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org

CHEMISTRY OF ANTICANCER THIAZOLE COMPOUNDS

Chawla Amit*, Sheelmani, Arashdeep Singh, Chawla Payal, Dhawan R K
Khalsa College of Pharmacy, Amritsar, Punjab, India

ABSTRACT:
In recent years heterocyclic compounds analogues and derivatives have attracted strong interest due to
their biological and pharmacological properties. A vast variety of thiazole derivatives having excellent
broad spectrum activity forms an invaluable part of the present research for researchers. The present
review focus on the different methods of synthesis of substituted thiazoles with potential activities that are
now in developing phase. The search for new biologically active thiazole analogues continues to be an
area of intensive investigation in medicinal chemistry. The present review describes ongoing research in
search for new thiazole compounds that can prove usefulness for the design of future target and
development of new drug molecules. Most of the compounds showed moderate to good anticancer
activity which are described in this review.

Keywords: Thiazole; Anticancer; Heterocyclics

INTRODUCTION Thiazole is aromatic, heterocyclic organic

Heterocyclic compounds are very
widely distributed in nature and are essential to
life in various ways[1]. The hetero cyclic
molecules which possess indole, pyrazole and
azetidine moieties exhibit wide range of
biological activities[2]. Synthesis of the basic
nucleus is well established and the proposed
derivatives can be synthesized based upon the
literature available about the reaction involved[3].
Indoles are one of the most important alkaloids
molecules found extensively in biological
systems, which play vital role in many of the
biochemical process. Indole ring constitutes an
important basic skelton and development of the
drug[4].
Thiazoles are a class of organic compounds
related to azoles with a common thiazole
functional group[5]. Thiazole was first described
by Hantzsch and Waber in 1887. Popp
confirmed its structure in 1889[6].
Corresponding Author:
Amit Chawala, Asst. professor
Khalsa college of pharmacy,
G.T.Road. Amritsar-143002, Punjab, India.
E-mail:* amitchawla@gmail.com
Mobile : +91-9592021088
compound that has a five-membered molecular
ring structure,C3H3N. The numbering starts from
the sulphur atom. Thiazole are well
repersentated in biomolecules[7].
Thiazoles molecules containing a thiazole
amine-moiety exhibit interesting biological
activities depending on the substitution pattern
at the thiazole ring[8].
Proposed work is based upon the development
of some newer structurally related compounds of
benzothiazoles and evaluation of biological
activity . Benzothiazoles are fused membered
rings, which contain the heterocycles bearing
thiazole. The basic structure of benzothiazole
consist of benzene ring fused with 4, 5 position
of thiazole. The two rings together constitute the
basic nucleus 1, 3-benzothiazle. Benzothiazoles
show antitumor activity,especially the phenyl-
substituted benzothiazoles[9
Recently thiazolidinone research area
unexpectedly became interesting and promising

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 Adv J Pharm Life sci Res, 2014 2;1:1-7
for oncology. In-depth study of PPARs allowed
putting forward and validating the concept of
anticancer potential existence of PPAR agonists
including thiazolidienedione. While applying the
research strategy through the past few years we
succeeded in gaining a number of interesting
synthetic results that make possible to extend the
field of the chemistry of thiazolidinone and
related heterocycles, especially in the scope of
drug-like molecules design[10]. Anticancer
activity evaluation of 4-thiazolidinones and
related heterocyclic systems and efficient
approaches to interpretation of structure–activity
correlation[11].
THIAZOLE ANTICANCER DRUGS
Kini S, et al[12] refluxed o-aminophenols
with substituted benzoic acid in presence of
polyphosphoric acid at higher temperature to get
aryl substituted benzothiazoles and evaluated
them against Human Cervical Cancer cell lines
as anticancer drugs.
Fig. 1
Stanton HLK, et al synthesized
benzothiazole containing phthalimide and
studied their anti-cancer activity on human
carcinoma cell lines[13].
Fig. 2
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A number of N-bis(trifluoromethyl)alkyl-N′-
thiazolyl and benzothiazolylureas have been
synthesized and evaluated by Luzina et al
against the human cancer cell lines[14]. The most
sensitive cell lines relative to the tested
compound was: (3) PC-3 (prostate cancer, log
GI50 −7.10), and SR (leukemia, log GI50−5.44)
human cancer cells. Synthesis and activity of a
series of 4-thiazolyl substituted analogs of novel
pyrrolocarbazole as poly(ADP-ribose)
polymerase-1-(PARP-1) inhibitors have been
disclosed by Dunn et al[15]. Among these
compounds, (4) found to be more potent.
Fig. 3
Fig. 4
All the synthesized compounds showed
remarkable antitumor activity against human
MCF7cell line. Compound 5b was the most
potent one comparing with the standard drug
DXR[16].
a, Ar = C6H5; b, Ar = C6H4-Cl-p; c, Ar = C6H4-Br-p
Fig. 5
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N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2- Compound 8 exhibited highest activity against

