Synthesis of thiazole linked chalcones and their pyrimidine analogues as anticancer agents

Article abstract of DOI:10.1080/00397911.2021.1884262

A series of nine novel thiazole linked chalcones, (E)-3-(4-methyl-2-(4(trifluoromethyl)phenyl)thiazol-5-yl)-1-phenylprop-2-en-1-one derivatives 7–15 were synthesized. To establish the structure–activity relationship (SAR), furthermore, the corresponding, ring-closed pyrimidine analogs 17–23 were synthesized. The derivatives thus obtained were evaluated for their anti-cancer activity against three genetically different colorectal cancer (CRC) cell lines. Thiazole derivatives 7, 9, and10 showed anti-cancer activity with GI50 values ranging from 0.19 to 100 μM. Importantly, compounds 7 and 10 outperformed the standard drug cisplatin in the tested cell lines and thus show promise for further optimization. Some of pyrimidine derivatives retain activity comparable to cisplatin in the HT-29 cell line, e.g. compounds 17 and 18 with IC50 of 25?μM, however, none of these compounds demonstrated improved antiproliferative activity as compared with the starting thiazole, thus the enone linker was critical for obtaining more active compounds in this series.

Full text of DOI:10.1080/00397911.2021.1884262

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of thiazole linked chalcones and their
pyrimidine analogues as anticancer agents
Chekrapani Kesari, Koteshwar Rao Rama, Khwajanezrabodin Sedighi, Jan
Stenvang, Fredrik Björkling, Shravankumar Kankala & Niranjan Thota
To cite this article: Chekrapani Kesari, Koteshwar Rao Rama, Khwajanezrabodin Sedighi, Jan
Stenvang, Fredrik Björkling, Shravankumar Kankala & Niranjan Thota (2021) Synthesis of thiazole
linked chalcones and their pyrimidine analogues as anticancer agents, Synthetic Communications,
51:9, 1406-1416, DOI: 10.1080/00397911.2021.1884262
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2021, VOL. 51, NO. 9, 1406–1416
https://doi.org/10.1080/00397911.2021.1884262
Synthesis of thiazole linked chalcones and their pyrimidine
analogues as anticancer agents
Chekrapani Kesaria, Koteshwar Rao Ramaa, Khwajanezrabodin Sedighib,
b
b
c
b
€
Jan Stenvang , Fredrik Bjorkling , Shravankumar Kankala , and Niranjan Thota
b
aDepartment of Chemistry, Mewar University, Chittorgarh, India; Department of Drug Design and
Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen,
c
Denmark; Department of Chemistry, Kakatiya University, Warangal, India
ABSTRACT
ARTICLE HISTORY
Received 21 October 2020
A series of nine novel thiazole linked chalcones, (E)-3-(4-methyl-2-
(4(trifluoromethyl)phenyl)thiazol-5-yl)-1-phenylprop-2-en-1-one deriv-
atives 7–15 were synthesized. To establish the structure–activity
relationship (SAR), furthermore, the corresponding, ring-closed pyr-
imidine analogs 17–23 were synthesized. The derivatives thus
obtained were evaluated for their anti-cancer activity against three
genetically different colorectal cancer (CRC) cell lines. Thiazole deriva-
tives 7, 9, and10 showed anti-cancer activity with GI50 values rang-
ing from 0.19 to 100 mM. Importantly, compounds 7 and 10
outperformed the standard drug cisplatin in the tested cell lines and
thus show promise for further optimization. Some of pyrimidine
derivatives retain activity comparable to cisplatin in the HT-29 cell
line, e.g. compounds 17 and 18 with IC50 of 25 mM, however, none
of these compounds demonstrated improved antiproliferative activity
as compared with the starting thiazole, thus the enone linker was
critical for obtaining more active compounds in this series.
