Substituted thiazoles VI. Synthesis and antitumor activity of new 2-acetamido- and 2 or 3-propanamido-thiazole analogs

Article abstract of DOI:10.1016/j.ejmech.2012.06.013

A novel series of 2-acetamido and 2 or 3-propanamido derivatives of 4- or 5-substituted-thiazoles was designed and synthesized. Structure elucidation of the new synthesized compounds was attained by the use of ¹H & ¹³C NMR, and Mass

Full text of DOI:10.1016/j.ejmech.2012.06.013

European Journal of Medicinal Chemistry 54 (2012) 615e625
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Substituted thiazoles VI. Synthesis and antitumor activity of new
2-acetamido- and 2 or 3-propanamido-thiazole analogs
,
,
*
Shahenda M. El-Messery a, Ghada S. Hassan b c, Fatmah A.M. Al-Omary b, Hussein I. El-Subbagh d
a Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt
b Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
c Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. 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 and 2 or 3-propanamido derivatives of 4- or 5-substituted-thiazoles was
designed and synthesized. Structure elucidation of the new synthesized compounds was attained by the
use of 1H & 13C NMR, and Mass spectrometry. Compounds were subjected to NCI in vitro assessment for
Received 12 March 2012
Received in revised form
28 May 2012
Accepted 7 June 2012
Available online 18 June 2012
their antitumor activity, at a single dose of 10 mM of test compounds. Compounds bearing straight chain
substituent or 4-phenyl function proved to be more active than their branched or 4-methyl congeners.
Compounds 37, 41 and 42 exhibited broad spectrum antitumor activity. Compounds 23 and 27 proved
lethal while compounds 18, 21, 32 and 37 showed remarkable GI values of 75.5, 69.3, 96.2 and 92.7% to
the Leukemia CCRF-CEM cell line, respectively.
Keywords:
Synthesis
Antitumor Screening
Substituted-thiazoles
1H & 13C NMR
Ó 2012 Elsevier Masson SAS. All rights reserved.
Mass spectrometry
1. Introduction
Our previous study supported these finding producing a number of
thiazole containing derivatives (CeF) with GI50 values range of
The term cancer encompasses a wide range of diseases including
lung cancer, colon cancer, as well as the more esoteric acute
leukemia. Malignant disease is widely prevalent and considered to
be the second to cardiovascular diseases as the cause of death in the
western world. It is one of the major challenges of this century,
which concerns the medical community all over the world. The
diversity of tumor types and the great similarity to normal cells are
the main obstacle preventing the reach of an ultimate remedy [1,2].
Thiazoles represent a class of heterocyclic compounds of
considerable importance in biological chemistry. They exist in
many condensed fused systems that were found to possess a wide
range of biological activity [3,4]. The antitumor activity of 2,4-
disubstituted thiazole analogs was reported and well documented
[5e11]; including the antitumor activity of the thiazole nucleoside
tiazofurin [12,13], the groove binding agent distamycin [13],
Netropsin (A), Thia-netropsin (B) [14e18], and the thiazole-
containing antitumor agent bleomycin [19e21]. These finding
supports the evidence that incorporation of thiazole moiety in
those compounds is contributing to the antitumor effectiveness.
0.08e2.9 mM, [7e11], Chart 1.
In view of these facts, an efficient and reproducible synthesis of
some 2-substituted amino-thiazole derivatives has been performed
as a structure related analogs of the previously mentioned groove
binding antitumor agents. The 2-amino function of the thiazole ring
is acylated with aliphatic acid chlorides of various lengths ending
with a variety of secondary amines, replacing the amidine and the
guanidine ends of Netropsin (A). The new synthesized compounds
were subjected to the NCI in vitro disease-oriented human cells
screening panel assay [22e25], to evaluate the effect of this struc-
ture alterations on the antitumor activity.
2. Results and discussion
2.1. Chemistry
The synthetic strategy to prepare the new target compounds N-
(thiazol-2-yl or 5-methyl-thiazol-2-yl)-2 or 3-(substituted amino)
acetamide or propanamide (9e23), ethyl 4-methyl-2-[2-
(substituted amino)-acetamido or 3-(substituted amino)-prop-
anamido]-thiazole-5-carboxylates (27e34), 2- or 3-(substituted
amino)-N-(4-phenyl-thiazol-2-yl)-acetamide or propanamide
* Corresponding author. Tel.: þ20 2 26186100; fax: þ20 2 26186111.
E-mail address: subbagh@yahoo.com (H.I. El-Subbagh).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.06.013

616
S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
NH
2
O
HN
CH
3
H C
3
O
H
N
O
N
NH
N
2
H
N
NH
N
2
N
N
H
HN
N
H
S
O
S
HN
H N
2
O
NH
O
Netropsin (A)
Thia-netropsin (B)
O
C H
NH
HN
O
2
5
O
N
EtOOC
S
N
C H
2
N
S
5
C H
NH
6
11
N
H
N
H
S
C
D
OCH
3
H CO
3
H CO
3
COOH
CH O
3
N
S
N
N
N
S
F
E
H CO
3
OCH
3
3
OCH
Chart 1. Structures of netropsin (A), thia-netropsin (B) and some literature thiazole active antitumor agents (CeF).
(38e42), N-(thiazol-2-yl or 4-methyl-thiazol-2-yl)-2-(substituted
amino)-propanamide (47e56), ethyl 4-methyl-2-[2-(substituted
amino)-propanamido]-thiazole-5-carboxylate (58e62) are out-
lined in Schemes 1e5.