hydroxyethyl)-1-piperazinyl)]-2-methyl-4- cervical cancer[24].
pyrimidinyl ] -amino)] -1,3-thiazole-5-
carboxamide is a novel multi-targeted kinase
inhibitor recently approved in several countries
for the treatment of chronic myelogenous
leukemia (CML) as well as Philadelphia
chromosome-positive acute lymphocytic Fig. 8
leukemia (ALL). Dasatinib exhibits greater Compound 9 was found to be non-selective (SR
potency than imatinib mesylate and inhibits the were between 0.66–2.06 and 0.84–1.66 at the
majority of kinase mutations in imatinib- GI50 and TGI levels respectively).
resistant CML[17-20]. Unlike imatinib, which
binds to the inactive conformation of Bcr-Abl,
dasatinib binds to the active form of the
enzyme[21]. The ability to inhibit SRC-family
kinases such as Hck and Lyn, in addition to
binding to the active conformation of BCR-
ABL, may both contribute to the effectiveness of
dasatinib against imatinib-resistant tumors[22].

Fig. 9
All the synthesized compounds showed
moderate cytotoxic activity towards both the cell
lines. Among the APTOM-4c exhibited
significant activity against MCF-7 and DLA cell
lines[26].
Fig. 6
Ten new aryl imidazoles incorporated with
chemotherapeutic pharmacophores have been
synthesized and evaluated for their anti bacterial
and short term anti cancer activity. Compound 7
showed the best anti cancer activity with CTC50 Fig. 10
value of 98.56 and 31.25 µg mL-1 against DLA
and EAC cell line17[23]. Compound 11 showed high inhibitory effects
against non-small cell lung cancer (NCI-H460)
and breast adenocarcinoma MCF-7),
[27]
respectively .

