Synthesis and biological evaluation of 2,4-disubstituted thiazole amide derivatives as anticancer agent

Article abstract of DOI:10.1007/s11696-018-0587-3

A series of novel 2,4-disubstituted thiazole amide derivatives were synthesized, and their antiproliferative activities were tested. Some of these compounds displayed good antiproliferative activity, especially for HT29 cell. Among these compounds, compound 5b inhibits A549, HeLa, HT29 and Karpas299 cells with IC₅₀ values of 8.64, 6.05, 0.63 and 13.87?μM, respectively. The western blot analysis and docking study provide important clues for further optimization of compound 5b as a potential c-Met inhibitor.

Full text of DOI:10.1007/s11696-018-0587-3

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https://doi.org/10.1007/s11696-018-0587-3
ORIGINAL PAPER
Synthesis and biological evaluation of 2,4‑disubstituted thiazole
amide derivatives as anticancer agent
Zhi‑Hua Zhang1 · Hong‑Mei Wu1 · Sai‑Nan Deng2 · Rui‑Xia Chai2 · Muriira Cyrus Mwenda2 · Yuan‑Yuan Peng2 ·
Dong Cai3 · Yu Chen4
Received: 6 April 2018 / Accepted: 1 September 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
A series of novel 2,4-disubstituted thiazole amide derivatives were synthesized, and their antiproliferative activities were
tested. Some of these compounds displayed good antiproliferative activity, especially for HT29 cell. Among these com-
pounds, compound 5b inhibits A549, HeLa, HT29 and Karpas299 cells with IC50 values of 8.64, 6.05, 0.63 and 13.87 μM,
respectively. The western blot analysis and docking study provide important clues for further optimization of compound 5b
as a potential c-Met inhibitor.
Keywords Thiazole derivatives · Synthesis · Anticancer activity
Introduction
activities (Bhat et al. 2013; Chang et al. 2012; El-Messery
et al. 2012; Smith et al. 2012; Hassan et al. 2012).
2-Aminothiazole derivatives, especially 4-phenylthiazol-
2-amines, have attracted interest over the last decades for
their multiple biological activities (Alam et al. 2011; Sid-
diqui et al. 2007; Zhou et al. 2008), and many derivatives
of 4-phenylthiazol-2-amine are well known as anticancer
agents 1–2 (Fig. 1). The position of the substituents on the
phenyl group and the type of the substituents on the 2-amino
group are responsible for the variety of antiproliferative
Recently, we have discovered many compounds that
possess anticancer activity, such as novel ALK inhibitors
(Gennäs et al. 2011; Tu et al. 2016) 3 and 4 (Fig. 1). These
active compounds are structurally similar to 4-phenylthiazol-
2-amines and display discrete structural overlap with the
4-phenylthiazol-2-amine scafold.
Crizotinib (PF-02341066), developed by Pfzer Inc., is
a potent inhibitor of c-Met and ALK with IC50 of 11 nM
and 24 nM in cell-based assays, respectively (Cui et al.
2011). This compound was approved by the FDA in 2014
for patients with bladder cancer, non-Hodgkin’s lym-
phoma, renal cell carcinoma and non-small cell lung cancer
(NSCLC) (Wilson et al. 2014). However, crizotinib induced
some adverse reactions, including vision disorder, nausea,
diarrhea, vomiting, constipation, edema, elevated transami-
nases, and fatigue (Solomon 2014).
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0587-3) contains
supplementary material, which is available to authorized users.