KEYWORDS
Anticancer activity; chalcone
derivatives; medicinal
chemistry; pyrimi-
dines; thiazoles
GRAPHICAL ABSTRACT
Introduction
Globally, colorectal cancer (CRC) ranks third in terms of incidence but second in terms
of mortality. Over 1.8 million new CRC cases and 881,000 deaths are estimated to occur
in 2018, accounting for about 10% of all cancer incidents and deaths.[1] Generally, most
CONTACT Niranjan Thota
Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Shravankumar Kankala
shravankankala@gmail.com Department of Chemistry, Kakatiya University, Warangal, India
thotaniranjan1@gmail.com
Department of Drug Design and Pharmacology, Faculty of
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Table 1.
Cell line MSI status KRAS
TP53
CIMP CIN
Localization
Primary tumor/metastasis Patient stage
HT29
HCT-116
LoVo
MSI
MSI
MSI
Wt
R273H
Wt
Wt
1
1
2
1
2
2
Colon
Colon ascendens
Colon
Primary tumor
Primary tumor
Primary tumor
Dukes’ C
Dukes’ C
Dukes’ C
G13D
G13D
A14V
MSI: microsatellite instability; CIMP: CpG island methylator phenotype; CIN: chromosomal instability
cytotoxic treatments of cancer are not efficient.[2] Presently, metastatic CRC (mCRC)
patients are treated with combinations of only three cytotoxic drugs (5-Fluorouracil
(5-FU), oxaliplatin, and irinotecan) and commonly co-administration of leucovorin
(folinic acid) potentiating the effect of 5-fluorouracil. The combinations mostly
applied are the FOLFOX regimen (leucovorin, 5-FU, and oxaliplatin) or the FOLFIRI
regimen (leucovorin, 5-FU, and irinotecan). These regimens have significantly
increased the response rates and survival of mCRC patients.[3] However, the major
problem is that only 30–50% of the patients show an objective, response to either
FOLFOX or FOLFIRI regimens, and progression of the cancer is a common out-
come.[4] These low response rates clearly reveals the serious problem of insufficient
efficiency of drugs and this emphasizes the need for investigations in novel anti-can-
cer drugs in CRC.
CRC is a genetically heterogeneous disease, which may contribute to differences in
response to drug treatment. CRC cells display genetic instability caused by chromosomal
instability (CIN), microsatellite instability (MSI), and the CpG island methylator pheno-
type (CIMP), which result in activation of proto-oncogenes such as KRAS and inactiva-
tion of tumor suppressor genes such as TP53 (p53).[5] Furthermore, mutations in KRAS
and TP53 are often observed. The presence or absence of certain genetic alterations
may determine the response to treatment and therefore it is important to study CRC
cell lines that harbor different combinations of the genetic alterations described above.
Importantly, CRC cell lines have been found to represent the main molecular subtypes
of primary cancers.[6] Therefore, we chose three genetically different CRC cell lines in
this study (HT29, HCT116, and LoVo) (Table 1).
Chalcone derivatives (1,3-diphenyl-2-propen-1-ones) are open-chain flavonoids
found in nature as secondary plant metabolites. These compounds show a broad
spectrum of biological activities including anticancer,[7] antibacterial,[8] antifungal,[9]
anti-diabetic,[10] anti-infective, and anti-inflammatory activities,[11] acting through
multiple mechanisms. Chalcone derivatives are reported to exhibit anticancer activity
in several types of cancer cells with different origin, such as breast, lung, prostate,
ovarian and colon cancer cells.[12–14] Structural modifications of both aryl rings in
chalcone, such as replacement of aryl rings with heteroaryl moieties, have provided
enhancement of the anticancer activity.[15–18] Accordingly, the preparation of novel
heterocycle-based chalcones is a promising path for improved compounds. A 1,3-thia-
zole ring has been used extensively as a scaffold in the identification of new lead
compounds in drug discoverywithin an extremely broad set of diseases includinginfec-
tion,[19] inflammation,[20] and cancer.[21] In relation to the present investigation, this
heterocycle has been used as a bioisostere replacing one of the aromatic rings in chal-
cone (Fig. 1).[22–24]

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C. KESARI ET AL.
Figure 1. Design of thiazole-based chalcones by hybridization of reported anticancer agent com-
pound II.
