromolar range [15]. Mechanistic
studies of these compounds revealed that the tubulin effects
were relatively modest and the apoptosis in the HT-29 cells
was accompanied by caspase activation and phosphatidylserine
externalization. Interestingly, the most potent compounds 15
and 16 strongly inhibited the activation of the kinase Akt
and also exhibited prominent anticancer activity. Further
mechanistic studies in colon adenocarcinoma (HT-29) cell
line revealed that these compounds are capable of blocking
cells in M phase without interfering with microtubule
dynamics (Figure 2) [16,17].
Buttar et al. [18] examined a series of imidazole--
vinyl--pyrimidine derivatives as anticancer agents. In
phospho-Tie-2 cell-based ELISA assay, compounds 17
and 18 exhibited IC
50
of 2.9 and 0.33 M, respectively.
Compound 17 showed reasonable selectivity in a large panel
of kinase assays, only inhibiting three other enzymes with an
IC
50
of < 10 M (p38, 1.6 M; Flt-4, 5.5 M; KDR,
7.0 M). In contrast to Tie-2, this compound (17) was inac-
tive in vascular endothelial growth factor receptors (VEGFr)
and p38 cellular assays and showed better oral exposure in a
mouse cassette dosing experiment (C
max
= 0.29 M following
a 1 mg/kg dose). Park et al. demonstrated the synthesis and
anticancer activity of a series of imidazo[2,1-b]thiazole deriv-
atives. Their in vitro antiproliferative activities against A375P
human melanoma cell line and NCI-60 cell line panel were
tested. Compounds 19, 20 and 21 showed superior activity
than sorafenib against A375P cell line [19]. Among them,
compounds 20 and 21 exhibited selectivity toward melanoma
cell lines than for other cancer types (Figure 3).
Recently, a series of 3-substituted 2-phenylimidazo[2,1-b]
benzothiazoles (22a -- h) [20] have been synthesized by
C-arylation of 2-arylimidazo-[2,1-b]benzothiazoles using
palladium acetate as catalyst in this laboratory, and the result-
ing compounds were evaluated for their anticancer activity.
Compounds 22a, 22e and 22h exhibited good antiproliferative
activity, with GI
50
values in the range of 0.19 -- 83.1 M.
Compound 22h showed potent anticancer efficacy against
60 human cancer cell lines, with a mean GI
50
value of
0.88 M. This compound also induced cell cycle arrest in
the G2/M phase and inhibited tubulin polymerization
followed by activation of caspase-3 and apoptosis. A high-
throughput tubulin polymerization assay showed that the
level of inhibition for compound 22h is similar to that of
combretastatin A-4 (CA-4). Molecular modeling studies also
supported a favorable binding of compounds 22a, 22e
and 22h to the colchicine-binding pocket of tubulin (Figure 4).
3. Chalcone derivatives
Chalcone scaffolds, such as 1,3-diaryl-2-propen-1-ones, are
prominent secondary metabolite precursors of flavonoids
and isoflavonoids in plants [21]. Structurally, they may be con-
sidered as open-chain flavonoids in which the two aromatic
rings are joined by a three-carbon a,b-unsaturated carbonyl
system. Chalcones (23) are easily synthesized by the (E)-selective
condensation reaction of acetophenones with substituted
benzaldehydes. They display a broad spectrum of pharmaco-
logical effects that include anticancer [22-26], anti-inflamma-
tory [27,28], immunomodulatory [29,30] and antibacterial [31,32]
activities; in addition they also exhibit antiprotozoan [33],
trypanocidal [34], leishmanicidal [35], antimalarial [36,37]
activities and modulation of P-glycoprotein (P-gp)-mediated
multidrug resistance [38]. Many chalcone-based compounds
have shown promising anticancer therapeutic efficacy for the
management of human cancers. Different research groups
have synthesized various chalcone derivatives and screened
them for their in vitro anticancer activity against a number
of cancer cell lines. Changes in their structure have offered a
high degree of diversity that has proven useful for the develop-
ment of new medicinal agents having improved potency and
lesser toxicity.
Introduction of various substituents into the two aryl
rings is also a subject of interest because it provides useful
structure--activity relationship (SAR) conclusions that help
in preparing pharmacologically active chalcones. Many such
substituted chalcones have shown potent anticancer activities.
Lawrence et al. and Ducki et al. have reported the synthesis of
trimethoxy-substituted chalcones [39,40] 24 and 25, that possess
potent anticancer activity and bind strongly to tubulin at a site
shared with, or close to, the colchicine-binding site [41,42]. The
anticancer activity and tubulin binding property of these chal-
cones is comparable with CA-4. The IC
50
value of compound
SD400 (3) against the K562 human chronic myelogenous
leukemia cell line is 0.21 nM, whereas CA-4 shows the IC
50
to be 2.0 nM. Compound 24 inhibits cell growth at low con-
centrations (IC
50
, P388 murine leukemia cell line 2.6 nM)
and shares many structural features common to other
tubulin-binding agents [43]. Interestingly a-methyl chalcone
(25) is more cytotoxic than compound 24, which bears a
hydrogen atom at the same site [44]. Presently, phosphate
prodrugs of compounds 24 and 25 are under preclinical
evaluation as shown in Figure 5.