* Dong Cai
Caidong0804@163.com
Inspired by the above-mentioned facts and in continuation
of our research program on inhibitory activities of 4-phe-
nylthiazol-2-amine derivatives, crizotinib was selected as
a backbone for the development of novel 2,4-disubstituted
thiazole amide derivatives (Fig. 2). Using a scafold modif-
cation strategy, we employed a substituted 4-phenylthiazol-
2-amine moiety instead of a substituted 3-(1H-pyrazol-4-yl)
pyridine fragment of crizotinib. The 2-amino function of
the 4-phenylthiazol-2-amine core was also acylated to pro-
duce the terminal 2-morpholinoacetamido fragment, whose
* Yu Chen
gzweishengwu@126.com
1
School of Chemical and Environmental Engineering,
Liaoning University of Technology, Jinzhou 121001, China
2
College of Pharmacy, Jinzhou Medical University,
Jinzhou 121001, China
3
College of Basic Science, Jinzhou Medical University,
Jinzhou 121001, China
4
School of Life Science and Biopharmaceutics, Shenyang
Pharmaceutical University, Shenyang 110016, China
Vol.:(0123456789)
1 3

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Fig. 1 Structures of known antineoplastic compounds 1–4
Experimental
Chemicals, reagents and instruments
All reagents were purchased and used without further purifca-
tion. Melting points were obtained in open capillaries using
a WRS-1B melting point apparatus (Shen Guang, China) and
were uncorrected. The 1H and 13C NMR spectra were recorded
on a 400/54 Premium Shielded NMR Magnet System (Agilent,
American). Mass spectral data were collected from an Agi-
lent 6200 Series TOF and 6500 Series Q-TOF LC/MS System
B.05.01. (B5125) in positive ion modes (Agilent, American).
Analytical TLC was performed on silica gel 60 F254 plates
(Merck, Germany).
4‑(4‑Nitrophenyl)thiazol‑2‑amine 1
A mixture of 2-bromo-1-(4-nitrophenyl) ethanone (2.44 g,
10.0 mmol) and thiourea (0.84 g, 10.0 mmol) was dissolved in
anhydrous ethanol (20 mL). The reaction mixture was refuxed
for 10 h. After confrmation of completion of the reaction by
TLC, the reaction mixture was cooled to room temperature
and then poured into cold water. It was then basifed using
saturated NaHCO3. The resulting yellow solid was collected
by suction fltration and washed with water. It was then dried
to yield compound 1.
Fig. 2 The rational design of the novel target compounds
Yellow solid; yield, 97.2%; m.p.: 273.4–274.6 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.28–8.19 (m, 2H), 8.09–8.00 (m,
2H), 7.42 (s, 1H), 7.26 (s, 2H); 13C NMR (101 MHz, DMSO-
d6) δ 169.0, 148.2, 146.3, 141.3, 126.7, 124.5, 107.0; HRMS
(m/z): calcd. for C9H8N3O2S (neutral M+H) 222.03372, found
222.03352.
nitrogen atoms of morpholine ring can form the ionic form,
similar to crizotinib (Cui et al. 2011; Huang et al. 2014;
Shaw et al. 2016). We also employed an amide moiety
instead of 2-amino and 3-alkoxy groups on the pyridine ring
of crizotinib which contain a hydrogen bond donor–acceptor
pair. To fnd a suitable replacement for the R group, various
substituents on the phenyl ring and non-aromatic fragments
were also included in the study. In this paper, we sought to
develop novel 2,4-disubstituted thiazole amides with anti-
proliferative activities. The general structure of the proposed
targeted compounds is shown in Fig. 2.
1 3

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2‑Chloro‑N‑(4‑(4‑nitrophenyl)thiazol‑2‑yl)acetamide 2
(m/z): calcd. For C15H19N4O2S (neutral M+H) 319.12287,
found 319.12336.
A solution of compound 1 (2.21 g, 10.0 mmol) and chloro-
acetic anhydride (3.42 g, 20.0 mmol) in acetonitrile (20 mL)
was heated at 70 °C for 16 h. The reaction mixture was then
concentrated and diluted with ethyl acetate. The organic
layer was washed with a solution of sodium bicarbonate and
water. The organics were combined, dried, fltered and the
solvent removed under vacuum to yield compound 2.