Fig. 7

Fig. 11

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 Adv J Pharm Life sci Res, 2014 2;1:1-7
Lester R. Marrison et al used Suzuki cross-
coupling for synthesis of 3- and 5-substituted 2-
pyrones, which show remarkable inhibitory
activity against bacteria, yeast and fungi, and 3-
Octenyl and 5-octanyl 2-pyrones shows anti
cancer activity against human ovarium
carcinoma and human chronic myelogenous
leukaemia cell lines at the micromolar level[28].
Fig. 12
Fahmy et al [40] synthesized a series of novel
fluorinated thiazolo[4,5-d]pyrimidine derivatives
and sceened their anticancer activity against 60
human tumor cell lines. Compounds 13 and 14
showed better anticancer activity against tumor
cell lines[29].
Fig. 13
Fig. 14
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Gududuru et al. tested a series of 2-
arylthiazolidine-4-carboxylic acid amides for
possible cytotoxic activity in prostate cancer.
Compound 15 was found to be most potent and
selective cytotoxic agent with IC50 of 0.55 lM
and 38-fold selectivity in PPC-1 cells[30].
Fig. 15
Compounds were evaluated against five human
prostate cancer cell lines. They reported that
increase in the alkyl chain enhanced the
antiproliferative activity while replacement of
the alkyl chain with aryl group reduced the
biological activity[31].
Fig. 16
Compound 17 was screened against nine types
of human cancer cells and showed significant
cytotoxic activity in case of lung cancer,
melanoma and renal cancer, where the reduction
in growth was found to be 75%, 97% and 84%,
respectively, at the concentration of 1.0 10 4
lm[32].
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Fig. 17
Compound 18 was screened against three human
cancer cell lines (HT-29, H460 and MDA-MB-
231) by MTT assay and exhibited IC50’s of
0.025, 0.075 and 0.77 lM, respectively. The
SAR study showed that substitution with smaller
electron-withdrawing fluorine atom at 5-position
of the indolin-2-one ring and 3-(diethylamino)
propyl group at the 3-position of 4-
thiazolidinone ring had positive contribution for
increasing antitumor activity[33].
Fig. 18
The SAR study revealed that anticancer activity
of compound 19 was affected by the nature of
substituent in position 5 of 4-thiazolidinone
cycle and introduction of 4-chlorophenoxy-N-
(4-methoxyphenyl)-acetamide group in 5-
position of 4-thiazolidinone core enhanced
potency[34].
Fig. 19
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A number of 5-bromo-3-[(3-substituted-5-
methyl-4-thiazolidinone-2-ylidene hydrazono]-
1H-2-indolinones (20) had been investigated for
their primary cytotoxic activity against 3-cell
line panel consisting of NCI-H460 (Lung),
MCF7 (Breast), and SF-268(CNS). It was
observed that thiosemicarbazone derivatives of
indolinones showed promising cytotoxicity
activity[35].
Fig. 20
ACKNOWLEDGEMENT
Authors are thankful to Hon. Secretary, Khalsa
College Charitable Society, Amritsar and
Director-Principal, Khalsa college of Pharmacy,
Amritsar for providing facilities to carry out this
project work.
REFERENCES
1. Achson A. An introduction to the chemistry of
heterocyclic compounds., Willy-
Intersciences;India; 2009 3rd ed.
2. Muralikrishna S, Raveendrareddy P,
Ravindranath LK, Harikrishna S, Jagadeeswara
Rao P.Synthesis Characterization and antitumor
activity of thiazole derivatives containing indole
moiety bearing-tetrazole. Der Pharma Chemica
2013;5:6:87-93.
3. Prabhu PP, Shastry CS, Sushant Sudhir Pande,
Panneer selvam T. Design, synthesis,
characterization and biological evaluation of
Benzothiazole-6-carboxylate derivatives.
Research IN Pharmacy 2011;1;2:6-12.
5
 Adv J Pharm Life sci Res, 2014 2;1:1-7
4. Muralikrishna S, Raveendrareddy P,
Ravindranath LK, Harikrishna S, Jagadeeswara
Rao P.Synthesis Characterization and antitumor
activity of thiazole derivatives containing indole
moiety bearing-tetrazole. Der Pharma Chemica
2013;5:6;87-93.
5. Shivaraj H, Gazi S, Patil S, Surwas S. Synthesis
and biological evaluation of some benzothiazole
derivatives. Asian J Research Chem. 2010;
3;2;421-427.
6. Yadav PS, Devprakash, Senthilkumar G
P.Benzothiazole: Different Methods of Synthesis
and Diverse Biological Activities. International
Journal of Pharmaceutical Sciences and Drug
Research 2011; 3;1; 01-07.
7. Nadeem Siddiqui, Satish Kumar Arya,Waquar
Ahsan, Bishmillah Azad .Diverse biological
activities of Thiazoles A Retrospect.Int.J. Drug
Dev. & Res. Oct-Dec 2011; 3;4: 55-67.
8. Schnürch M, Waldner B, Hilber K , Mi-
hovilovic MD.Bioorganic & Medicinal
Chemistry Letters 2011; 21;. 7; 2149-2154.
9. Theocharisa S, Margeli A, Kouraklis G.
Peroxisome proliferator activated receptor-
gamma ligands as potent antineoplastic agents