Design and development of imidazothiazole--chalcone derivatives as potential anticancer drugs
Expert Opin. Drug Discov. (2013) 8(3) 291
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The anticancer activity of chalcones is believed to be a
result of their binding to tubulin and preventing it from
polymerizing into microtubules. Tubulin is a protein that
exists as a heterodimer of two homologous a- and b-subunits.
Many molecules based on a chalcone scaffold have been syn-
thesized to improve their biological profile, including their
capability as sequence selective DNA interactive and cross-
linking agents. However, trihydroxychalcone (26) represents
1 3 2 4
5 7 6
9 11 10
8
N
N
H N
N
N
HN
S
OCH
3
NO
2 Cl
H
3
CO
N
N S
H
N
OCH
3
H
3
CO
O
N
N
N
HN
S
NH
2
OCH
3
OCH
3
NH
N
N
N
HN
S
NH
2
NO
2
Cl
H
3
C CH
3
NH
N
N
N
N
HN
S
NO
2
NH
2
Cl
H
3
C
NH
N
N
N
HN
S
NO
2
NH
2
Cl
NH
N
N
N
HN
S
NH
2
NO
2
O
2
N
NH
N
N
N
HN
S
NH
2
NO
2
NH
N
N
N
HN
S
NH
2
NO
2
Cl
NH
N
N
N S
HN
NH
2
OCH
3
NO
2
Cl
H
3
CO
NH
N
N
N N S
HN
NH
2
H
3
C
H
3
C
NH
Figure 1. Recent advances on structural modifications of imidazothiazoles and their derivatives.
12
15 16
13 14
H
N
O
N
N S
CH
3 H
3
C
H
3
CO
H
N
O
N
N
N S
H
3
CO
OCH
3
H
N
O
N
N S
H
N
O
N
N S
CH
3
H
3
C
Cl
H
N
O
HO
N
N
S
CH
3
H
3
C
Figure 2. Chemical structures of antitumor imidazothiazole derivatives.
A. Kamal et al.
292 Expert Opin. Drug Discov. (2013) 8(3)
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a new class of tyrosinase inhibitors [45]. Some of the natural
chalcones are found in a variety of plant sources. These natu-
ral compounds have served as valuable leads for further design
and synthesis of more active analogues. Further, a variety of
trimethoxy acetophenone-derived chalcones (27 -- 30) have
been synthesized by different groups and evaluated for their
cytotoxicity [46-49]. These compounds show promising activity
against different cancer cell lines (Figure 6).
Natural and synthetic chalcones have shown to possess
strong antiproliferative effects in both primary and established
ovarian cancer cells [50] and in gastric cancer HGC-27 cells [51].
The majority of the naturally occurring chalcones contain
either hydroxyl (-OH) or methoxy (-OCH
3
) substituents in
both the aromatic rings [52]. Naturally occurring licochalcone
A (31), a chalcone derivative found in the licorice root, has
been associated with a wide variety of anticancer effects.
Recent studies have shown that these chalcones induce apo-
ptosis in a variety of cell types, including breast cancers [53,54].
Xanthohumol (32) is the most abundant prenylated chalcone
in hop cones (Humulus lupulus L) and exhibits an interesting
spectrum of pharmacological effects. Besides its remarkable
antiproliferative activity against different cancer cell lines [55],
xanthohumol also exhibits apoptotic [56] activity as well as
chemopreventive effects [57,58]. Furthermore, several in vitro
studies substantiated effects on enzymes and transcription fac-
tors that are involved in the genesis of cancer [59,60]. Isoliquir-
itigenin (33) demonstrated significant chemopreventive
activities against lung, breast, prostate and colorectal can-
cers [61]. Flavokawain A (34) suppresses bladder tumor growth
at a dose of 50 mg/kg of body weight in a mouse xenograft
model (Figure 7) [44].
Kumar et al. [62] have synthesized and reported indolyl chal-
cones (35) that are very potent and selective anticancer agents
with IC
50
values 0.03 and 0.09 M, against PaCa-2 cell line.
Lawrence et al. [63] reported a new chalcone derivative (36)
which possesses good anticancer activity (Figure 8).