General procedure for the synthesis of compounds 5a‑o
To a mixture of compound 4 (32 mg, 0.1 mmol) and trieth-
ylamine (20 mg, 0.2 mmol) in CH2Cl2 (20 mL), substituted
acyl chloride (0.15 mmol) was added over a period of 10 min
at 5 °C, and the reaction mixture was stirred at room tem-
perature overnight. The reaction mixture was poured into
H2O (500 mL) and extracted with CH2Cl2. The organic layer
was washed with water, dried over anhydrous Na2SO4 and
concentrated under vacuum. The residual solid was puri-
fed by column chromatography on silica gel to give a target
compound.
1
Yellow solid; yield, 84.1%; m.p.: 215.5–216.7 °C; H
NMR (400 MHz, Chloroform-d) δ 8.38–8.27 (m, 2H),
8.09–7.98 (m, 2H), 7.49–7.41 (m, 1H), 7.34–7.25 (m, 1H),
4.41–4.32 (m, 2H); 13C NMR (101 MHz, Chloroform-d) δ
170.4, 159.1, 151.6, 148.0, 144.4, 126.6, 124.2, 111.9, 42.0;
HRMS (m/z): calcd. For C11H9ClN3O3S (neutral M+H)
298.00531, found 298.00479.
2‑Morpholino‑N‑(4‑(4‑nitrophenyl)thiazol‑2‑yl)acetamide 3
3‑Methyl‑N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)
phenyl)benzamide 5a Yellow solid; yield, 74.8%; m.p.:
197.0–198.9 °C; IR (KBr): υ 3043, 1873, 1852, 1770,
A mixture of compound 2 (2.97 g, 10.0 mmol), morpholine
(0.96 g, 11.0 mmol), KI (0.17 g, 1.0 mmol) and anhydrous
K2CO3 (4.14 g, 30.0 mmol) in absolute ethanol (50 mL) was
heated under refux. After confrmation of completion of
the reaction by TLC, the excess of ethanol was removed
under vacuum and the residue extracted with CH2Cl2, The
organic layer was washed with cold water, dried and the
solvent removed under vacuum. The residue was crystallized
from ethanol to give the product.
1
1750,1479, 1345, 1265, 1238 cm−1; H NMR (400 MHz,
DMSO-d6) δ 12.09 (s, 1H), 10.33 (s, 1H), 7.95–7.84 (m,
4H), 7.79 (m, 2H), 7.58 (s, 1H), 7.44 (s, 2H), 3.64 (t,
J=4.5 Hz, 4H), 3.34 (s, 2H), 2.59–2.53 (m, 4H), 2.43 (s,
3H); 13C NMR (101 MHz, DMSO-d6) δ 168.9, 166.1, 157.8,
149.1, 139.3, 138.2, 135.3, 132.6, 130.1, 128.8, 128.5,
126.4, 125.3, 120.7, 107.5, 66.6, 60.8, 53.4, 21.4; HRMS
(m/z): calcd. For C23H25N4O3S (neutral M+H) 437.16474,
found 437.17644.
1
Yellow solid; yield, 88.2%; m.p.: 215.0–216.3 °C; H
NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.29 (d,
J=8.7 Hz, 2H), 8.03 (d, J=8.7 Hz, 2H), 7.40 (s, 1H), 3.85
(t, J = 4.6 Hz, 4H), 3.32 (s, 2H), 2.68 (t, J = 4.6 Hz, 4H);
13C NMR (101 MHz, chloroform-d) δ 168.5, 157.5, 147.7,
147.1, 140.1, 126.6, 124.2, 111.5, 66.8, 61.4, 53.9; HRMS
(m/z): calcd. For C15H17N4O4S (neutral M+H) 349.09705,
found 349.09688.
3,4‑Dichloro‑N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)
phenyl)benzamide 5b Gray solid; yield, 77.0%; m.p.:
246.7–248.7 °C; IR (KBr): υ 3043, 1867, 1846, 1570,
1
1555,1473, 1342, 1268, 1239 cm−1; H NMR (400 MHz,
DMSO-d6) δ 12.10 (s, 1H), 10.52 (s, 1H), 8.25 (d, J=3.9 Hz,
1H), 7.94 (m, 3H), 7.86 (s, 2H), 7.86 (m, 1H), 7.60 (d,
J=4.0 Hz, 1H), 3.63 (d, J=5.2 Hz, 4H), 3.34 (d, J=4.0 Hz,
2H), 2.55 (d, J=5.4 Hz, 4H); 13C NMR (101 MHz, DMSO-
d6) δ 168.9, 163.6, 157.8, 148.9, 138.8, 135.6, 134.8, 131.7,
131.2, 130.5, 130.0, 128.5, 126.5, 120.8, 107.7, 66.6, 60.8,
53.4; HRMS (m/z): calcd. For C22H21Cl2N4O3S (neutral
M+H) 491.07114, found 491.07138.