Results and discussion
Thus, a series of 4-amino-5-cinnamoylthiazoles have recently been prepared and eval-
uated for anticancer activity (Fig. 1, comp. II).[25] The cytotoxicity was determined in
three different cancer cell lines (breast carcinoma MCF-7, human liver cancer HepG2,
and human colon adenocarcinoma SW480). (E)-1-(4-Amino-2-(pyrrolidin-1-yl)thiazol-
5-yl)-3-(2,4-dichlorophenyl)prop-2-en-1-one was the most potent compound found dur-
ing the in vitro structure–activity relationship (SAR) study.[25] Inspired by this,
we describe herein the synthesis and anticancer activity of a novel series of structurally
analogs (E)-3-(4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)-1-phenyl prop-2-en-
1-one derivatives (Fig. 1, comp. III), as a continuation of our ongoing effort on the syn-
thesis of anticancer agents.[25–30]
4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-carbaldehyde (5) was a key inter-
mediate for the preparation of the new thiazole derivatives. The thiazole building block
5 was synthesized in 3 steps (Scheme 1). First, the thiazole ring was formed reacting 4-
(trifluoro)thiobenzamide (1) with ethyl 2-chloroacetate (2) to get ethyl 4-methyl-2-(4-
(trifluoromethyl)phenyl)thiazole-5-carboxylate (3). Ester 3 was reduced by LiAlH4 to
obtain the corresponding alcohol 4, followed by Dess–Martin oxidation to furnish
target aldehyde intermediate 5 (Scheme 1). With the building block 5 in hand, the thia-
zole derivatives 7–15 were prepared in high yield by Claisen–Schmidt condensation
using a diverse set of substituted acetophenones (Scheme 1). The SARs were further
explored by masking the enone system as pyrimidine derivatives (17–23). Four of the
active compounds 7, 10, 11, 14 were conveniently transformed into pyrimidines using
selected guanidines (16, Scheme 1). In our new series, the A ring is substituted by a
CF3 group in the para-position (Fig. 1). To assess the influence of this electron-with-
drawing substitution the corresponding methyl derivative was prepared (7a) using the
same synthetic method. All the new synthesized compounds were characterized using
NMR, and mass spectrometry (Supporting Information).
Biological studies: anticancer activity
The antiproliferative activity of the 17 novel thiazole derivatives (7–15 and 17–23) was
assessed in three genetically different CRC cell lines as described above, HT29, HCT116,

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Scheme 1. Synthesis thiazole linked chalcone derivatives 7–15 and their pyrimidines deriva-
tives 17–23.
and LoVo using a standard MTT assay. Initially, a broad concentration ranges from
12.5 to 50 mM was chosen to identify active thiazole derivatives.
Compounds 7, 9, and 10 showed dose-dependent activity in all three cancer cell lines
(Fig. 2A–C). Furthermore, 14 and 7a showed antiproliferative activity at the highest
concentration (50 mM). Cisplatin was active in all three cancer cell lines and thus used
as a positive antiproliferative control. Based on these results, IC50 values for inhibition
was determined for the active compounds 7, 9, 10, 14, 7a, and cisplatin (Fig. 3A–C).
The same activity was presented as best fit sigmoidal curves for all the active com-
pounds (see the Supporting Information Figs. S1–S3).
As observed from the IC50 values, the antiproliferative activity of the individual com-
pounds varied among the cancer cell lines, as was also the case for cisplatin. Two com-
pounds 7 and 10 were found more potent than reference compound cisplatin in all
three cell lines, thus, showed a good activity in cell lines of different genetic background
(Table 2).
Structure–activity relationship (SAR) studies
The presence of an electron-withdrawing group in C ring of the thiazole (Fig. 1) such
as COOH (7), NO2 (9, 10) provided active compounds whereas introduction of the
electron-donating groups in the C ring such as CH3 (8), F (11) OMe (12, 13) Br (14),

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C. KESARI ET AL.
