Substituted thiazoles VII. Synthesis and antitumor activity of certain 2-(substituted amino)-4-phenyl-1,3-thiazole analogs

Article abstract of DOI:10.1016/j.bmcl.2012.08.095

A novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazoles (11-34) was designed and synthesized. Compounds were subjected to National Cancer Institute (NCI) in vitro assessment for their antitumor activity, at a single dose of 10 μM. Most of the investigated compounds exhibited broad-spectrum antitumor activity. Compounds 19 and 28 believed to be the most active members in this study, with MG-MID GI ₅₀, TGI, and LC₅₀ values of 2.8, 11.4, 44.7; and 3.3, 13.1, 46.8, respectively. Compounds 19 and 28 proved to be nine and sevenfold more active than the standard antitumor drug 5-FU, respectively.

Full text of DOI:10.1016/j.bmcl.2012.08.095

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6318–6323
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted thiazoles VII. Synthesis and antitumor activity of certain
2-(substituted amino)-4-phenyl-1,3-thiazole analogs
Ghada S. Hassan a,b, Shahenda M. El-Messery c, Fatmah A. M. Al-Omary a, Hussein I. El-Subbagh d,
⇑
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia
b Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt
c Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt
d Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311 Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazoles (11–34) was
Received 12 June 2012
Revised 20 August 2012
Accepted 24 August 2012
Available online 3 September 2012
designed and synthesized. Compounds were subjected to National Cancer Institute (NCI) in vitro assess-
ment for their antitumor activity, at a single dose of 10 lM. Most of the investigated compounds exhib-
ited broad-spectrum antitumor activity. Compounds 19 and 28 believed to be the most active members
in this study, with MG-MID GI50, TGI, and LC50 values of 2.8, 11.4, 44.7; and 3.3, 13.1, 46.8, respectively.
Compounds 19 and 28 proved to be nine and sevenfold more active than the standard antitumor drug
5-FU, respectively.
Keywords:
Synthesis
Antitumor screening
Substituted-1,3-thiazole
Ó 2012 Elsevier Ltd. All rights reserved.
Thiazole containing heterocyclic compounds attracted the
interest of medicinal chemists due to their synthetic feasibility
and their incorporation into variety of therapeutically active
agents. They represent a wide range of biological potencies includ-
ing antibacterial, antifungal, anti-HIV, antihypertension, antiin-
flammatory, anticancer, anticonvulsant, and antidepressant.1–6
Meanwhile, DNA is one of the major targets of anticancer drugs
since the development of the nitrogen mustards. Targeting DNA
of tumor cells has been one of the most effective clinical strategies
for many DNA intercalators such as groove binders and anticancer
antibiotics.7–10 In addition, mechanisms of 1,3-thiazole and related
heterocycles antitumor activity may be associated with the affinity
to anticancer biotargets, such as phosphatase of a regenerating
liver (PRL-3),11,12 non-membrane protein tyrosine phosphatase
NH2
HN
CH3
O
H
CH3
N
O
N
NH2
N
O
NH2
HN
N
H
N
N
N
HN
O
H
N
H
S
S
NH
H2N
O
O
Thia-netropsin (2)
Netropsin (1)
O
NH
HN
O
C2H5
N
C2H5
COOH
O
CH3O
S
EtOOC
N
N
N
S
C6H11
NH
N
N
N
H
S
S
H
4
5
3
Chart 1. Structures of netropsin (1), thia-netropsin (2), and some literature thiazole antitumor agents (3-5).
⇑
Corresponding author.
E-mail address: subbagh@yahoo.com (H.I. El-Subbagh).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.095