N‑(4‑(4‑aminophenyl)thiazol‑2‑yl)‑2‑morpholinoacetamide
4
Compound 3 (0.35 g, 1.0 mmol) was dissolved in ethanol
(20 mL) and SnCl2·2H2O (0.45 g, 2.0 mmol) was added.
The mixture was refuxed for 4 h and ethanol was evap-
orated under vacuum. The residue was dissolved into
CH2Cl2 (40 mL) and then washed with dilute NaOH solu-
tion (1 mol/L, 3×20 mL) and water (3×20 mL), dried and
evaporated to dryness to give the product.
2,4‑Dichloro‑N‑(4‑(2‑(2‑morpholinoacetamido)thia‑
zol‑4‑yl)phenyl)benzamide 5c Gray solid; yield, 79.1%;
m.p.: 231.3–232.9 °C; IR (KBr): υ 3040, 1870, 1846,
1567, 1556,1476, 1345, 1265, 1233 cm−1; 1H NMR
(400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.08 (s, 1H), 8.98
(s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.54–7.45 (m, 5H), 7.14
(t, J = 1.9 Hz, 1H), 3.57 (t, J = 4.6 Hz, 4H), 3.27 (s, 2H),
2.49 (d, J = 4.5 Hz, 3H); 13C NMR (101 MHz, DMSO-d6)
δ 168.9, 164.4, 157.9, 148.9, 138.7, 136.1, 135.3, 131.6,
130.8, 130.4, 129.7, 127.9, 126.6, 120.1, 107.7, 66.6,
1
Yellow solid; yield, 85.3%; m.p.: 181.5–182.8 °C; H
NMR (400 MHz, chloroform-d) δ 10.39 (s, 1H), 7.66 (d,
J=7.8 Hz, 2H), 6.97 (s, 1H), 6.74 (d, J=7.8 Hz, 2H), 3.81
(d, J=9.4 Hz, 4H), 3.26 (d, J =3.8 Hz, 2H), 2.63 (s, 4H);
13C NMR (101 MHz, chloroform-d) δ 168.2, 156.8, 150.3,
146.4, 127.2, 125.1, 115.1, 105.1, 66.8, 61.6, 53.9; HRMS
1 3

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60.8, 55.4, 53.3; HRMS (m/z): calcd. For C22H21Cl2N4O3S
For C22H22FN4O3S (neutral M+H) 441.13966, found
441.14350.
(neutral M+H) 491.07114, found 491.07255.
3‑Chloro‑N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)
phenyl)benzamide 5d Yellow solid; yield, 74.0%; m.p.:
196.0–197.5 °C; IR (KBr): υ 3040, 1867, 1846, 1565,
4‑Fluoro‑N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)
phenyl)benzamide 5h White solid; yield, 74.5%; m.p.:
205.6–206.8 °C; IR (KBr): υ 3043, 1869, 1846, 1570,
1
1
1553,1476, 1345, 1265, 1239 cm−1; H NMR (400 MHz,
1550,1476, 1348, 1268, 1239 cm−1; H NMR (400 MHz,
DMSO-d6)δ12.09(s,1H),10.48(s,1H),8.04(d,J = 1.9Hz,
1H), 7.99–7.83 (m, 5H), 7.70 (dd, J = 7.9, 2.0 Hz, 1H),
7.64–7.58 (m, 2H), 3.64 (t, J = 4.6 Hz, 4H), 3.34 (s, 2H),
2.55 (t, J = 4.7 Hz, 4H); 13C NMR (101 MHz, DMSO-d6)
δ 168.9, 164.5, 157.8, 149.0, 138.9, 137.3, 133.6, 131.9,
130.9, 130.4, 127.8, 126.9, 126.5, 120.9, 107.7, 66.6,
60.8, 53.4; HRMS (m/z): calcd. For C22H22ClN4O3S (neu-
tral M+H) 457.11011, found 457.11013.