Curr. Med. Chem. Anticancer Agents.–2003;3; ;
3;239–251.
10. Murphy G J, Holder J C. PPAR-gamma
agonists: therapeutic role in diabetes,
inflammation and cancer Trends
Pharmacol.Sci.–2000;21; 12;. 469–474
11. Lesyk RB, Zimenkovsky BS, Kaminskyy DV,
Kryshchyshyn AB, Ya Havryluk D, Atamanyuk
DV, Yu Subtel’na I, Khyluk DV.
Thiazolidinone motif in anticancer drug
discovery.Experience of DH LNMU medicinal
chemistry scientific group. 2011; 27; 2;107–117.
12. Kini S, Swain S, Gandhi A. Synthesis and
Evaluation of novel benzothiazole Derivates
against Human Cervical Cancer cell lines.Ind J
Pharm Sci. 2007; Jan-Feb: 46-50.
13. Wang M, Gao M, Mock B, Miller K, Sledge G,
Hutchins G, Zheng Q. Synthesis of C-11
labelled fluorinated 2-arylbenzothiazoles as
Advanced Journal of Pharmacie and Life science Research
www.ajplronline.org
novel potential PET cancer imaging agent.
Bioorg Med Chem.2006; 14
14. Luzina EL, Popov AV. Synthesis and anticancer
activity of N-bis(trifluoromethyl)alkyl-NK-
thiazolyl and N-bis(trifluoromethyl)alkyl-NK-
benzothiazolylureas. Eur J Med Chem 2009; 44.
15. Dunn D, Husten J, Ator MA, Chatterjee S.
Novel poly(ADP-ribose polymerase-1inhibitors .
BioorgMed Chem 2007; 17: 542-545.
16. Asmaa A. Magd-El-Din1, Amira S. Abd-El-
All1, Hanaa M. F. Roaiah1 and Mashalla M.S.
El-Baroudy1 .New Synthesis of Furochromenyl
Imidazo [2a-1b] Thiazole Derivatives Studies on
Their Antitumor Activities. Journal of
American Science2010;6;5.
17. Shah, NP, Tran C, Lee FY, Chen P,Norris D,
Sawyers CL. Science 2004; 305-399.
18. Lombardo LJ, Lee FY, Chen P, Norris D,
Barrish JC, Behnia K, Castaneda S,Cornelius
LAM, Das J, Doweyko AM, Fairchild C, Hunt
JT, Inigo I,Johnston K, Kamath A, Kan D, Klei
H, Marathe P,Pang S, Peterson RI, Pitt S,
Schieven G L, Schmidt R J, Tokarski J, Wen M
L, Wityak J, Borzilleri R J. Med. Chem.2004:47;
6658.
19. Copland M, Hamilton A, Elrick L J, Baird J
W,Allan E K, Jordanides N, Barow M,
Mountford J C, HolyoakeT L, Blood 2006:
107;4532.
20. McIntyre J A, Castaner J, Bayes M. Drugs of the
Future 2006: 31;291.
21. Tokarski JS, Newitt J A, Chang CY J, Cheng J
D,Wittekind M, Kiefer SE,Kish K, Lee F Y F,
Borzillerri R, Lombardo L J, Xie D, Zhang Y,
Klei H E.Cancer Res. 2006: 66;579.
22. O’Hare T, Walters D K, Stoffregen E P, Jia T,
Manley PW, Mestan J,Cowan-Jacob SW,Lee F
Y, Heinrich M C, Deininger M W, Druker B J,
Cancer Res.2005:65; 4500.
23. Sharma GK,Sharma Nk, pathak D.Microwave
assisted synthesis of some subsituted imidazole
derivative as potencial antibacterial and
anticacer agents. Indian J. chem,2013;52;266-
272.
6
 Adv J Pharm Life sci Res, 2014 2;1:1-7
24. Prasanthy GK,Venkata Romana , Koti reddy
V,Nirmala K,Kumar ramesh N.synthesis of
biological evaluation of 1-subsituted imidazole
derivative. Int. J.Pharma,2011;1:92-99.
25. Anna Kryshchyshyn, Dmytro Atamanyuk ,
Roman Lesyk . Fused Thiopyrano[2,3-
d]thiazole Derivatives as Potential Anticancer
Agents. May 2012;3
26. Jisha Mol, Kamalabhai Amma VK, Babu G and
Biju CR.Synthesis, characterization and invitro
anticancer screening of novel thiazole-1,3,4-
oxadiazole hybrid analogues.
27. Rafat M Mohareb , Daisy H Fleita and Ola K
Sakka.Novel Synthesis of Hydrazide-Hydrazone
Derivatives and Their Utilization in the
Synthesis of Coumarin, Pyridine, Thiazole and
Thiophene Derivatives with Antitumor
Activity.Molecules 2011, 16, 16-27; doi:
10.3390/molecules16010016.
28. Lester RM, Dickinson JM, Ian JSF. Suzuki
cross-coupling approches to the 5-substituted-4-
methoxy-6-methyl-2-pyrones. Bioorg Med
Chem Lett 2003;13:2667-71.
Advanced Journal of Pharmacie and Life science Research
www.ajplronline.org
29. Shiv Jee Kashyap*, Pramod Kumar Sharma,
Vipin Kumar Garg, Rupesh Dudhe, Nitin
Kumar. Review on Synthesis and Various
Biological Potential of Thiazolopyrimidine
Derivatives. Journal of Advanced Scientific
Research .Shiv Jee Kashyap et al, J Adv Sci Res,
2011, 2;3; 18-24 18 .
30. Abhishek Kumar Jain a, Ankur Vaidya a,
Veerasamy Ravichandran b, Sushil Kumar
Kashaw a,Ram Kishore Agrawal.Recent
developments and biological activities of
thiazolidinone derivatives.Bioorganic &
Medicinal Chemistry.
31. Gududuru, V.; Hurh, H.; Dalton, J. T.; Miller, D.
D. Bioorg. Med. Chem. Lett. 2004; 14; 5289.
32. Rahman, V. P. M.; Mukhtar, S.; Ansari, W. H.;
Lemiere, G. Eur. J. Med. Chem. 2005;40;173.
33. Wang, S.; Zhao, Y.; Zhang, G.; Lv, Y.; Zhang,
N.; Gong, P. Eur. J. Med. Chem. 2011;46;3509.
34. Havrylyuk, D.; Mosula, L.; Zimenkovsky, B.;
Vasylenko, O.; Gzella, A.; Lesyk, R. Eur. J.
Med. Chem. 2010: 45; 5012.
35. Karali, N.; Terzioglu, N.; Gursoy, A. Arch.
Pharm. Pharm. Med. Chem. 2002;8;374.
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