The 2-amino function of 2-amino-thiazole (1), 2-amino-5-
methyl-thiazole (2), ethyl 2-amino-4-methyl-thiazole-5-carboxylate
(24) and 2-amino-4-phenyl-thiazole (35) were acylated with either
2-chloroacetyl chloride (3) or 3-chloropropionyl chloride (4) and
potassium carbonate in dry toluene or methylene chloride to yield
2-[2-chloroacetamido or 3-chloropropanamido]-thiazole or 5-
methyl-thiazole (5e8), ethyl 2-[2-chloroacetamido or 3-
chloropropanamido]-4-methyl-thiazole-5-carboxylates (25, 26) and
2-[2-chloroacetamido or 3-chloropropanamido]-4-phenyl-thiazoles
(36, 37). The 1H NMR spectra of the synthesized intermediates (5, 7,
25, and 36) proved to accommodate the eCOCH2Cl moiety into the
structures of 1, 2, 24, and 35 by the appearance of singlet integrated
for two protons at a range of d 2.52e4.43 ppm depending on the type
of substituent on the thiazole ring. The integration of eCOCH2CH2Cl
moiety to produce the intermediates 6, 8, 26, and 37 was also
proved by the appearance of a set of two triplets integrated for four
O
O
N
N
K2CO3
Cl
(CH2)n
Cl
+
(CH2)n
Cl
NH2
R
N
H
R
S
S
Toluene
3: n = 1
4: n = 2
1: R = H
R = H, CH3; n = 1, 2
2: R = CH3
5-8
Secondary Amine
O
N
(CH2)n
R2
N
H
R1
S
R1 = H, CH3; R2 = 2o amines, n = 1, 2
9-23
Scheme 1. Synthesis of the target compounds 9e23.

S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
617
H3C
H3C
O
O
N
N
K2CO3
Cl
(CH2)n
Cl
+
(CH2)n
Cl
NH2
EtOOC
N
H
EtOOC
S
S
Toluene
25: n = 1
24
3:
n = 1
26: n = 2
4: n = 2
Secondary Amine
H3C
O
N
(CH2)n
N
EtOOC
S
H
R
R = 2o amines, n = 1, 2
27-34
Scheme 2. Synthesis of the target compounds 27e34.
protons at a range of
d
2.93e3.92 ppm. The target compounds 9e23,
methyl-thiazole (43), were acylated with 2-chloropropionyl chlo-
ride (44), potassium carbonate in dry toluene, to yield 2-[2-
chloropropanamido]-thiazole or 4-methyl-thiazole (45 or 46),
27e34 and 38e42 were obtained by the reaction of the 2-
chloroacetamido or 3-chloropropanamido derivatives 5e8, 25, 26,
36, 37 with variety of secondary amines in dry toluene (Schemes 1e3,
Table 1). 1H NMR spectra proved the inclusion of the secondary
amines into the structures of the target compounds 9e23, 27e34 and
and
ethyl
2-[2-chloropropanamido]-4-methyl-thiazole-5-
carboxylate (57) respectively. The 1H NMR spectra of the synthe-
sized intermediates (45, 46, and 57) proved to accommodate the
eCOCH(CH3)Cl moiety into the structures of 1, 43 and 44 by the
appearance of the characteristic pattern of a methyl doublet at
38e42. Morpholine appeared as two singlets at
triplets at 2.64, 3.73 ppm integrated for eight protons; piperazines
showed either two sets of singlets at 2.69, 3.17, two sets of triplets at
2.13, 2.17 or one multiplet at 2.62e2.83 ppm integrated for eight
d 2.51, 3.56 or two
d
d
d
1.59 or 1.63 ppm along with
a
methine quartet at
d
d
d
4.80e4.83 ppm. The target compounds (47e56), and (58e62),
protons, while piperidines appeared as two multiplets at
d
1.50,
were obtained by reacting 2-chloropropanamide derivatives (45,
46, and 57) with variety of secondary amines in dry toluene
(Schemes 4 and 5, Table 1). The same pattern of 1H, 13C NMR and
Mass spectra described earlier was also noticed for the target
compound 47e56, and 58e62.
2.72 ppm integrated for ten protons. 13C NMR and Mass spectral
analyses confirmed the aforementioned findings.
Similarly, the 2-amino function of 2-aminothiazole (1), ethyl 2-
amino-4-methyl-thiazole-5-carboxylate (24), and 2-amino-4-
O
O
N
N
K2CO3
Toluene
Cl
(CH2)n
Cl
+
(CH2)n
Cl
NH2
N
H
S
S
35
3:
n = 1
36: n = 1
37: n = 2
4:
n = 2
Secondary Amine
O
N
(CH2)n
N
S
H
R
o
,
R = 2 amines, n = 1 2
38-42
Scheme 3. Synthesis of the target compounds 38e42.

618
S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
R
R
O
O
N
N
K2CO3
CH3
Cl
CH3
Cl
+
NH2
N
H
S
S
Toluene
Cl
44
1:
45:
R = H
R = H
43: R = CH3
46: R = CH3
Secondary Amine
R
O
N
CH3
R1
N
H
S
R = H, CH3; R1 = 2o amines
47-56
Scheme 4. Synthesis of the target compounds 47e56.
2.2. Preliminary in vitro anticancer screening
a wide range of sensitivity towards the 2-acyl straight chain analogs
N-(thiazol-2-yl or 5-methyl-thiazol-2-yl)-2 or 3-(substituted
amino)-acetamide or propanamide (18e23), ethyl 4-methyl-2-[2-
(substituted amino)-acetamido or 3-(substituted amino)-prop-
anamido]-thiazole-5-carboxylates (27e34), 2- or 3-(substituted
The newly synthesized compounds (5e62) were subjected to
the National Cancer Institute (NCI) in vitro disease-oriented human
cells screening panel assay for in vitro antitumor activity. A single
dose (10
mM) of the test compounds was used in the full NCI 60 cell
amino)-N-(4-phenyl-thiazol-2-yl)acetamide
or
propanamide
lines panel assay which includes nine tumor subpanels namely;
Leukemia, Non-small cell lung, Colon, CNS, Melanoma, Ovarian,
Renal, Prostate, and Breast cancer cells [22e25]. The data reported
as mean-graph of the percent growth of the treated cells, and
presented as percentage growth inhibition (GI%) caused by the test
compounds (Tables 2 and 3).
(38e42). Compounds 23 and 27 proved lethal to CCRF-CEM cell
line; compounds 32 and 37 showed remarkable growth inhibitory
activity against the same cell line with GI values of 96.2 and 92.7%,
respectively; while compounds 18 and 21 showed moderate
growth inhibitory activity against the same cell line with GI values
of 75.5 and 69.3%, respectively.