DMSO-d6) δ 12.12–12.07 (m, 1H), 10.40 (d, J=4.4 Hz,
1H), 8.07 (d, J=6.7 Hz, 2H), 7.96–7.83 (m, 4H), 7.62–7.56
(m, 1H), 7.41 (p, J=6.1 Hz, 2H), 3.63 (d, J=5.7 Hz, 4H),
3.36–3.30 (m, 2H), 2.71 (d, J=7.7 Hz, 4H); 13C NMR
(101 MHz, DMSO-d6) δ 168.9, 165.7, 164.9, 163.3, 157.8,
149.0, 139.1, 131.8, 131.7, 130.9, 130.8, 130.2, 126.4,
120.8, 115.9, 115.7, 107.6, 66.6, 60.8, 53.4; HRMS (m/z):
calcd. For C22H22FN4O3S (neutral M+H) 441.13966, found
441.14684.
3‑Bromo‑N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)
phenyl)benzamide 5e Yellow solid; yield, 74.0%; m.p.:
196.0–197.5 °C; IR (KBr): υ 3042, 1869, 1852, 1565,
N‑ ( 4 ‑ ( 2 ‑ ( 2 ‑ M o r p h o l i n o a c e t a m i d o ) t h i a z o l ‑ 4 ‑ y l )
phenyl)‑3‑(trifuoromethyl)benzamide 5i Gray solid; yield,
70.1%; m.p.: 210.0.8–211.9 °C; IR (KBr): υ 3043, 1870,
1
1555,1476, 1342, 1265, 1237 cm−1; H NMR (400 MHz,
1
DMSO-d6) δ 12.06 (s, 1H), 10.42 (s, 1H), 8.12 (s, 1H),
7.95–7.90 (m, 1H), 7.90–7.74 (m, 5H), 7.54 (d, J = 1.7 Hz,
1H), 7.48 (t, J = 7.9 Hz, 1H), 3.58 (t, J = 4.6 Hz, 4H), 3.28
(s, 2H), 2.53–2.45 (m, 4H); 13C NMR (101 MHz, dmso)
δ 168.9, 164.4, 157.8, 149.0, 138.9, 137.5, 134.8, 131.1,
130.7, 130.4, 127.3, 126.5, 122.1, 120.8, 107.7, 66.6, 60.8,
53.4; HRMS (m/z): calcd. For C22H22BrN4O3S (neutral
M+H, neutral M+H+2) 501.05960, found 501.067777,
503.06605.
1846, 1567, 1553,1476, 1345, 1271, 1239 cm−1; H NMR
(400 MHz, DMSO-d6) δ 12.09 (s, 1H), 10.60 (s, 1H), 8.31
(m, 2H), 8.01 (d, J=7.7 Hz, 1H), 7.96–7.84 (m, 5H), 7.61
(s, 1H), 3.64 (d, J=5.6 Hz, 4H), 3.34 (s, 2H), 2.56 (d,
J=5.3 Hz, 4H); 13C NMR (101 MHz, DMSO-d6) δ 168.9,
164.5, 157.8, 149.0, 138.8, 136.2, 132.3, 130.5, 130.2,
130.0, 129.8, 129.4, 128.6, 126.5, 125.8, 124.7, 124.6,
123.1, 121.0, 107.7, 66.6, 60.8, 53.4; HRMS (m/z): calcd.
For C23H22F3N4O3S (neutral M+H) 491.13647, found
491.13990.