G. S. Hassan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6318–6323
6319
Br
Br
Br
O
N
O
N
N
(CH2)n
(CH2)n
R
NH2
NH2
NH2
N
S
N
H
S
S
H
Cl
6
9: n = 1
10: n = 2
11-16
Cl
Cl
Cl
O
Cl
(CH2)n
Cl
7: n = 1
8: n = 2
Secondary Amine
O
N
O
N
N
(CH2)n
Cl
(CH2)n
R
K2CO3 / Toluene
N
H
N
H
S
S
S
18: n = 1
17
20-25
19:
n = 2
H3C
H3C
H3C
O
O
N
S
N
S
N
(CH2)n
Cl
(CH2)n
R
N
H
N
H
S
29-34
27:
n = 1
26
28: n = 2
11, 20, 29: R = morpholine, n = 1
12, 21, 30: R = morpholine, n = 2
13, 22, 31: R = N-methyl-piperazine, n = 1
14, 23, 32: R = N-methyl-piperazine, n = 2
15, 24, 33:
16, 25, 34:
R = N-phenyl-piperazine, n = 1
R = N-phenyl-piperazine, n = 2
Scheme 1. Synthesis of the target compounds 11–34.
(SHP-2),13 JNK-stimulating phosphatase-1 (JSP-1),14 tumor necro-
sis factor TNFa,15 antiapoptotic biocomplex Bcl-XL-BH3,16 integrin
avb3,17 etc. Necroptosis inhibitors have been recently identified
among 1,3-thiazole related compounds.18 On the other hand ben-
zothiazole ring belongs to the privilleged scaffolds in modern
medicinal chemistry19 particularly in discovering of new antican-
cer agents. Various benzothiazole derivatives were proposed as
inhibitors of fatty acid amide hydrolase (FAAH),20 Raf kinase
(Raf-1)21 and B-cell lymphoma protein BCL-2.22
the antitumor activity. The 2-amino function of the 4-(4-substi-
tuted phenyl)-1,3-thiazoles was also acylated with aliphatic acid
chlorides of various length to produce 2-acetamido- or 2-propa-
namido-analogs fitted at the terminal end with variety of second-
ary amines as an attempt for isosteric simulation of the amidine
and the guanidine functions of netropsin (1) with the hope to lo-
cate new lead compound(s). The synthesized compounds (Scheme
1, Table 1) were subjected to the NCI in vitro disease-oriented hu-
man cells screening panel assay,41–43 to evaluate the effect of this
structural alterations on the antitumor activity. The synthesis of
compounds 11, 20 and 29 were previously reported.44
The clinical efficacy of the groove binders tiazofurin, distamy-
cin, netropsin (1), thia-netropsin (2), and bleomycin pointed out
the importance of the 1,3-thiazole moieties and their contribution
to enhance the antitumor activity, Chart 1,23–32 The antitumor
activity of 2, 4-disubstituted 1,3-thiazole analogs was reported
and well documented.33–40 Many substituted thiazole analogs
were prepared and screened for their antitumor activity, most of
them proved to possess promising activity against numerous tu-
mor cell lines. Certain 1,3-thiazole containing derivatives (3–5,
Chart 1) proved to be effective antitumor agents with GI50 range
The synthesized compounds 11–34 were subjected to the Na-
tional Cancer Institute (NCI) in vitro disease-oriented human cells
screening panel assay for in vitro antitumor activity. A single dose
(10 lM) of the test compounds were used in the full NCI 60 cell
lines panel assay which includes nine tumor subpanels namely;
Leukemia, Non-small cell lung, Colon, CNS, Melanoma, Ovarian, Re-
nal, Prostate, and Breast cancer cells.41–43 The data reported as
mean-graph of the percent growth of the treated cells, and pre-
sented as percentage growth inhibition (GI%) caused by the test
compounds (Table 2).
In the present investigation, most of the tested compounds
showed broad spectrum antitumor activity. Compounds 24, 31,
and 34 displayed modest potency against the tested tumor cell
lines and considered to be the least effective members. Concerning
activity toward individual cell lines, compound 19 proved to be
lethal to Non-small cell lung cancer cell line HOP-92, Renal cancer
RXF 393, and Breast cancer MDA-MB-468; while compound 28
proved to be lethal to Non-small cell lung cancer cell line NCI-
H23, Renal cancer TK-10, and Breast cancer MDA-MB-468. Colon
cancer cell line HT29 proved to be sensitive toward compound
14 with GI value of 80.4%, while Leukemia cell lines CCRF-CEM,
of 0.08–2.9 l
M.35–39
In view of these facts, an efficient and reproducible synthesis of
some 2-(substituted amino)-4-phenyl-1,3-thiazole derivatives has
been developed recently in our laboratory as structurally related
analogs of the previously mentioned groove binding agents. Those
4-phenyl-1,3-thiazole analogs displayed a broad range of cancer
in vitro growth inhibition according to the pattern generated in
the NCI-60 cell line screening assay.40 The finding that aromatic
substitution at position 4- of the 1,3-thiazole ring contribute to
the antitumor activity encouraged further investigation; some
new 2-amino-4-(4-substituted phenyl)-1,3-thiazole analogs bear-
ing 4-chloro-, 4-bromo- or 4-methyl-phenyl moieties, were syn-
thesized to explore the electronic effect of such substituent on