The obtained data revealed that some of the tested subpanel
tumor cell lines exhibited variable sensitivity profiles against most
of the tested compounds. Leukemia CCRF-CEM cell line exhibited
Compound 3-chloro-N-(4-phenyl-thiazol-2-yl)-propanamide
(37, Fig. 1) showed a remarkably broad-spectrum antitumor activity
against all tumor cell lines used in the assay. Compound 37 proved
H3C
O
H3C
EtOOC
O
N
N
CH3
Cl
K2CO3
CH3
+
Cl
N
H
NH2
EtOOC
S
S
Toluene
Cl
44
24
57
Secondary Amine
H3C
O
N
CH3
N
H
EtOOC
S
R
R = 2o amines
58-62
Scheme 5. Synthesis of the target compounds 58e62.

S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
619
Table 1
Physicochemical properties of the newly synthesized compounds 5e62
R1
H3C
R1
O
O
O
N
N
N
CH3
CH3
(CH2)n
R3
N
H
N
H
N
H
R2
EtOOC
S
S
S
R3
R3
57-62
5-42
45-56
.
Compd
R1
R2
R3
n
Solvent
Yield %
Mp ꢀC
Molecular formulasa
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
COOC2H5
COOC2H5
COOC2H5
COOC2H5
Cl
Cl
Cl
Cl
1
2
1
2
1
2
1
2
2
1
2
1
2
1
2
1
2
2
1
2
1
2
1
2
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethylacetate
Pet.ether
Ethanol
Ethylacetate
Ethanol
Ethylacetate
Pet.ether
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethylacetate
e
45
54
61
71
33
54
63
75
59
44
69
63
66
59
46
55
54
48
57
40
59
49
60
76
59
72
68
55
55
60
63
58
65
61
79
71
66
53
72
53
71
62
58
66
150e4
183e6
176e9
171e2
98e9
63e6
137e8
82e4
C5H5ClN2OS
C6H7ClN2OS
C6H7ClN2OS
C7H9ClN2OS
C8H13N3OS
10
11
12
13
16
18
19
21
23
25
26
27
28
30
31
32
33
34
36
37
39
41
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
N(CH3)2
N(CH3)2
piperidino
piperidino
morpholino
N-methyl-piperazino
N-methyl-piperazino
N-phenyl-piperazino
N-phenyl-piperazino
Cl
C9H15N3OS
C11H17N3OS
C12H19N3OS
C11H17N3O2S
C11H18N4OS
C12H20N4OS
C16H20N4OS
C17H22N4OS
C9H11ClN2O3S
C10H13ClN2O3S
C11H17N3O3S
C12H19N3O3S
C14H21N3O4S
C14H22N4O3S
C15H24N4O3S
C19H24N4O3S
C20H26N4O3S
C11H9ClN2OS
C12H11ClN2OS
C16H20N4OS
C21H22N4OS
C6H7ClN2OS
C7H9ClN2OS
C10H17N3OS
C11H19N3OS
C11H17N3OS
C12H19N3OS
C10H15N3O2S
C11H17N3O2S
118e9
103e5
78e80
164e7
176e9
112e4
102e5
201e3
163e5
149e51
125e7
138e40
98e101
87e9
144e5
153e5
122e4
207e9
176e9
85e8
Oil
Oil
108e10
70e2
98e101
60e4
163e5
149e51
179e82
154e6
110e2
95e8
130e3
124e6
119e21
144e7
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
phenyl
phenyl
phenyl
phenyl
H
CH3
H
CH3
H
CH3
H
CH3
H
Cl
N(CH3)2
N(CH3)2
morpholino
N-methyl-piperazino
N-methyl-piperazino
N-phenyl-piperazino
N-phenyl-piperazino
Cl
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
H
H
H
H
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Cl
N-methyl-piperazino
N-phenyl-piperazino
Cl
1
1
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Cl
N(CH2CH3)2
N(CH2CH3)2
piperidino
piperidino
morpholino
morpholino
N-methyl-piperazino
N-methyl-piperazino
N-phenyl-piperazino
N-phenyl-piperazino
Cl
N(CH2CH3)2
piperidino
morpholino
N-methyl-piperazino
N-phenyl-piperazino
e
Ethanol
Ethanol
Pet.ether
Ethylacetate
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
C11H18N4OS
CH3
H
CH3
e
C12H20N4OS
C16H20N4OS
C17H22N4OS
C10H13ClN2O3S
C14H23N3O3S
C15H23N3O3S
C14H21N3O4S
C15H24N4O3S
C20H26N4O3S
e
e
e
e
e
a
Analyzed for C,H,N; results were within ꢁ0.4% of the theoretical values for the formulas given.
lethal to non-small cell lung cancer cell lines HOP-92, NCI-H522;
Breast cancer cell line MDA-MB-468 and of remarkable activity
against Leukemia cell lines CCRF-CEM, RPMI-8226; CNS cancer SF-
539; Ovarian cancer OVCAR-3; Renal cancer UO-31, RXF-393;
Prostate cancer DU-145 with GI values of 92.7, 93.1, 81.5, 98.0, 83.2,
80.4, 89.9%, respectively. Compound 37 showed moderate activity
against Colon cancer cell lines HCT-116, HT29, HCT-15, SW-620;
Melanoma SK-MEL-2; Renal cancer A498; Breast cancer MCF7 and
BT-549 with GI% values of 78.3, 76.1, 73.0, 70.7, 71.2, 78.4, 75.9 and
74.5% respectively (Table 2).
Compound 3-(4-methyl-piperazin-1-yl)-N-(4-phenylthiazol-2-yl)-
propanamide (40), showed GI value of 54% against Renal cancer
UO-31 cell line, while 2-(4-phenyl-piperazin-1-yl)-N-(4-phenyl-
thiazol-2-yl)-acetamide (41) showed GI value of 54.6% against
Colon cancer HCT-15 and 51.4% against Renal cancer UO-31 cell line.
In addition, 3-(4-phenyl-piperazin-1-yl)-N-(4-phenyl-thiazol-2-
yl)-propanamide (42) showed GI% values of 59.6, 52.5, 67.5, 68.9%
against non-small cell lung cancer HOP-92, Melanoma SK-MEL-5,
Renal cancer A498 and UO-31 cell lines (Fig. 2, Table 2).