4‑Bromo‑N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)
phenyl)benzamide 5f Yellow solid; yield, 74.0%; m.p.:
191.1–193.0 °C; IR (KBr): υ 3046, 1870, 1849, 1565,
N‑ ( 4 ‑ ( 2 ‑ ( 2 ‑ M o r p h o l i n o a c e t a m i d o ) t h i a z o l ‑ 4 ‑ y l )
phenyl)‑4‑(trifuoromethyl)benzamide 5j Gray solid; yield,
72.2%; m.p.: 208.7–210.0 °C; IR (KBr): υ 3043, 1864,
1
1547,1473, 1345, 1256, 1238 cm−1; H NMR (400 MHz,
1
DMSO-d6) δ 12.06 (s, 1H), 10.39 (s, 1H), 7.92–7.78 (m,
6H), 7.76–7.71 (m, 2H), 7.54 (s, 1H), 3.57 (t, J = 4.6 Hz,
4H), 3.28 (s, 2H), 2.53–2.45 (m, 4H); 13C NMR (101 MHz,
DMSO-d6) δ 168.9, 165.0, 157.8, 149.0, 139.0, 134.3,
131.9, 130.3, 130.2, 126.5, 125.8, 120.8, 107.6, 66.6,
60.8, 53.4; HRMS (m/z): calcd. For C22H22BrN4O3S (neu-
tral M+H) 501.05960, found 501.067777, 503.06600.
1846, 1567, 1556,1479, 1345, 1268, 1233 cm−1; H NMR
(400 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.61 (s, 1H), 8.18
(d, J=8.1 Hz, 2H), 7.99–7.85 (m, 6H), 7.61 (s, 1H), 3.64 (t,
J=4.6 Hz, 4H), 3.34 (s, 2H), 2.59–2.51 (m, 4H); 13C NMR
(101 MHz, DMSO-d6) δ 168.9, 164.8, 157.8, 149.0, 139.1,
138.9, 132.0, 131.6, 130.5, 129.0, 128.7, 126.5, 125.9,
125.9, 125.9, 125.8, 125.7, 123.0, 120.9, 107.7, 66.6, 60.8,
53.4; HRMS (m/z): calcd. For C23H22F3N4O3S (neutral
M+H) 491.13647, found 491.13719.
3‑Fluoro‑N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)
phenyl)benzamide 5g White solid; yield, 72.7%; m.p.:
200.1–201.9 °C; IR (KBr): υ 3040, 1867, 1846, 1567,
N‑(4‑(2‑(2‑morpholinoacetamido)thiazol‑4‑yl)phenyl)
furan‑2‑carboxamide 5k White solid; yield, 86.6%; m.p.:
190.1–192.2 °C; IR (KBr): υ 3046, 1870, 1849, 1566,
1550,1479, 1342, 1250 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 12.03 (s, 1H), 10.27 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H),
7.87–7.74 (m, 4H), 7.52 (s, 1H), 7.32 (d, J = 3.4 Hz, 1H),
6.68 (dd, J = 3.5, 1.8 Hz, 1H), 3.57 (t, J = 4.6 Hz, 4H),
3.27 (s, 2H), 2.50–2.47 (m, 4H); 13C NMR (101 MHz,
DMSO-d6) δ 168.9, 157.8, 156.6, 149.0, 147.8, 146.3,
1
1558,1479, 1351, 1274, 1239 cm−1; H NMR (400 MHz,
DMSO-d6) δ 12.08 (s, 1H), 10.44 (s, 1H), 7.92–7.79
(m, 6H), 7.61 (t, J = 7.6 Hz, 2H), 7.50 (d, J = 9.6 Hz,
1H), 3.64 (d, J = 5.6 Hz, 4H), 3.34 (d, J = 4.1 Hz, 2H),
2.70 (s, 4H); 13C NMR (101 MHz, DMSO-d6) δ 168.9,
164.6, 163.6, 161.1, 157.8, 149.0, 138.9, 137.6, 137.6,
131.1, 131.0, 130.4, 126.5, 124.3, 120.9, 119.1, 118.9,
115.0, 114.8, 107.7, 66.6, 60.8, 53.4; HRMS (m/z): calcd.
1 3