(A)
120
NS compounds testet on HT-29 cells
100
80
60
40
20
0
(B)
NS compounds testet on HCT116 cells
120
100
80
60
40
20
0
NS compounds testet on LoVo cells
(C)
120
100
80
60
40
20
0
Figure 2. (A–C) Dose dependent antiproliferative activity of all the synthesized chalcones. The three
columns for each compound represent concentrations of 12.5, 25, and 50 mM, respectively.
and NHBoc (15) gave compounds with less or no activity (Table 2). In addition, when
we replace the CF3 substituent in A ring with CH3 in our most active compounds 7 we
observed reduced activity 7a, thus, an electron-withdrawing group in A ring seems to
promote activity. In comparison with chalcone and previously published anticancer

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(A)
HT29
150
100
50
0
Drug concentraꢀon
7
9
10
14
7a
Cisplaꢀn
(B)
HCT116
150
100
50
0
Drug concentraꢀon
10 14 7a
7
9
Cisplaꢀn
(C)
LoVo
150
100
50
0
Drug concentraꢀon
10 14 7a
7
9
Cisplaꢀn
Figure 3. Dose dependent antiproliferative activity of most potent compounds 7, 9, 10, 14, 7a, and
cisplatin with increased concentration range (from 0.195 to 100 mM).
thiazoles based on this scaffold, the reversal of the direction of the enone linker did not
affect the activity negatively. As an alternative method to explore the importance of the
enone structural fragment, we converted some of the active thiazole derivatives to the
corresponding pyrimidine analogs (17–23). Even though some of these derivatives
retain activity comparable to cisplatin in the HT-29 cell line, e.g. compounds 17 and 18
which are derivatives of compound 7 (Table 2), none of these compounds demonstrated
improved antiproliferative activity, as compared with the starting thiazole, in any of the
cancer cell lines used (Table 2). Thus, we concluded that the structural change imposed

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C. KESARI ET AL.
Table 2. IC50 values of most activity compounds and comparisons with Cisplatin.
IC50 value (mM)
S.No
Compound
HT-29
HCT-116
LoVo
1
2
3
7
9
10
7.94
36.82
4.89
3.12
5.49
6.28
2.21
23.96
1.17
4
5
6
7
8
9
10
11
12
13
14
7a
17
18
19
20
21
22
26.62
51.78
24.91
25.33
44.06
46.58
31.44
N.A.
23.25
10.54
23.86
23.34
30.22
31.37
37.57
28.16
53.93
10.55
22.72
7.12
23.71
23.10
29.93
28.43
65.86
44.48
38.92
5.19
23
Cisplatin
41.64
25.76
N.A.: not analyzed
by the ring-formation provides a sterically more demanding structure, which is not
favorable, and the somewhat more flexible enone linker was critical for obtaining more
active compounds in this series.
Materials and methods
Cell lines
The cell lines HCT116 and HT29 were obtained from the NCI/Development Therapeutics
Program, while LoVo was obtained from the American Tissue Culture Collection. Cells
were maintained at 37 C, 5% CO2 in RPMI 1640 þ Glutamax growth medium (Invitrogen,
Naerum, Denmark) supplemented with 10% fetal calf serum (Invitrogen).
The cell line identities of the cell lines were confirmed using short tandem repeat
DNA analysis (IdentiCell-Cell Line Authentication Service, Aarhus University Hospital,
Aarhus, Denmark) (Jensen et al. PMID: 25759163). In addition, all cell lines were recur-
rently tested, and determined to be mycoplasma-free (Mycoplasma PCR Detection Kit,
Minerva Biolabs, Berlin, Germany).