The 2-acyl branched chain analogs N-(thiazol-2-yl or 4-methyl-
thiazol-2-yl)-2-(substituted amino)-propanamides (47e56), ethyl
Compounds 40e42 showed moderate broad-spectrum anti-
tumor activity against all tumor cell lines used in the assay.
4-methyl-2-[2-(substituted
amino)-propan-amido]-thiazole-5-

620
S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
Table 2
Percentage growth inhibition (GI %) of in vitro subpanel tumor cell lines at 10 mM concentration of compounds 18e42
Subpanel tumor cell lines
% Growth Inhibition (GI %)a
18
21
22
23
27
30
32
34
37
40
41
42
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
75.5
e
69.3
e
e
e
e
e
e
e
L
e
L
e
e
e
e
e
e
96.2
e
e
e
e
e
e
e
92.7
17.9
69.3
40.7
93.1
65.4
14.4
11.6
e
22.7
22.0
20.0
31.3
25
31.4
e
e
e
e
e
e
e
e
e
e
32.6
37.9
16.8
19.9
e
e
e
e
35.7
11.7
e
e
e
e
e
51.8
e
14.3
20.3
e
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-322M
NCI-H460
NCI-H522
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
53.1
24.1
51.4
L
29.3
34.7
29.2
63.6
L
e
17.6
e
17.9
24.8
20.8
59.6
26.6
31.4
13.0
11.3
21.3
12.1
e
e
11.4
e
e
15.9
e
e
e
e
e
e
14.5
24.5
17.4
e
e
e
26.6
e
e
21.9
e
e
17.5
e
25.6
19.1
18.6
11.3
25.0
29.7
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
12.9
e
16.5
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
55.6
15.8
78.3
73.0
76.1
52.6
70.7
e
e
e
e
e
e
e
12.4
e
e
e
17.7
54.6
23.8
e
41.7
20.6
e
10.7
10.9
e
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
63.0
46.3
81.5
29.3
60.6
55.8
e
e
22.3
13.6
15.4
10.3
28.6
15.6
e
15.9
e
e
e
10.1
29.7
e
30.5
e
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-62
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
15.5
e
e
47.8
68.2
52.7
68.2
71.2
19.4
48.9
39.0
11.1
12.7
e
11.5
23.4
13.6
e
25.7
e
12.0
e
e
e
e
e
e
13.4
e
e
e
e
11.6
e
e
e
e
e
e
e
e
31.9
36.6
52.5
33.2
e
e
11.1
Ovarian cancer
IGORV1
OVCAR-3
OVCAR-4
OVCAR-5
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
50.0
98.0
24.8
35.7
56.1
59.6
10.6
e
26.5
e
33.5
26.1
36.2
18.8
23.6
34.6
e
e
e
e
OVCAR-8
NCI/ADR-RES
e
e
13.0
23.0
Renal cancer
786-0
A498
e
e
e
e
e
e
e
e
36.7
78.4
50.7
69.3
80.4
57.2
83.2
e
e
18.1
67.5
16.4
37.7
11.8
33.5
68.9
e
e
e
e
e
e
e
12.8
e
e
44.1
16.2
36.6
e
ACHN
e
e
e
e
e
e
e
e
CAKI-1
RXF 393
SN12C
e
e
e
e
e
e
12.5
e
e
15.9
11.1
17.2
54.0
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
17.3
51.4
UO-31
10.2
13.1
24.3
12.8
14.8
10.6
19.3
19.7
Prostate cancer
PC-3
DU-145
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
57.9
89.8
10.9
e
26.3
e
28.3
18.2
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
16.3
e
e
e
e
e
75.9
53.5
e
11.8
11.6
10.5
16.5
19.3
29.2
e
12.7
e
e
14
26.1
BT-549
e
74.5
11.3

S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
621
Table 2 (continued )
Subpanel tumor cell lines
% Growth Inhibition (GI %)a
18
21
22
23
27
30
32
34
37
40
41
42
T-47D
MDA-MB-468
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
55.2
L
e
e
29.7
30.4
20.4
33.4
25.2
a
-, GI < 10%; nt, not tested; L, compound proved lethal to the cancer cell line.
carboxylates (58e62) proved to be less active antitumor agents
than their straight chain congeners. Only compound 54, was able to
inhibit the growth of some selected tumor cell lines, such as
Leukemia CCRF-CEM, Non-small cell lung cancer NCI-H522, Colon
cancer HCT-116, Melanoma LOX IMVI, and Breast cancer MCF7 cell
lines with GI values of 41.1, 66.3, 30.1, 46.4 and 35.6%, respectively
(Table 3).
4. Experimental part
Melting points (ꢀC) were determined on Mettler FP80 melting
point apparatus and are uncorrected. Microanalyses were per-
formed on a Perkin-Elmer 240 elemental analyzer at the Central
Research Laboratory, College of Pharmacy, King Saud University. All
of the new compounds were analyzed for C, H and N and agreed
with the proposed structures within ꢁ0.4% of the theoretical
values. 1H, 13C NMR were recorded on Bruker 500 MHz FT spec-
trometer (the Central Research Laboratory, College of Pharmacy,
King Saud University), Varian XL 500 MHz FT spectrometer and
NMR spectrometer (Varian Inc., Palo Alto, California, USA)
500 MHz, (Cairo National Research Center); chemical shifts are
2.3. Structureeactivity correlation
Compounds of the present investigation belong to 2-substituted
thiazole analogs, connected either to 2-(substituted amino)-
acetamido- or 3-(substituted amino)-propanamido- functions
representing a straight chain substitution, in addition to a series of
2-(substituted amino)-propanamido- function representing
a branched chain derivatives. The other side of the 2-aminothiazole
ring is either un-substituted or posses 4- or 5-methyl; 4-methyl and
5-ethyl carboxylate; represent aliphatic substitution or 5-phenyl;
represent aromatic substitution.
The obtained results revealed that the introduction of the
acyl chain of three carbon length (3-propanamido function) to
the 2-aminothiazole contribute to the antitumor activity more
than the acyl chain of two carbon length (2-acetamido moiety)
as examplified by compounds 31 versus 32 and 36 versus 37.