Curcumin, a polyphenolic natural compound (37) derived
from dietary spice turmeric, possesses diverse pharmacological
effects, including anticancer, anti-inflammatory, antioxidant
and antiangiogenic activities [64,65]. A series of chalcone
dimers has been reported as potent inhibitors of various
cancer cells at very low concentrations. Compound 3,5-bis
(2-fluorobenzylidene)-4-piperidone (38, also known as
EF24) is the first synthetic analog of curcumin [66]. Other
analogues, 3,5-bis(benzylidene)-4-piperidones (39, also
known as CLEFMA and compound 40) [67] have been
advanced as synthetic analogs of curcumin with anticancer
and anti-inflammatory properties (Figure 9).
The cyclic chalcone analogues, E-2-arylmethylene-1-inda-
nones, E-2-arylmethylene-1-tetralones and E-2-arylmethy-
lene-1-benzosuberones have been synthesized and their
cytotoxicities determined against different cancer cell lines.
Among these cyclic chalcones, compounds 41a, 41b, 42a
and 42b have shown potential anticancer activity against
human cancer cell lines. These compounds inhibit RNA and
17
20 21
18 19
N
N
N
N S
NH
2
N
N
N
N S
NH
2
O
N
H
H
N
N
N
N
N
S
HO
O
N
H
H
N
N
N
N
N
S
OH
HO
O
N
N
N
H
N
N
H
H
N
N
S
CF
3
H
3
CO
Figure 3. Structures of imidazothiazole conjugates.
S
N
N
R
H
3
CO
22 a h
22a R = 4-hydroxy-3-methoxy benzyl
22b R = 2,4-dimethoxy benzyl
22c R = 2,6-dimethoxy benzyl
22d R = 3,4,5-trimethoxy benzyl
22e R = 3 thiophenyl
22f R = 3 pyridinyl
22g R = 3 pyrazinyl
22h R = 3 naphthyl
Figure 4. Biologically active 3-substituted-2-phenylimidazo
[2,1-b]benzothiazoles.
Design and development of imidazothiazole--chalcone derivatives as potential anticancer drugs
Expert Opin. Drug Discov. (2013) 8(3) 293
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protein syntheses and induced apoptosis which are likely
major mechanisms whereby cytotoxicity is mediated [68].
The active compound 41b in these cyclic chalcones affects
the mitochondrial function as well as causes mitochondrial
DNA damage. Compound 42b also shows good activity in
targeting Alzheimers disease by inhibition of AChE-induced
Ab aggregation (Figure 10) [69].
Valdameri et al. [38] have synthesized a series of chalcone
derivatives (43 -- 46) that play a major role in anticancer-
drug efflux and related tumor multidrug resistance. Potent
O
A B
23 Basic chalcone scaffold 25 SD400 24
O
A B
H
3
CO
H
3
CO
OCH
3
OCH
3
OH
O
A
B
H
3
CO
H
3
CO
OCH
3
OCH
3
OH
Figure 5. Structures of potential anticancer chalcones.
27 28 26
HO
OCH
3
OH
OH
O
H
3
CO
H
3
CO
OCH
3
OH
O
H
3
CO
H
3
CO
NO
2
OCH
3
O
30 29
H
3
CO
H
3
CO
OCH
3
OCH
3
B(OH)
2
O
H
3
CO
H
3
CO
OCH
3
OCH
3
O
Figure 6. Some chemical structures of trimethoxy acetophenone-derived chalcones.
O
OH
OH HO
O
OH HO H
3
CO
O
OH HO OCH
3
O OH
H
3
CO OCH
3
OCH
3
31 Licochalcone A
33 Isoliquiritigenin
34 Flavokawain A
32 Xanthohumol
Figure 7. Chemical structures of naturally occurring chalcones with apoptosis-inducing ability.
O
N
OCH
3
OCH
3
O
OCH
3
OCH
3
OCH
3
N
H
36 MDL 35
Figure 8. Structures of anticancer chalcones.
A. Kamal et al.
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and selective breast cancer resistance protein (BCRP) inhibi-
tors (ATP-binding cassette sub-family G member 2,
ABCG2) with low cytotoxicity were investigated among a
library of chalcones derivatives (1,3-diarylpropenones), by
evaluating their inhibitory effect on the transport of mitoxan-
trone, a known ABCG2 substrate. Six compounds producing
complete inhibition with IC
50
values < 0.5 M and high
selectivity for ABCG2 were identified. The number and posi-
tion of methoxy substituents appeared to be critical for both
ABCG2 inhibition and cytotoxicity. The best compounds,
with potent inhibition and low toxicity, contained an N-
methyl-1-indolyl (44) or a 6-hydroxyl-2,4-dimethoxy-
1-phenyl (43) moiety (A-ring) possessing two methoxy groups
at positions 2 and 6 of the 3-phenyl moiety (B-ring). Methoxy
substitution contributed to inhibition at positions 3 and 5,
but had a negative effect at position 4, and where as 3,4,5-
tri methoxy substitution on the B-ring markedly increased
cytotoxicity and hence, not preferable (Figure 11).