Compound sensitivity analysis and MTT assay
Compounds were diluted in growth medium at appropriate concentrations immediately
prior to use. In vitro compound sensitivity was determined using the methylthiazolyldi-
phenyl-tetrazolium bromide (MTT) (Sigma-Aldrich, St. Louis, MO, USA) assay. Cells
were seeded in 96-well plates, and a range of compound concentrations was added the
following day. Following 48 h of compound exposure, the medium was discarded, and
the plates were incubated with medium containing MTT (0.5 mg/ml) for 3 h. Acidified
(0.02 M HCl) sodium dodecyl sulfate (20%, Sigma-Aldrich) was added to dissolve the
formed formazan. Optical density at 570 and 670 nm for background was measured,
and the cell viability was calculated in percent compared to untreated cells. Experiments
were repeated at least three times and the mean IC50-value standard deviation
was determined.

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Experimental
General
All commercially available starting materials and reagents were used without further
purification. The solvents were dried and deoxygenated by refluxing and storing them
over sodium. Chemical reactions were monitored with thin-layer chromatography using
pre-coated silica gel 60 (0.25 mm thickness) plates. Flash column chromatography was
1
performed on silica gel 60 (0.040–0.063 mm). H and 13C spectra were recorded with a
400 MHz instrument at 298 K in DMSO and CDCl3, using the residual signals from
DMSO (1H: d ¼ 2.50 ppm; 13C: d ¼ 39.52 ppm) CHCl3 (1H: d ¼ 7.26 ppm; 13C:
d ¼ 77.2 ppm) as internal standard.
General procedures for the synthesis of chalcones derivatives (7–15)
To the stirred solution of aryl methyl ketone (1.0 eq.) and aldehyde (1.0 eq.) in ethanol,
was added KOH (1.0 eq.) solution drop wise at 0 ꢀC and the reaction mixture was
stirred for 1 h at same temperature, the reaction was monitored by TLC. After comple-
tion of the reaction, the reaction mixture was filtered and washed with water 2–3 times,
collect the solid, and dried under vacuum to get yellow solid compounds. The above
solid was recrystallized with ethanol to get pure yellow solid compounds with
good purity.
Spectral data of the compounds 7 and 8
(E)-4-(3-(4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)acryloyl)benzoic acid (7)
Yellow solid: Yield ¼ 85%: 1H NMR (400 MHz, DMSO): d 8.19 ꢁ 8.05 (m, 6H),
7.96 ꢁ 7.86 (m, 3H), 7.55 (d, J ¼ 15.1 Hz, 1H), 2.61 (s, 3H): 13C NMR (101 MHz,
DMSO) d 187.95, 164.87, 158.28, 139.36, 135.85, 133.08, 130.47, 129.52, 128.28, 127.06,
126.38, 126.35, 125.24, 123.57, 15.66. LC-HRMS: m/z calcd for [C21H14F3NO3S þ H]þ
418.0644, Found: 418.0639.
(E)-1-(2-hydroxy-5-methylphenyl)-3-(4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-
yl)prop-2-en-1-one (8)
1
Pale-yellow solid: Yield ¼ 86%; H NMR (400 MHz, DMSO) d 12.07 (s, 1H), 8.18 (d,
J ¼ 8.1 Hz, 2H), 8.02 ꢁ 7.88 (m, 4H), 7.67 (d, J ¼ 15.0 Hz, 1H), 7.38 (dd, J ¼ 8.3, 2.1 Hz,
1H), 6.91 (d, J ¼ 8.4 Hz, 1H), 2.63 (s, 3H), 2.31 (s, 3H). 13C NMR (101 MHz, DMSO) d
191.28, 158.81, 157.79, 136.51, 135.22, 132.29, 129.85, 129.59, 127.43, 126.44, 126.04,
125.75, 123.16, 119.91, 117.16, 116.90, 19.26, 15.03. LC-HRMS: m/z calcd for
[C21H16F3NO2S þ H]þ 404.0921, Found: 404.0916.
Conclusions
In summary, we synthesized and evaluated a novel series of thiazole linked chalcone
analogs as anticancer agents. Many of these thiazole analogs showed significant antipro-
liferative activity in CRC cell lines HT29, HCT-116, and Lovo. Out of all the thiazole

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C. KESARI ET AL.
analogs three compounds 7, 9, and 10 were active in all three cancer cell lines and
showed increased potency as compared with the control drug cisplatin. To further mod-
ify the structure of the new thiazole analogs, we prepared the corresponding cyclic pyr-
imidine derivatives shielding the enone fragment in the structure, however, none of
these derivatives showed improved activity. Collectively, the SAR investigation per-
formed provides guidance for further improvement of this compound class.