The introduction of the branched acyl chain (2-propanamido
function) produced compounds with diminished antitumor
activity such as 47e56 and 58e62 with the exception of
expressed in d ppm with reference to TMS. Mass spectral (MS) data
were obtained on a Perkin-Elmer, Clarus 600 GC/MS and Joel JMS-
AX 500 mass spectrometers. Thin layer chromatography was per-
formed on precoated (0.25 mm) silica gel GF254 plates (E. Merck,
Germany), compounds were detected with 254 nm UV lamp. Silica
gel (60ꢂ230 mesh) was employed for routine column chromatog-
raphy separations. All the fine chemicals and reagents used were
purchased from Aldrich Chemicals Co, USA. Compounds 9, 14, 15,17,
20, 22, 29, 38, 40, and 42 were previously reported [26e30].
4.1. Chemistry
4.1.1. N-(Thiazol-2-yl or 5-methyl-thiazol-2-yl)-2-chloro-
acetamide or 3-Chloro-propanamide (5e8)
A mixture of 2-aminothiazole (1) or 2-amino-5-methylthiazole
(2, 0.01 mol), potassium carbonate (2.07 g, 0.015 mol) in dry toluene
(50 ml) was stirred at room temperature, while 2-chloroacetyl
chloride (3, 1.7 g, 1.2 ml, 0.015 mol) or 3-chloropropionyl chloride
(4, 1.9 g, 1.4 ml. 0.015 mol), was added dropwise. Stirring continued
for 36 h, solvent was then removed in vacuo and the residue
obtained was triturated with water, filtered, dried and recrystallized
compound 54 which retained
a moderate broad-spectrum
antitumor activity.
Moreover, comparison of the antitumor results of the aliphatic
substituted thiazoles 18e34 and the aromatic counterparts
37e42; revealed that aromatic phenyl substitution favor the
activity rather than 4- or 5-methyl; 4-methyl and 5-ethyl
carboxylate derivatization. This is clear in case of compound 37
with its broad spectrum antitumor activity against nearly all 60
cell lines used in this study. The various terminal amines used for
the substitution of the other end of the propanamide function did
really alter the magnitude of antitumor activity as shown in 37
versus 42.
(Table 1). 5: 1H NMR (DMSO-d6)
J ¼ 3.0 Hz, thiazole-H), 7.41 (d, 1H, J ¼ 2.5 Hz, thiazole-H), 11.05 (brs,
1H, NH). MS m/z (%):176 (12, Mþ). 6: 1HNMR (DMSO-d6)
2.96 (t, 2H,
d 3.87 (s, 2H, CH2), 7.32 (d, 1H,
d
J ¼ 7.5 Hz, CH2), 3.90 (t, 2H, J ¼ 7.5 Hz, CH2), 7.23 (d, 1H, J ¼ 2.5 Hz,
thiazole-H), 7.48 (d,1H, J ¼ 2.5 Hz, thiazole-H),12.3 (brs,1H, NH).13C
NMR
7: 1H NMR (DMSO-d6)
thiazole-H), 12.29 (brs, 1H, NH). 13C NMR
155.7,164.6. MS m/z (%): 190 (1.74, Mþ). 8: 1H NMR (DMSO-d6)
(s, 3H, CH3), 2.93 (t, 2H, J ¼ 12.5 Hz, CH2), 3.89 (t, 2H, J ¼ 12.5 Hz,
d
39.0, 39.6,113.5,137.9,157.9,168.0 MS m/z (%): 190 (0.62, Mþ).
d
2.35 (s, 3H, CH3), 4.36 (s, 2H, CH2), 7.17 (s,1H,
11.0, 42.3, 126.8, 134.9,
2.34
3. Conclusion
d
d
In conclusion, an interesting class of 2-substituted amino-
thiazoles bearing straight and branched substituent with
different carbon chain length was designed and synthesized.
Antitumor evaluation indicated different pharmacological profiles
of these new compounds which substantiate the merits of further
CH2), 7.13 (s,1H, thiazole-H),12.07 (brs,1H, NH).13C NMR
d 11.0, 40.2,
126.2, 129.6, 135.0, 155.9, 167.8. MS m/z (%): 204 (22.3, Mþ).
4.1.2. N-(Thiazol-2-yl or 5-methyl-thiazol-2-yl)-2 or
exploration.
3-chloro-N-(4-phenyl-thiazol-2-yl)-propanamide
3-(substituted amino)-acetamide or propanamide (9e23)
(37) is a broad-spectrum antitumor agent showing effectiveness
toward nearly all cell lines belonging to different tumor
subpanels. Compound 37 is the most active member of this study.
The obtained remarkable antitumor potency using aromatic
substituent of the thiazole core could be considered as useful
template for future development and further derivatization or
modification to obtain more potent and selective antitumor
agents.
To a stirred solution of 5e8 (0.01 mol) in dry toluene (50 ml), the
appropriate amine (0.04 mol) was added dropwise. The reaction
mixture was heated under reflux for 3e5 h. Solvent was then
distilled under reduced pressure, the obtained residue was tritu-
rated with ice-water, filtered, dried and recrystallized (Table 1) 10:
1H NMR (DMSO-d6)
d
2.31 (s, 9H, eN(CH3)2 and CH3), 3.11 (s, 2H,
CH2), 7.01 (s, 1H, thiazole-H), 10.2 (brs, 1H, NH). 13C NMR
10.6,
45.0, 61.3, 66.0,126.7,133.5,154.9, 167.5. MS m/z (%): 199 (3.95, Mþ).
d

622
S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
Table 3 (continued)
Table 3
Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10
concentration of compounds 53e61.
mM
Subpanel tumor cell lines % Growth inhibition (GI %)a
53
54
55 56
58
59
60
61
Subpanel tumor cell lines % Growth inhibition (GI %)a
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
T-47D
53
54
55 56
58
59
60
61
e
e
e
e
e
e
35.6
13.3
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
e
41.1
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
11.2
e
13.3
e
e
e
12.1
e
MDA-MB-468
11.1
e
a
-, GI < 10%; nt, not tested; L, compound proved lethal to the cancer cell line.