Juvale et al. [70] have synthesized chalcones (47 -- 49) and
benzochalcones with different substituents (such as OH,
OCH
3
, Cl) on ring A and B of the chalcone structure. All
synthesized compounds were tested by Hoechst 33342
accumulation assay to determine inhibitory activity in
MCF-7 MX and MDCK cells expressing BCRP. The com-
pounds were also screened for their P-gp and multidrug
resistance-associated protein 1 inhibitory activity in the cal-
cein AM accumulation assay and were found to be selective
toward inhibition of BCRP. Substituents at position 2 and
4 on chalcone ring A were found to be essential for activity;
additionally there was a great influence of substituents on
ring B. Presence of 3,4-dimethoxy substitution on ring B
was found to be optimal, while presence of 2- and 4-chloro
substitution also showed a positive effect on BCRP inhibition.
BCRP/ABCG2 belongs to the ATP-binding cassette family of
transport proteins. BCRP has been found to confer multidrug
resistance in cancer cells. The development of potent and spe-
cific BCRP inhibitors is important as a strategy to overcome
resistance due to BCRP overexpression (Figure 12).
Zuo et al. [71] have synthesized a series of biaryl-based
chalcones that were designed as a combination of the natural
chalcone and biphenyl moieties, by sequential Knoevenagel
reaction and microwave-assisted Suzuki coupling. Sulforhod-
amine B assay was performed to evaluate the cell viability
inhibitory abilities of these compounds against five cancer
cell lines (A549, CNE2, SW480, MCF-7 and HepG2) from
different tissues. Their nuclear factor-kB (NF-kB) nuclear
translocation inhibitory activities were further investigated
by high content analysis-based assay. Most of the compounds
showed moderate-to-strong anticancer and NF-kB nuclear
translocation inhibition activities. Compounds 50 and 51
exhibit potent inhibitory activities toward CNE2 cell growth
with some extent of selectivity to other cell lines, suggesting
that these compounds (50 and 51) could serve as leads for
novel anti-NPC drug discovery. Furthermore, several
compounds, such as 52, 53, 54 and 55, were found to be
potent leads against different cancer cell lines (Figure 13).
Mielcke et al. [72] have synthesized quinoxaline-derived
chalcones and evaluated their anticancer activity against
human glioma cell lines. Eight synthetic quinoxaline-derived
O Cl Cl
O
O
N
OH
O
N
H
F F
O OH
OCH
3
HO
H
3
CO
OH
O
OCH
3
CH
3
H
3
CO
N HO OH
37 Curcumin
39 CLEFMA 40
38 EF24
Figure 9. Structures of potential anticancer bischalcones.
41a
42a 42b
41b
O
OCH
3
O
CH
3
N
O
O
NO
2
Figure 10. Structures of potent anticancer cyclic chalcones.
Design and development of imidazothiazole--chalcone derivatives as potential anticancer drugs
Expert Opin. Drug Discov. (2013) 8(3) 295
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chalcones, structurally based on the selective PI3Kg inhibitor
AS605240, were evaluated for antiproliferative activity and
viability inhibition using glioma cell lines of human and rat
origin (U-138 MG and C6, respectively), at different concen-
trations and time periods of incubation. The results reveal that
four chalcone derivatives (56a -- d), possessing methoxy groups
on the A ring, inhibited either cell proliferation or viability, in
a time- and concentration-dependent manner, with an efficacy
greater than that seen for the positive control (AS605240).
Flow cytometry analysis demonstrated that incubation of
C6 cells with compound 56b led to G1 phase arrest, indicating
an interference with apoptosis. It is noteworthy that
compound 56b also inhibits Akt activation, allied to the
stimulation of ERK MAP kinase (Figure 14).
Vogel et al. [73] have synthesized and evaluated the cytotox-
icity, antioxidative and anti-inflammatory activity and the
O OH R
2
4
B
6
R
R
A
R
4
6
2
43 R = OCH
3 44 1-Indolyl-3-phenylpropenones
45 3-Indolyl-1-phenylpropenones 46 1,3-Diindolyl-propenones
O
2
6
4
R
1
H
3
C
N
O
H
3
C
H
3
C
N N
O
2
4
6
H
3
C
N
H
3
CO
OH
3
C
Figure 11. Chemical strucutres of the indole chalcones.
O
A
1
6
5
4
3
2
2
3
4
5
B
1
6
O
A
1
6
5
4
3
2
2
3
4
5
B
1
6
47 48
O
A
1
6
5
4
3
2
2
3
4
5
B
1
6
49
Figure 12. Structures of benzo chalcones as breast cancer agents.