Acknowledgments
The authors are thankful to Faculty of Health and Medical Sciences, University of Copenhagen.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
[1] Bray, F.; Ferlay, J.; Isabelle, S.; Rebecca, L. S.; Lindsey, A. T.; Ahmedin, J. Global Cancer
Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36
Cancers in 185 Countries. CA Cancer J. Clin. 2018, 68, 394–424. DOI: 10.3322/caac.21492.
[2] Fojo, T.; Parkinson, D. R. Biologically Targeted Cancer Therapy and Marginal Benefits:
Are we Making Too Much of Too Little or Are we Achieving Too Little by Giving Too
Much? Clin. Cancer Res. 2010, 16, 5972–5980. DOI: 10.1158/1078-0432.CCR-10-1277.
[3] Glimelius, B.; Cavalli-Bjorkman, N. Metastatic Colorectal Cancer: Current Treatment and
Future Options for Improved Survival. Medical Approach-Present Status. Scand. J.
Gastroenterol. 2012, 47, 296–314. DOI: 10.3109/00365521.2012.640828.
ꢀ
[4] Tournigand, C.; Andre, T.; Achille, E.; Lledo, G.; Flesh, M.; Mery-Mignard, D.; Quinaux,
E.; Couteau, C.; Buyse, M.; Ganem, G.; et al. FOLFIRI Followed by FOLFOX6 or the
Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. J. Clin.
Oncol. 2004, 22, 229–237. DOI: 10.1200/JCO.2004.05.113.
[5] Tannaz, A.; Jon, D. W.; Quyen, C.; Glenn, M. Genetic Alterations in Colorectal Cancer.
Gastrointest. Cancer Res. 2012, 5, 19–27.
[6] Mouradov, D.; Sloggett, C.; Jorissen, R. N.; Love, C. G.; Li, S.; Burgess, A. W.; Arango, D.;
Strausberg, R. L.; Buchanan, D.; Wormald, S.; et al. Colorectal Cancer Cell Lines Are
Representative Models of the Main Molecular Subtypes of Primary Cancer. Cancer Res.
2014, 74, 3238–3247. DOI: 10.1158/0008-5472.CAN-14-0013.
[7] Syam, S.; Abdelwahab, S. I.; Al–Mamary, M. A.; Mohan, S. Synthesis of Chalcones with
Anticancer Activities. Molecules. 2012, 17, 6179–6195. DOI: 10.3390/molecules17066179.
[8] Nielsen, S. F.; Boesen, T.; Larsen, M.; Schønning, K.; Kromann, H. Antibacterial
Chalcones-Bioisosteric Replacement of the 40-hydroxy Group. Bioorg. Med. Chem. 2004,
12, 3047–3054. DOI: 10.1016/j.bmc.2004.03.071.
[9] Lahtchev, K. L.; Batovska, D. I.; Parushev, S. P.; Ubiyvovk, V. M.; Sibirny, A. A.
Antifungal Activity of Chalcones: A Mechanistic Study Using Various Yeast Strains. Eur.
J. Med. Chem. 2008, 43, 2220–2228. DOI: 10.1016/j.ejmech.2007.12.027.
[10] Hsieh, C. T.; Hsieh, T. J.; El–Shazly, M.; Chuang, D. W.; Tsai, Y. H.; Yen, C. T.; Wu,
S. F.; Wu, Y. C.; Chang, F. R. Synthesis of Chalcone Derivatives as Potential anti-Diabetic
Agents. Bioorg. Med. Chem. Lett. 2012, 22, 3912–3915. DOI: 10.1016/j.bmcl.2012.04.108.
[11] Nowakowska, Z. A Review of anti-Infective and anti-Inflammatory Chalcones. Eur. J.