6320
G. S. Hassan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6318–6323
Table 1
Physicochemical properties of the newly synthesized compounds 9–34
Br
H3C
Cl
O
N
O
O
N
N
(CH2)n
(CH2)n
R
(CH2)n
R
N
S
N
H
N
H
S
S
H
R
9-16
18-25
27-34
Compound
R
n
Solvent
Yield (%)
Mp °C
Molecular formulaea
C11H8BrClN2OS
9
Cl
Cl
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
—
66
60
59
68
73
62
82
67
64
55
65
59
70
68
71
73
70
73
73
61
64
78
72
70
89–92
180–2
115–8
162–4
153–5
Oil
10
11
12
13
14
15
16
18
19
20
21
22
23
24
25
27
28
29
30
31
32
33
34
C
C
C
C
C
C
12H10BrClN2OS
15H16BrN3O2S
16H18BrN3O2S
16H19BrN4OS
17H21BrN4OS
21H21BrN4OS
Morpholine
Morpholine
N-Methylpiperazine
N-Methylpiperazine
N-Phenylpiperazine
N-Phenylpiperazine
Cl
Ethylacetate
Ethanol
Ethanol
Ethylacetate
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethylacetate
Ethanol
Ethanol
Ethylacetate
Ethanol
Ethanol
Ethylacetate
Ethanol
Ethanol
144–7
76–78
169–71
164–6
132–5
146–8
140–2
128–30
142–5
181–3
165–7
151–3
144–6
159–60
166–9
155–7
151–4
134–6
C22H23BrN4OS
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
11H8 Cl2N2OS
12H10Cl2N2OS
15H16ClN3O2S
16H18ClN3O2S
16H19ClN4OS
17H21ClN4OS
21H21ClN4OS
22H23ClN4OS
12H11ClN2OS
13H13ClN2OS
16H19N3O2S
17H21N3O2S
17H22N4OS
Cl
Morpholine
Morpholine
N-Methylpiperazine
N-Methylpiperazine
N-Phenylpiperazine
N-Phenylpiperazine
Cl
Cl
Morpholine
Morpholine
N-Methylpiperazine
N-Methylpiperazine
N-Phenylpiperazine
N-Phenylpiperazine
18H24N4OS
22H24N4OS
23H26N4OS
a
Analysed for C,H,N; results were within 0.4% of the theoretical values for the given formulae.
Table 2
Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10 lM concentration of compounds 11–34
Subpanel tumor cell lines
1
14
15
19
23
24
25
28
31
33
34
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
15.3
12.6
25.1
33.2
28.9
—
24.9
37.7
52.4
38.1
30.5
—
22.2
27.1
70.7
47.6
33.6
—
88.3
28.5
63.0
61.3
92.8
77.7
18.3
20.6
22.4
51.8
17.6
—
—
—
—
—
—
—
16.3
19.6
21.6
36.3
25.4
—
88.3
41.4
21.1
43.3
80.9
88.5
—
—
11.4
13.4
—
13.4
—
—
23.7
—
—
—
—
—
14.9
—
—
—
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-322M
NCI-H522
Colon cancer
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
10.3
19.5
10.9
—
14.5
13.9
11.1
28.2
22.2
10.8
25.0
42.7
19.1
26.0
17.2
28.5
30.8
26.7
—
39.9
29.6
49.0
L
51.0
29.0
16.9
95.6
—
—
—
12.7
60.2
—
—
—
—
12.0
—
—
23.7
14.1
13.7
27.8
18.7
77.3
50.3
16.2
50.5
22.0
L
—
—
—
—
—
—
—
—
31.4
32.5
—
—
—
18.9
21.4
—
23.8
16.6
—
10.2
—
14.5
15.6
—
11.9
19.7
42.2
28.0
11.2
—
—
20.2
22.5
20.5
34.5
55.9
41.0
31.1
—
10.7
—
10.8
—
—
—
21.0
33.1
26.1
37.7
—
15.8
79.3
61.4
78.0
43.8
76.0
13.3
13.3
18.1
23.8
—
—
16.4
—
—
—
—
19.4
—
18.6
—
—
22.5
46.2
25.9
21.0
82.4
65.2
—
—
—
—
—
—
15.2
—
10.6
—
—
—
—
—
—
—
—
—
42.5
42.6
80.4
—
—
—
—
—
—
14.4
—
10.5
29.8
—
12.8
14.4
31.4
20.9
47.9
33.6
17.0
20.9
—
23.9
17.9
-
51.7
29.8
94.6
26.2
58.8
55.4
14.2
—
14.8
19.7
26.8
16.5
—
—
—
—
—
—
—
24.2
—
—
14.9
—
46.3
30.2
25.2
73.1
34.6
48.5
—
—
—
—
42.2
—
13.9
27.3
—
—
12.1
—
—
—
—
—
—
—
U251