e
e
11: 1H NMR (DMSO-d6)
J ¼ 5.5 Hz, CH2), 2.63 (t, 2H, J ¼ 5.5 Hz, CH2), 7.00 (s, 1H, thiazole-H),
12.50 (brs, 1H, NH). 13C NMR
11.6, 32.0, 44.4, 54.5, 63.4, 127.2,
134.2, 156.8, 169.9. MS m/z (%): 213 (7.42, Mþ). 12: 1H NMR (DMSO-
d6) 1.40 (s, 3H, CH3), 1.53e1.58 (m, 6H, piperidine-H), 2.33 (t, 4H,
J ¼ 1.5 Hz, piperidine-H), 3.11 (s, 2H, CH2), 7.01 (s, 1H, thiazole-H),
10.32 (brs, 1H, NH). 13C NMR
11.7, 23.5, 26.0, 29.7, 55.1, 61.7,
63.4, 127.8, 134.5, 155.9, 168.6 MS m/z (%): 239 (6.10, Mþ). 13: 1H
NMR (DMSO-d6)
d 2.33 (s, 9H, eN(CH3)2 and CH3), 2.54 (t, 2H,
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-322M
NCI-H460
NCI-H522
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
d
10.9
e
e
e
e
11.7
e
d
19.8
e
e
d
e
e
66.3
e
d
1.45 (s, 3H, CH3), 1.62 (t, 2H, J ¼ 5.5 Hz, CH2),
2.28e2.31 (m, 6H, piperidine-H), 2.39 (t, 4H, J ¼ 12.5 Hz, piperidine-
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
H), 2.66 (t, 2H, J ¼ 5.5 Hz, CH2), 6.98 (s, 1H, thiazole-H), 12.30 (brs,
1H, NH). 13C NMR
d 11.4, 23.8, 25.6, 31.3, 39.6, 40.4, 53.4, 63.4, 126.4,
e
30.1
25.5
e
134.4, 156.2, 169.7. MS m/z (%): 253 (13.6, Mþ). 16: 1H NMR (DMSO-
d6)
d
2,28 (s, 3H, CH3), 2.46 (t, 2H, J ¼ 5.0 Hz, CH2), 2.64 (t, 4H,
e
J ¼ 11.0 Hz, morpholine-H), 2.77 (t, 2H, J ¼ 5.5 Hz, CH2), 3.73 (t, 4H,
e
J ¼ 10.5 Hz, morpholine-H), 7.09 (s, 1H, thiazole-H), 12.34 (brs, 1H,
NH). 13C NMR
d 11.6, 29.7, 31.5, 53.0, 53.7, 63.4, 66.8, 127.4, 134.3,
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
156.7, 169.5. MS m/z (%): 255 (9.04, Mþ). 18: 1H NMR (DMSO-d6)
e
e
e
e
e
e
e
e
e
e
e
e
24
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
d
2.13 (t, 4H, J ¼ 6.0 Hz, piperazine-H), 2.17 (t, 4H, J ¼ 5.0 Hz,
e
e
e
e
piperazine-H), 2.52 (s, 3H, CH3), 2.63 (s, 3H, piperazine-CH3), 3.13
e
e
e
e
(s, 2H, CH2), 6.98 (s, 1H, thiazole-H), 10.08 (brs, 1H, NH). 13C NMR
e
e
e
e
15.5
e
e
16.4
e
24.4
e
d
10.0, 11.7, 45.7, 53.2, 54.9, 60.8, 63.4, 128.0, 134.5, 155.7, 168.0. MS
23.5
m/z (%): 254 (6.32, Mþ). 19: 1H NMR (DMSO-d6)
d
2.30 (s, 3H, CH3),
2.32 (s, 5H, CH3 and CH2), 2.53 (t, 6H, J ¼ 11.5 Hz, CH2 and
piperazine-H), 2.68 (t, 4H, J ¼ 11.5 Hz, piperazine-H), 7.00 (s, 1H,
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
e
e
e
e
e
e
e
e
e
46.4
17.6
25.5
11.2
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
thiazole-H),12.23 (brs, 1H, NH). 13C NMR
d 11.6, 31.3, 45.7, 52.2, 53.1,
54.9, 127.3, 134.6, 156.4, 169.6. MS m/z (%): 268 (0.54, Mþ). 21: 1H
NMR (DMSO-d6) 2.35 (s, 3H, CH3), 2.66 (s, 4H, piperazine-H), 2.84
d
(brs, 1H, NH), 3.04 (s, 4H, piperazine-H), 3.46 (s, 2H, CH2), 6.78 (t,
e
11.3
e
1H, J ¼ 6.5 Hz, Ar-H), 6.93 (d, 2H, J ¼ 7.0 Hz, Ar-H), 7.14 (s, 1H,
thiazole-H), 7.20 (t, 2H, J ¼ 14.0 Hz, Ar-H). 13C NMR
d 11.1, 39.0, 39.8,
24
45.5, 48.2, 49.2, 52.5, 60.0, 115.4, 118.8, 126.3, 128.9, 134.7, 151.0,
155.7, 167.9. MS m/z (%): 316 (5.49, Mþ). 23: 1H NMR (DMSO-d6)
Ovarian cancer
IGORV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
d
2.33 (s, 3H, CH3), 2.55e3.00 (m, 8H, CH2CH2 and piperazine-H),
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
3.25e3.55 (m, 4H, piperazine-H), 6.77 (t, 1H, J ¼ 10.0 Hz, Ar-H),
e
16.2
e
6.93 (d, 2H, J ¼ 5.0 Hz, Ar-H), 7.11 (s, 1H, thiazole-H), 7.20 (t, 1H,
J ¼ 10.0 Hz, Ar-H), 8.32 (brs, 1H, NH). 13C NMR
d 11.1, 32.5, 39.5, 45.5,
48.1, 49.2, 52.3, 53.3, 115.3, 118.8, 125.9, 128.2, 128.9, 134.6, 151.0,
e
e
156.1, 169.8. MS m/z (%): 330 (3.81, Mþ).