Med. Chem. 2007, 42, 125–137. DOI: 10.1016/j.ejmech.2006.09.019.
[12] Maioral, M. F.; Gaspar, P. C.; Rosa Souza, G. R.; Mascarello, A.; Chiaradia, L. D.; Licinio,
M. A.; Moraes, A. C.; Yunes, R. A.; Nunes, R. J.; Santos-Silva, M. C. Apoptotic Events

R
SYNTHETIC COMMUNICATIONSV
1415
Induced by Synthetic Naphthylchalcones in Human Acute Leukemia Cell Lines. Biochimie.
2013, 95, 866–874. DOI: 10.1016/j.biochi.2012.12.001.
[13] Jamier, V.; Marut, W.; Valente, S.; Chereau, C.; Chouzenoux, S.; Nicco, C.; Lemarechal,
H.; Weill, B.; Kirsch, G.; Jacob, C.; Batteux, F. Chalcone-Coumarin Derivatives as
Potential anti-Cancer Drugs: An in Vitro and in Vivo Investigation. Anticancer Agents
Med. Chem. 2013, 14, 963–974. DOI: 10.2174/1871520613666131224124445.
[14] Drutovic, D.; Chripkova, M.; Pilatova, M.; Kruzliak, P.; Perjesi, P.; Sarissky, M.; Lupi, M.;
Damia, G.; Broggini, M.; Mojzis, J. Benzylidenetetralones, Cyclic Chalcone Analogues,
Induce Cell Cycle Arrest and Apoptosis in HCT116 Colorectal Cancer Cells. Tumour Biol.
2014, 35, 9967–9975. DOI: 10.1007/s13277-014-2289-y.
[15] Mathew, B.; Suresh, J.; Anbazghagan, S.; Paulraj, J.; Krishnan, G. K. Heteroaryl Chalcones:
Mini Review about Their Therapeutic Voyage. Biomed. Prev. Nutr. 2014, 4, 451–458. DOI:
10.1016/j.bionut.2014.04.003.
[16] Firoozpour, L.; Edraki, N.; Nakhjiri, M.; Emami, S.; Safavi, M.; Ardestani, S. K.;
Khoshneviszadeh, M.; Shafiee, A.; Foroumadi, A. Cytotoxic Activity Evaluation and QSAR
Study of Chromene-Based Chalcones. Arch. Pharm. Res. 2012, 35, 2117–2125. DOI: 10.
1007/s12272-012-1208-2.
[17] Noushini, S.; Alipour, E.; Emami, S.; Safavi, M.; KabudanianArdestani, S.; Gohari, A. R.;
Shafiee, A.; Foroumadi, A. Synthesis and Cytotoxic Properties of Novel (E)-3-Benzylidene-
7-Methoxychroman-4-One Derivatives. DARUJ. Pharm. Sci. 2013, 21, 31. DOI: 10.1186/
2008-2231-21-31.
[18] Letafat, B.; Shakeri, R.; Emami, S.; Noushini, S.; Mohammadhosseini, N.; Shirkavand, N.;
Kabudanian Ardestani, S.; Safavi, M.; Samadizadeh, M.; Letafat, A.; et al. Synthesis and
in Vitro Cytotoxic Activity of Novel Chalcone-like Agents. Iran. J. Basic Med. Sci. 2013,
16, 1155–1162.
[19] Ankita, K.; Nayana, A.; Arpita, D.; Anshul, S.; Surajit, K. G.; Udaya, P. S.; Hans, R. B.
Review on Synthetic Chemistry and Antibacterial Importance of Thiazole Derivatives.
Curr. Drug Discov. Technol. 2018, 15, 214–228. DOI: 10.2174/157016381466
6170911144036.
[20] Konstantinos, L.; Maria, F.; Athina, G. Thiazoles and Thiazolidinones as COX/LOX
Inhibitors. Molecules. 2018, 685, 23.
[21] Adileh, A.; Saeed, E.; Setareh, M.; Alireza, F. Thiazole in the Targeted Anticancer Drug
Discovery. Future Med. Chem. 11, 15. DOI: 10.4155/fmc-2018-0416.