F
O
OCH
3
F
H
2
N
O
OH
OCH
3
H
2
N OCH
3
OH
O
F
N
H
2
N
H
3
CO
H
3
CO
OCH
3
OCH
3
O
50
52
F
H
2
N
O
OH
OCH
3
54 55
F
O
OCH
3
OCH
3
51
53
Figure 13. Chemical structures of antitumor biphenyl-based chalcones.
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influence of A-ring modifications on the pharmacological
effect of a new series of chalcones. These chalcones were
designed by the combination of the B-ring fragments of heli-
chrysetin, xanthohumol, xanthohumol C and xanthohumol
H with ferulic or caffeic acid moieties on A ring. Com-
pounds 57 and 58, both Phase II metabolites of xanthohumol
in rats, and compound 59, a related synthetic chalcone,
exhibit cytotoxic activity against HeLa cells with an IC
50
value
of 7.3 0.4 M (Figure 15).
A new class of chalcone hybrids were synthesized by Clai-
sen--Schmidt condensation and tested for their cytotoxic
activity against PC-3 (prostate cancer), HT-29 (colon cancer),
B-16 (mouse macrophages) and NCI-H460 (lung cancer) cell
lines. All the new hybrid chalcones exhibited moderate-to-
excellent selectivity toward PC-3 cell lines [74]. Some of the
compounds, 60a, 60b and 60c (IC
50
= 8.4, 7.9 and 5.9 M),
showed significant activity against PC-3 cell line (Figure 16).
Singh et al. [75] have prepared a series of novel 1,2,3-triazole
tethered b-lactam-chalcone bifunctional hybrids via click
chemistry approach utilizing azide--alkyne cycloaddition
reactions. These triazole derivatives were then evaluated as
anticancer agents against four human cancer cell lines. The
presence of a cyclohexyl substituent at N-1 of b-lactam ring
and methoxy substituents, preferably at ortho position on
ring A and para position on ring B on chalcones markedly
improved the anticancer profiles of the synthesized scaffolds.
The most potent of the test compounds (61a and 61b) exhib-
ited IC
50
values of < 1, 67.1, < 1 and 6.37 M against
A-549 (lung), PC-3 (prostate), THP-1 (leukemia) and
Caco-2 (colon) cell lines, respectively (Figure 17).
NF-kB is a transcription factor that regulates inflammation,
immunity, apoptosis, cell proliferation and differentiation of
the cells after binding to DNA and activating gene transcrip-
tion [76]. NF-kB is a dimer of five possible subunits: RelA
(p65), p50, p52, c-Rel and RelB, and the p65:p50 heterodimer
is the predominant form [77]. NF-kB is bound to an inhibitory
protein (IkB-a) in the cytoplasm, when it is in an inactive
form. Numerous extracellular stimuli, including bacteria,
viruses, inflammatory cytokines, growth factors, ultraviolet
(UV) and oxidative stress cause the phosphorylation of the
inhibitory protein IkB-a by IkB kinase (IKK) and subse-
quently the ubiquitination and degradation of IkB-a by
proteasome to release NF-kB. The released NF-kB migrates
into the nucleus to bind with DNA and activate the trans-
cription of inflammatory and other target genes, including
COX-2, inducible NO synthase, cyclin D1 and Bcl-2 [78].
In cancer treatment, some of the chemotherapeutic drugs
that induce apoptosis lose their activities because they activate
NF-kB to induce cancer cell proliferation, which brings che-
moresistance to cancer cells [79]. NF-kB inhibition can restore
the capability of chemotherapeutic agents to repress cancer
cells inducing apoptosis. IKK inhibitors prevent phosphoryla-
tion of IkB-a, and proteasome inhibitors inhibit degradation
of IkB-a, precluding NF-kB activation. Both are essential
steps for NF-kB activation. Therefore, anticancer activities
of chalcone-based compounds may be a result of its inhibitory
activities against the NF-kB signaling pathways [80]. In fact,
quite a few chalcone-based compounds (62 -- 65) [81-83] have
been reported to inhibit the NF-kB signaling pathway, and
some of them are shown in Figure 18.
In the past few years, the authors research group have
synthesized different types of chalcone conjugates and have
evaluated their biological activity. Among them, chalcone-
linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates
have shown enhanced DNA-binding affinity and promising
anticancer activity on a large number of human cancer cell
lines. Compounds 66a -- c and 67a -- c enhance the CT-
DNA DTm values in the respective ranges of 1.7 -- 8.1

C
and 1.0 -- 9.0

C. Compound 66a has been evaluated for its

in vitro activity against the standard 60 human tumor cell
lines, derived from nine cancer types (leukemia, non-small-
cell lung, colon, CNS, melanoma, ovarian, renal, prostate
and breast cancer). This compound showed good anticancer
potency in a wide spectrum of cell lines with 50% cell growth
inhibition (GI
50
) values ranging from 0.01 to 0.40 M [84].