e
Renal cancer
786-0
A498
4.1.3. Ethyl 2-[2-chloroacetamido or 3-chloropropanamido]-4-
methylthiazole-5-carboxylate (25, 26)
e
e
e
e
e
e
e
e
e
e
e
e
e
e
12
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
A
solution of ethyl 2-amino-4-methylthiazole-5-carboxylate
ACHN
e
e
e
e
(24, 1.8 g, 0.01 mol), potassium carbonate (2.07 g, 0.015 mol) in dry
toluene(50 ml)wasstirredatroomtemperature, while2-chloroacetyl
chloride (3, 1.7 g, 1.2 ml, 0.015 mol) or 3-chloropropionyl chloride
(4,1.9 g,1.4 ml. 0.015 mol), was added dropwise. The reaction mixture
was heated under refluxfor4e6 h, andcontinuedasmentionedunder
CAKI-1
RXF 393
SN12C
TK-10
UO-31
e
e
e
12.2
e
e
e
e
e
11.5
e
e
e
e
e
e
19.4
e
17.9
13.4 14.2 13.1
compounds 5e8, (Table 1). 25: 1H NMR (DMSO-d6)
d
1.24 (t, 3H,
J ¼ 7.0 Hz,CH2CH3), 2.38(s, 3H,CH3),2.52(s,2H,CH2), 4.12e4.17(q, 2H,
CH2CH3), 9.17 (brs,1H, NH).13C NMR
11.3,13.1, 29.7, 43.2,109.7,145.1,
164.0,166.9,175.1. MS m/z (%): 262 (0.15, Mþ). 26: 1H NMR (DMSO-d6)
1.23 (t, 3H, J ¼ 7.0 Hz, CH2CH3),1.96(s, 3H, CH3), 3.28 (t, 2H, J ¼ 4.5 Hz,
Prostate cancer
PC-3
DU-145
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
d
d

S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
623
O
N
N
H
Cl
S
Fig. 1. Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10 mM concentration of compound 37.
CH2CH2), 3.67 (t, 2H, J ¼ 4.5 Hz, CH2CH2), 4.15e4.18 (q, 2H, CH2CH3),
d6)
d
1.28 (t, 3H, J ¼ 8.7 Hz, CH3CH2), 2.43 (s, 3H, CH3), 2.76 (s, 6H,
9.17 (brs, 1H, NH). 13C NMR
d
12.4, 13.5, 29.4, 44.5, 45.7, 108.4, 144.0,
eN(CH3)2), 2.96 (t, 2H, J ¼ 4.4 Hz, CH2), 3.38 (t, 2H, J ¼ 4.2 Hz, CH2),
165.7, 166.9, 177.2. MS m/z (%): 276 (1.53, Mþ).
4.09e4.19 (q, 2H, CH2CH3), 5.28 (brs, 1H, NH). MS m/z (%): 285 (6.02,
Mþ). 30: 1H NMR (DMSO-d6)
d
1.23 (t, 3H, J ¼ 14.0, Hz CH3CH2), 2.38
4.1.4. Ethyl 4-methyl-2-[2-(substituted amino)-acetamido or
3-(substituted amino)-propanamido]-thiazole-5-carboxylates
(27e34)
(s, 3H, CH3), 2.51 (s, 4H, morpholine-H), 2.56 (t, 2H, J ¼ 4.5 Hz, CH2),
3.34(t, 2H, J ¼ 5.0 Hz, CH2), 3.56 (s, 4H, morpholine-H), 4.12e4.17 (q,
2H, CH2CH3), 7.71 (brs, 1H, NH). 13C NMR
d 14.3, 17.1, 39.0, 39.3, 39.7,
To a stirred solution of 25 or 26 (0.01 mol) in dry toluene
(50 ml), the appropriate amine (0.04 mol) was added dropwise. The
reaction mixture was heated under reflux for 3e5 h, and continued
as mentioned under compounds 9e23, (Table 1). 27: 1H NMR
40.0, 41.4, 52.8, 59.7, 66.1, 107.3, 159.3, 161.9, 170.2. MS m/z (%): 327
(13.4, Mþ). 31: 1H NMR (DMSO-d6)
d
1.18 (t, 3H, J ¼ 7.1 Hz, CH3CH2),
2.17 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.90 (t, 4H, J ¼ 6.8 Hz, piperazine-H),
3.15 (t, 4H, J ¼ 7.2 Hz, piperazine-H), 3.43 (s, 2H, CH2), 4.24e4.36 (q,
(DMSO-d6)
(s, 6H, eN(CH3)2), 3.32 (s, 2H, CH2), 4.12e4.17 (q, 2H, CH2CH3), 8.92
(brs, 1H, NH). 13C NMR
12.4, 13.5, 29.4, 44.5, 45.7, 108.4, 144.0,
165.7, 166.9, 177.2. MS m/z (%): 271 (5.40, Mþ). 28: 1H NMR (DMSO-
d
1.23 (t, 3H, J ¼ 7.2 Hz, CH3CH2), 2.38 (s, 3H, CH3), 2.45
2H, CH2CH3), 5.50 (brs, 1H, NH). 13C NMR
d 13.5, 14.2, 29.1, 44.0, 52.0,
52.2, 53.4, 53.6, 62.3, 112.1, 149.0, 163.8, 165.4, 175.4. MS m/z (%): 326
1
d
(10.2, Mþ). 32: H NMR (DMSO-d6)
d
1.21 (t, 3H, J ¼ 6.8 Hz, CH3CH2),
2.14 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.73e2.79 (m, 4H, piperazine-H),
O
O
O
N
N
N
N
N
N
H
N
N
H
N
N
H
S
S
S
N
N
CH3
41
40
42
Fig. 2. Percentage growth inhibition (GI %) of in vitro subpanel tumor cell lines at 10 mM concentration of compounds 40e42.