[22] Romagnoli, R.; Baraldi, P. G.; Brancale, A.; Ricci, A.; Hamel, E.; Bortolozzi, R.; Basso, G.;
Viola, G. Convergent Synthesis and Biological Evaluation of 2-amino4-(30, 40, 50-
Trimethoxyphenyl)-5-Aryl Thiazoles as Microtubule Targeting Agents. J. Med. Chem.
2011, 54, 5144–5153. DOI: 10.1021/jm200392p.
[23] Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Camacho, M. E.; Preti, D.; Aghazadeh
Tabrizi, M.; Bassetto, M.; Brancale, A.; Hamel, E.; Bortolozzi, R.; et al. Synthesis and
Biological Evaluation of 2-Substituted-4-(30,40,50-trimethoxyphenyl)-5-aryl Thiazoles as
Anticancer Agents. Bioorg. Med. Chem. 2012, 20, 7083–7094. DOI: 10.1016/j.bmc.2012.10.
001.
[24] Romagnoli, R.; Baraldi, P. G.; Salvador, K. M.; Preti, D.; Aghazadeh Tabrizi, M.; Brancale,
A.; Fu, X.-H.; Li, J.; Zhang, S.-Z.; Hamel, E.; et al. Discovery and Optimization of a Series
of 2-aryl-4-Amino-5-(30,40,50-Trimethoxybenzoyl)Thiazoles as Novel Anticancer Agents.
J. Med. Chem. 2012, 55, 5433–5445. DOI: 10.1021/jm300388h.
[25] Adileh, A.; Rezvan, E.; Setareh, M.; TayebehOghabi, B.; Zahra, E.-S.; Keivan, M.; Maliheh,
S.; Saeed, E.; Alireza, F. Synthesis and Biological Evaluation of 4-Amino-5-
Cinnamoylthiazoles as Chalcone-like Anticancer Agents. Eur. J. Med. Chem. 2018, 145,
404–412.
[26] Majeed, R.; Sangwan, P. L.; Chinthakindi, P. K.; Khan, I.; Dangroo, N. A.; Thota, N.;
Hamid, A.; Sharma, P. R.; Saxena, A. K.; Koul, S. Synthesis of 3-O-Propargylated Betulinic
Acid and its 1,2,3-Triazoles as Potential Apoptotic Agents. Eur. J. Med. Chem. 2013, 63,
782–792. DOI: 10.1016/j.ejmech.2013.03.028.

1416
C. KESARI ET AL.
[27] Kankala, S.; Kankala, R. K.; Gundepaka, P.; Thota, N.; Nerella, S.; Gangula, M. R.;
Guguloth, H.; Kagga, M.; Vadde, R.; Vasam, C. S. Regioselective Synthesis of Isoxazole-
Mercaptobenzimidazole Hybrids and Their in Vivo Analgesic and anti-Inflammatory
Activity Studies. Bioorg. Med. Chem. Lett. 2013, 23, 1306–1309. DOI: 10.1016/j.bmcl.2012.
12.10.
[28] Kotha, S.; Goyal, D.; Bitra, A.; Thota, N.; Kruger, H. G.; Anand, R. Diversity Oriented
Approach toTriazole Based Peptidomimetics as Mammalian Sterile 20 Kinase Inhibitors.
RSC Adv. 2013, 3, 24447–24454. DOI: 10.1039/c3ra44318c.
€
[29] Kankala, S.; Thota, N.; Bjorkling, F.; Taylor, M. K.; Vadde, R.; Balusu, R. Silver Carbene
Complexes: An Emerging Class of anticancer agents. Drug Dev. Res. 2019, 80, 188–199.
DOI: 10.1002/ddr.21478.
[30] Singh, P.; Amit, A.; Vipan, K. Recent Developments in Biological Activities of Chalcones:
A Mini Review. Eur. J. Med. Chem. 2014, 85, 758–777. DOI: 10.1016/j.ejmech.2014.08.03.