Combining these two core pharmacophore (chalcones and
DC-81) structures with modifications at A-C8/C-C2-position
of PBD ring system yielded analogues with improved efficacy
which showed promising in vitro anticancer activity ranging
from < 0.1 to 2.92 M. These studies revealed that the triazole
56a 56b
A
OCH
3
O
B A
A A
N
N
56c 56d
O
OCH
3
N
N
OCH
3
B
O
OCH
3
N
N
OCH
3
B
O
N
N
OCH
3
OCH
3
B
Figure 14. Anticancer quinoxaline chalcones.
Design and development of imidazothiazole--chalcone derivatives as potential anticancer drugs
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compound 68d is the most effective member of series and it
has been taken for detailed investigations [85].
A series of novel chalcone-linked imidazolones were
prepared and evaluated for their anticancer activity against a
panel of 53 human tumor cell lines derived from nine differ-
ent cancer types: leukemia, lung, colon, CNS, melanoma,
ovarian, renal, prostate and breast. Some of these hybrids
(69 -- 71) showed good anticancer activity with GI
50
values
ranging from 1.26 to 13.9 M. When breast carcinoma cells
(MCF-7) were treated with 10 M concentration of com-
pounds TMAC, CA-4, 69 and 71, cell cycle arrest was
observed in G2/M phase. Surprisingly, the increased concen-
tration of the same compound to 30 M caused accumulation
of cells in G0/G1 phase of the cell cycle [86]. A series of
chalcone--amidobenzothiazole conjugates (72a -- k and 73a,b)
have been synthesized and evaluated for their anticancer
activity [87]. All these compounds exhibited potent activity
and the IC
50
of two of the more potent compounds (72a
and 72f) against different cancer cell lines are in the range of
0.85 -- 3.3 M. Flow cytometric analysis revealed that these
compounds induced cell cycle arrest at G2/M phase in
A549 cell line leading to caspase-3-dependent apoptotic
cell death. The tubulin polymerization assay (IC
50
of
compound 72a is 3.5 M and compound 72f is 5.2 M)
and immuofluorescence analysis showed that these com-
pounds effectively inhibit microtubule assembly at both
OCH
3
OCH
3
OH
A
O
HO
B
O
OH
OH OH
O OCH
3
HO
O
O
OCH
3
OH
A
O
HO
B
57 58 59
Figure 15. Chemical structures of pharmacological effective chalcones.
O O Ph
Ph
N
N
Cl
O
O Ph
Ph
N
N
O
O
OCH
3
60a 60b
O Ph
Ph
N
N
O
O
O
2
N
60c
Figure 16. Different chalcones exhibiting antitumor activity.
61a
O
O
N
N
N
N
O
OCH
3
B A
H
3
CO
61b
O
O
N
N
N
N
O
OCH
3
OCH
3
B A
H
3
CO
Figure 17. Structure of lead compound and target hybrid compounds.
A. Kamal et al.
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molecular and cellular levels in A549 cells. Further, annexin
staining also suggested that these compounds induced cell
death by apoptosis. Moreover, docking experiments have
shown that they efficiently interact and bind with tubulin pro-
tein. Overall, this investigations demonstrated that the chalco-
ne--amidobenzothiazole conjugates are promising anticancer
agents with potent apoptotic-inducing activities via targeting
tubulin (Figure 19).
4. Imidazothiazole--chalcone conjugates
Some of the recent advances in the development of anticancer
agents involve structural modification of chalcones to improve
their bioavailability and to study the role of various substitu-
ents on the aryl rings [88]. In addition, heterocyclic derivatives
of chalcones wherein the B ring is replaced by a heterocycle
have been systematically investigated. Imidazothiazoles are
66a n = 1
66b n = 2
66c n = 3
68a i n = 1 3
68d n = 3
67a n = 1
67b n = 2
67c n = 3
69 R = Ph
70 R = OCH
3
71 R = Cl
73a R = H
73b R = CH
3
OCH
3
H
3
CO
OH
O
O
O
( )
n
N
N
H
O
OCH
3
H
3
CO
O
O
O
N
N
N HO
( )
n
N
N
H
O
OCH
3
OCH
3
O
O
O
N
R
N
H
N
H
H
3
CO
H
3
CO
HO
H
3
CO
O
O
N
NH
R
OCH
3
H
3
CO
OH
O
O
O
O
H
( )
n
H
N
N
O
OCH
3
OCH
3
O
O
O N
S
R
N
H
H
3
CO
H
3
CO
72a k
72a R = H
72f R = OCF
3
Figure 19. Structures of chalcone-linked PBD conjugates (66 -- 68), chalcone-linked imidazolones (69 -- 71) and chalcone-
linked amidobenzothiazoles (72 and 73).