G. S. Hassan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6318–6323
6321
Table 2 (continued)
Subpanel tumor cell lines
1
14
15
19
23
24
25
28
31
33
34
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian cancer
IGORV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
—
12.4
—
—
—
—
23.7
—
31.8
24.6
33.7
50.6
—
23.4
76.2
36.4
71.6
11.6
13.8
15.7
23.9
14.5
—
39.4
13.7
40.1
43.1
44
12.8
15.4
15.2
15.4
—
—
46.1
—
—
—
—
—
—
—
11.7
—
20.3
—
—
—
—
—
—
10.1
—
20.5
45.1
29.1
56.1
36.9
54.2
31.0
16.6
41.3
41.8
—
—
—
—
—
—
—
—
—
17.2
—
—
17.6
—
—
27.6
—
23.6
—
12.1
—
—
—
—
—
—
16.3
44.7
68.1
72.7
21.2
46.8
43.0
38.7
29.0
15.0
17.4
—
—
—
—
20.4
—
—
15.6
—
22.9
—
34.3
—
—
48.9
89.8
16.4
35.7
52.8
51.2
25.7
18.4
—
—
10.4
—
—
—
—
—
—
—
—
—
—
—
63.1
45.3
81.5
29.3
60.6
55.8
63.0
—
—
—
—
—
—
—
33.8
—
28.1
—
—
21.0
—
14.9
—
11.1
—
—
—
—
—
11.9
30.9
—
15.6
21.9
—
17.0
—
—
—
—
Renal cancer
ACHN
CAKI-1
RXF 393
SN12C
—
28.9
—
—
—
15.9
30.2
38.1
31.9
22.5
50.8
15.7
33.5
13.6
23.7
28.3
54.6
39.2
52.5
L
48.3
—
—
—
—
—
—
—
34.4
—
—
—
11.9
—
45.1
55.6
43.8
33.2
L
—
12.0
—
10.4
—
19.9
—
24.6
—
17.0
—
48.2
—
14.1
—
—
—
24.2
47.4
32.9
20.2
48.6
TK-10
UO-31
30.6
70.1
38.6
61.3
41.2
Prostate cancer
PC-3
17.8
24.6
28.5
59.7
15.3
21.1
12.0
69.5
—
31.1
16.1
Breast cancer
MCF7
MDA-MB-231/ATCC
BT-549
T-47D
MDA-MB-468
13.7
23.4
12.9
25.2
25.7
28.8
64.3
32.5
34.9
48.7
41.2
22.2
13.6
41.8
55.6
55.8
44.6
89.9
52.1
L
28
—
—
—
19.0
—
10.9
—
—
—
—
65.9
53.5
72.3
55.2
L
12.7
34.2
12.8
—
20.9
—
—
20.8
23.1
—
—
—
—
—
25.6
29.1
28.8
62.8
—
Prominent GI values are bolded.
—, GI <10%; L, compound proved lethal to the cancer cell line.
RPMI-8226; proved to be sensitive toward compound 19 with GI
values of 88.3 and 92.8% and 28 with GI values of 88.3 and
80.9%, respectively. Compound 19 exhibited remarkable activity
against Non-small cell lung cancer cell line NCI-H522, CNS cancer
SF-539; Ovarian cancer OVCAR-3; Breast cancer BT-549 with GI
values of 95.6, 94.6, 89.8, 89.9%, respectively (Fig. 1 and Table 2).
Compounds 19 and 28 proved to be the most active member of
this study. They passed the primary anticancer assay at an arbi-
trary concentration of 10 lM. Consequently, those active com-
pounds were carried over and tested against a panel of 60
different tumor cell lines at a 5-log dose range.29–31 Three response
parameters, GI50, TGI, and LC50 were monitored for each cell line,
using the known drug 5-Fluorouracil (5-FU) as a positive control.
Compound 19 proved to be ninefold more active than 5-FU, with
MG-MID GI50, TGI, and LC50 values of 2.8, 11.4, 44.7
lM, respec-
tively; while compound 28 proved to be sevenfold more active
Figure 1. Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10 lM concentration of compounds 19, 28.