62 BMS 181156 63 Cardamonin
65 Butein 64 AGN193198
O
COOH
O
O N COOH
OCH
3
O OH
HO
OH
OH
OH
O
HO
Figure 18. Chemical structures of chalcone-based NF-kB inhibitors.
Design and development of imidazothiazole--chalcone derivatives as potential anticancer drugs
Expert Opin. Drug Discov. (2013) 8(3) 299
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also well-known compounds and many derivatives of this
fused ring system have been evaluated for potential biological
activity particularly for antitumor activity [11,12]. In view of
the potent bioactivity of imidazothiazoles and chalcones, we
designed and synthesized new chalcone derivatives incorporat-
ing an imidazothiazole skeleton and evaluated their anticancer
activity. The promising activity obtained prompted us to
investigate their role in the cell proliferation and apoptosis
of human breast cancer cell line (MCF7). Further, it was con-
sidered of interest to investigate the effect of these compounds
on regulatory proteins of cell cycle progression [89].
The imidazothiazole--chalcone derivatives (80a -- p) were
prepared by the Claisen--Schmidt condensation of appropri-
ately substituted acetophenones (79a -- f) by treatment with
imidazo[2,1-b]thiazole aldehydes (78a -- h) in the presence
of NaOH (10%) as shown in Scheme 1. The imidazo[2,1-b]
thiazole aldehydes were obtained by means of Vilsmeier reaction
of the corresponding imidazo[2,1-b]thiazoles (77a -- h), which in
turn were prepared from the appropriate 2-aminothiazole (75)
and bromoketones (74) as shown in Scheme 1 and Table 1.
All the synthesized compounds showed significant antican-
cer activity in the cell panel assay of NCI and the cell viability
assay with log GI
50
values ranging from -7.51 to -4.00.
Detailed biological evaluation of these derivatives toward the
MCF-7 cell line was also carried out. The FACS analysis
showed more population in sub-G1 phase indicating that
these imidazothiazole--chalcones derivatives have apoptosis-
inducing ability. These effects were accompanied by changes
in expression of key proteins in the G1 phase of the cell cycle.
Further modulation of the expression and function of the cell
cycle regulatory proteins provide the mechanism for the
inhibition of growth and also downregulation of cyclins and
upregulation of CDK4, thereby resulting in downregulation
of phosphor-Rb (ser780) that suggests cell cycle blocking in
the G1 phase. Further, it was observed that the G1/S check
point-associated tumor suppressor proteins, such as p53,
p21, p27 and chk2 protein levels, were upregulated that results
in the induction of cell cycle arrest in G1 phase. These studies
also support that the upregulation of p53 and concomitant
downregulation of NF-kB in these compounds ultimately
lead to apoptosis. In this study an insight in the cell cycle reg-
ulatory role as well as apoptotic-inducing ability of these new
chalcones was extensively examined. Thus, this study revealed
that the caspase-mediated apoptotic pathway is responsible for
the apoptosis-inducing ability of the imidazothiazole--chalcone
conjugates (Figure 20) and these compounds are potential
candidates for the detailed biological investigations,
particularly for the treatment of breast cancer.
5. Expert opinion
Despite the availability of anticancer agents derived from
natural products and synthetic derivatives, the development
of a safe and site-specific anticancer drug still remains a chal-
lenge. The major obstacles in this endeavor are the association
of toxicity with drugs which is due to lack of specificity, as
these agents kill healthy cells and the drug resistance which
have arisen in recent years. The combination therapy employ-
ing different chemotherapeutic agents has been used to com-
bat this problem with some success. However, the possibility
of the development of drug resistance still remains. Keeping
pace with these challenges, around the world and from this
laboratory, a good number of diverse molecules with a novel
mode of action have been developed based on imidazothia-
zoles, chalcones and imidazothiazole--chalcone hybrids.
Cytotoxicity assays ona panel of humancancer cell lines as well
as preclinical and clinical studies of imidazothiazole--chalcone
derivatives exhibited that these compounds could be developed
74 75
79a f 78a h
80a p
77a h
acetone
reflux, 6 8 h
10% aq. NaOH,
12 h, rt, 75 85%
POCl
3
, DMF
reflux, 1 h, 70 80%
O
Br
R
2
R
S
N
N
O
R
2
R
1
N
N S
CHO
R
2
R
+
+
CH
3
O
R
1
NH
2
N
S
R
reflux, 1 h,
85 95%
2N HCl
R
2
R
N
N S
76
R
2
NH
N O
.HBr
S
R
Scheme 1. Synthesis of imidazothiazole--chalcone conjugates.
A. Kamal et al.
300 Expert Opin. Drug Discov. (2013) 8(3)
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as promising chemotherapeutics for the use of cancer. Interest-
ingly, some of the new-generation imidazothiazole, chalcone
and imidazothiazole--chalcone derivatives possess enhanced
potency in comparison with most of the standard anticancer
agents. Based on the impressive efficacy and potency data in ani-
mal models, many molecules of this type are being evaluated in
the clinic and are at different stages. A number of structurally
related imidazothiazoles, chalcones and imidazothiazole--chalcone
derivatives have been reported to exert antitumor effects;
however, their mechanism of action is not yet fully evaluated for
their lead optimization and clinical development. These studies
assume importance in the context of the recent interest in drug
design based on pharmacophore conjugation approach. This
approach may possibly enhance the potency of previously uncon-
jugated agents that display little or no antitumor activity on their
own. Importantly, the hybrid molecule strategy is not
recommended for the entities when their targets are too different.
Drug development for cancer treatment remains as challenging as
ever, despite the identification of numerous potential drug
candidates, due to toxicity issues and the many obstacles in
pharmacokinetics. Based on the biological importance of
imidazothiazole--chalcone conjugates, it is of considerable interest
in the design and synthesis of newconjugates as anticancer agents.
Combination chemotherapy with drugs of different mechanisms
of action is one of the methods that is adopted to treat cancer.
Alternatively, a single drug which incorporates two pharmaco-
phores with different modes of action may be employed for treat-
ment. It is anticipated that the search for novel chemotherapeutic
agents basedonimidazothiazole--chalcone conjugates may provide
more efficient and safer anticancer drugs in the years to come.
Now efforts are being focused toward the intervention of conju-
gate molecules as anticancer agents eventually to develop effective
chemotherapeutics for the treatment of human malignancies.
Declaration of interest
MK Reddy and A Viswanath are Senior Research Fellows for
the Division of Organic Chemistry of the Indian Institute of
Chemical Technology (CSIR-IICT). A Kamal is an Acting
Director (Outstanding Scientist) of the CSIR-IICT, Hydera-
bad. The authors have no competing interests to declare and
have received no payment in support of this manuscript.
Apoptosis
p53
Chk2
G1 phase
Cdk4
Cyclin D1 Cyclin E
S-phase
NF-B
Cell cycle
Apoptosis
Cdk2
Caspase activation
Figure 20. Schematic diagram representing the action of
imidazothiazole--chalcone conjugates on modulate cell cycle
and apoptosis: Conjugates arrest cells at G1 phase of cell cycle
affecting the cyclin E/Cdk2 and cyclin D1/Cdk4. The tumor
suppressor protein p53 was induced in compound-treated cells
by suppressing NF-kB protein. The balance between p53 and
NF-kBcontrols theapoptotic event by inducingcaspaseproteins.
Table 1. Representative chemical structures of imidazothiazole--chalcone conjugates (80a -- p).
80a p
R
S
N
N
O
R
2
R
1
Entry Compound R R
1
R
2
1 80a H Trimethoxyphenyl 4-Methoxyphenyl
2 80b H Trimethoxyphenyl 4-Fluorophenyl
3 80c H Trimethoxyphenyl 2-Thienyl
4 80d H Trimethoxyphenyl Trifluoromethyl
5 80e H Trimethoxyphenyl 3,4-Dimethoxyphenyl
6 80f H 3,4-Dimethoxyphenyl Trifluoromethyl
7 80g CH
3
Trimethoxyphenyl 4-Methoxyphenyl
8 80h CH
3
Trimethoxyphenyl 4-Fluorophenyl
9 80i CH
3
Trimethoxyphenyl 2-Thienyl
10 80j H 2-Pyrrolyl 4-Methoxyphenyl
11 80k H 2-Thienyl 4-Methoxyphenyl
12 80l H 3,5-Difluorophenyl 4-Methoxyphenyl
13 80m H 3,4-Benzodioxolyl 4-Methoxyphenyl
14 80n H 3,4-Benzodioxolyl 4-Fluorophenyl
15 80o H 3,4-Dimethoxyphenyl 4-Methoxyphenyl
16 80p H 3,4-Dimethoxyphenyl 4-Fluorophenyl
Design and development of imidazothiazole--chalcone derivatives as potential anticancer drugs
Expert Opin. Drug Discov. (2013) 8(3) 301
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Affiliation
Ahmed Kamal

, Methuku Kashi Reddy &

Arutla Viswanath

Author for correspondence

CSIR -- Indian Institute of Chemical Technology,
Division of Organic Chemistry,
Tarnaka, Hyderabad 500607, India
Tel: +91 40 27193157; Fax: +91 40 27193189;
E-mail: ahmedkamal@iict.res.in
A. Kamal et al.
304 Expert Opin. Drug Discov. (2013) 8(3)
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