6322
G. S. Hassan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6318–6323
Figure 2. Compounds 19, 28 median growth inhibitory (GI50, lM), Total growth inhibitory (TGI, lM) and median lethal (LC50, lM) concentrations of in vitro subpanel tumor
cell lines.
Figure 3. Full panel mean-graph midpoint (lM) of compounds 19, 28 in comparison with 5-FU.
Table 3
Compounds 19, 28 median growth inhibitory (GI50
, lM), total growth inhibitory (TGI, lM) and median lethal (LC50, lM) concentrations of in vitro subpanel tumor cell lines
Compound
Activity
I
II
III
IV
V
VI
VII
VIII
IX
MG-MIDa
19
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
2.2
8.9
90.2
2.0
6.1
3.9
13.5
44
3.2
11.9
39.2
3.1
3.2
4.1
21.8
67
4.8
31.3
61.1
1.7
7.9
32.1
2.8
12.5
39.3
2.8
2.4
8.8
55.9
3.3
32.3
62.1
2.8
19.0
51.5
6.3
14.7
50.9
4.8
17.6
50.2
13.1
47.6
4.2
13.4
44.3
13.8
42.2
3.8
16.8
63.4
11.4
44.7
3.3
13.1
46.8
28
21.5
20.3
b
61.5
b
5-FU
15.1
8.4
72.1
70.6
61.4
45.6
22.7
76.4
22.6
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
LC50
I, leukemia; II, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V, melanoma; VI, ovarian cancer; VII, renal cancer; VIII, prostate cancer; IX, breast cancer.
a
Full panel mean-graph midpoint (
l
M.
M).
b
Compounds showed values >100
l
than 5-FU, with MG-MID GI50, TGI, and LC50 values of 3.3, 13.1,
46.8 M, respectively (Figs. 2 and 3, Table 3).
Compounds of the present investigation belong to 2-amino-1,3-
thiazole analogs, bearing either to 2-(substituted amino)acetam-
ido- or 3-(substituted amino)propanamido-functions at position
2- and 4-bromo, 4-chloro or 4-methyl-phenyl at position 4. The ob-
tained results revealed that 2-chloro-N-[4-(4-substitutedphenyl)-
1,3-thiazol-2-yl]-acetamides (9, 18, and 27) devoid of any antitu-
mor potency. Displacement of the chlorine atom of 2-chloroacet-
amide function of 9, 18, and 27 with variety of secondary amines
produced 2-substituted amino-acetamide analogs with variable
potency. Only compounds bearing either morpholine, N-methyl-
l

G. S. Hassan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6318–6323
6323
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piperazine or N-phenyl-piperazine showed antitumor activity as
exemplified by compounds 11, 15, 24, 31 and 34.
Replacement of the 2-chloroacetamide function of 18 and 27 by
3-chloro-propanamide produced compound 19 and compound 28,
respectively with broad spectrum antitumor activity. Displace-
ment of the chlorine atom of 3-chloropropanamide function of
19 and 28 with variety of secondary amines produced 3-substi-
tuted amino-propanamide analogs with either abolished or dimin-
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phenyl-piperazine proved to be active with diminished potency as
shown in 14, 23, 25, and 34.
In general, the length of the carbon chain linking the 1,3-thia-
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new compounds which substantiate the merits of further explora-
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Acknowledgements
Thanks are due to the NCI, Bethesda, MD, USA for performing
the antitumor testing of the synthesized compounds.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.
2012.08.095.
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