624
S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
3.02e3.08 (m, 4H, piperazine-H), 3.13 (m, 4H, CH2CH2), 4.34e4.59 (q,
2H, CH2CH3), 7.25 (brs, 1H, NH). 13C NMR
12.9, 13.4, 29.5, 42.8, 51.9,
52.8, 54.2, 55.1, 61.7, 62.8, 112.8, 145.9, 163.7, 166.0, 178.9. MS m/z (%):
340 (7.91, Mþ). 33: 1H NMR (DMSO-d6)
4.1.8. N-(Thiazol-2-yl or 4-methyl-thiazol-2-yl)-2-(substituted
amino)-propanamides (47e56)
To a stirred solution of 45 or 46 (0.01 mol) in dry toluene
(50 ml), the appropriate amine (0.04 mol) was added dropwise. The
reaction mixture was heated under reflux for 3e5 h and continued
as mentioned under compounds 9e23, (Table 1). 47: 1H NMR
d
d
1.26 (t, 3H, J ¼ 7.1 Hz,
CH3CH2), 2.37 (s, 3H, CH3), 2.63e2.85 (m, 8H, piperazine-H), 3.21 (s,
2H, CH2), 3.57 (brs, 1H, NH), 4.05e4.25 (q, 2H, CH2CH3), 6.52e7.23 (m,
5H, Ar-H). MS m/z (%): 388 (5.9, Mþ). 34: 1H NMR (DMSO-d6)
d
1.20 (t,
(DMSO-d6)
d
1.34 (t, 6H, J ¼ 5 Hz, CH2CH3), 1.49 (d, 3H, J ¼ 5.5 Hz,
3H, J ¼ 7.1 Hz, CH3CH2), 1.98 (s, 3H, CH3), 2.73e2.91 (m, 8H,
CH3), 1.58e1.64 (q, 4H, CH2CH3), 3.08 (q, 1H, CH), 7.52 (d, 1H,
J ¼ 15.0 Hz, Ar-H), 7.45 (d, 1H, J ¼ 15.0 Hz, Ar-H), 9.05 (brs, 1H, NH).
piperazine-H), 3.22e3.41 (m, 4H, CH2CH2), 4.04e4.12 (q, 2H, CH2CH3),
7.52e7.86 (m, 5H, Ar-H), 8.04 (brs, 1H, NH). 13C NMR
d
12.9, 13.4, 28.5,
13C NMR
d 13.1, 13.4, 17.2, 44.3, 44.6, 60.5, 113.5, 132.6, 167.8, 175.9.
45.2, 45.5, 51.6, 51.8, 112.4, 118.2, 118.7, 121.4, 130.2, 130.3, 149.0, 150.3,
MS m/z (%): 227 (21.4, Mþ). 48: 1H NMR (DMSO-d6)
d 1.19 (d, 3H,
163.5, 169.4, 175.7. MS m/z (%): 402 (1.96, Mþ).
J ¼ 5.0 Hz, CH3), 1.40 (t, 6H, J ¼ 5.0 Hz, CH2CH3), 2.22e2.32 (q, 4H,
CH2CH3), 3.07 (s, 3H, CH3), 3.88 (q, 1H, CH), 6.47 (s, 1H, Ar-H), 9.01
4.1.5. 2- or 3-Chloro-N-(4-phenyl-thiazol-2-yl)-acetamide or
propanamide (36e37)
(brs, 1H, NH). 13C NMR
d
12.9, 13.3, 13.5, 17.9, 44.5, 44.6, 61.1, 114.2,
135.0, 165.9, 175.5. MS m/z (%): 241 (3.5, Mþ). 49: 1H NMR (DMSO-
d6)
A solution of 2-amino-4-phenylthiazole (35, 1.7 g, 0.01 mol) in
dry toluene (50 ml), potassium carbonate (2.07 g, 0.015 mol) was
stirred at room temperature, while 2-chloroacetyl chloride (3, 1.7 g,
1.2 ml, 0.015 mol) or 3-chloropropionyl chloride (4, 1.9 g, 1.4 ml.
0.015 mol), was added dropwise. The reaction mixture was heated
under reflux for 4e6 h, and continued as mentioned under
d
1.36 (d, 3H, J ¼ 4.5 Hz, CH3),1.50 (m, 2H, piperidine-H),1.67 (m,
4H, piperidine-H), 2.60e2.72 (t, 4H, J ¼ 5.0 Hz, piperidine-H), 3.17
(q, 1H, CH), 7.25 (d, 1H, J ¼ 7.5 Hz, Ar-H), 7.44 (d, 1H, J ¼ 7.5 Hz, Ar-
H), 8.95 (brs, 1H, NH). 13C NMR
d 16.2, 25.3, 25.7, 25.9, 51.9, 52.1,
62.3, 113.0, 133.7, 162.7, 173.7. MS m/z (%): 239 (27.1, Mþ). 50: 1H
NMR (DMSO-d6)
d
1.29 (d, 3H, J ¼ 10.0 Hz, CH3), 1.45 (m, 2H,
compounds 5e8, (Table 1). 36: 1H NMR (DMSO-d6)
d
4.43 (s, 2H,
piperidine-H), 1.65e1.66 (m, 4H, piperidine-H), 1.89 (s, 3H, CH3),
2.19 (t, 4H, J ¼ 10.0 Hz, piperidine-H), 3.16 (q, 1H, CH), 6.00 (brs, 1H,
NH), 7.27 (s, 1H, Ar-H). MS m/z (%): 253 (1.9, Mþ). 51: 1H NMR
CH2), 7.32 (t, 1H, J ¼ 14.5 Hz, Ar-H), 7.44 (t, 2H, J ¼ 15.5 Hz, Ar-H),
7.69 (s, 1H, thiazole-H), 7.90 (d, 2H, J ¼ 7 Hz, Ar-H), 12.66 (brs, 1H,
NH). 13C NMR
d
42.3, 108.6, 125.7, 127.9, 128.5, 134.0, 149.0, 157.4,
(DMSO-d6)
d
1.33 (d, 3H, J ¼ 5.0 Hz, CH3), 2.59 (t, 4H, J ¼ 5.0 Hz,
165.1. MS m/z (%): 252 (1.32, Mþ). 37: 1H NMR (DMSO-d6)
d
2.99 (t,
morpholine-H), 3.30 (t, 4H, J ¼ 5 Hz, morpholine-H), 3.76 (q, 1H,
CH), 6.97 (d, 1H, J ¼ 7.0 Hz, Ar-H), 7.43 (d, 1H, J ¼ 7.0 Hz, Ar-H), 10.51
2H, J ¼ 11.5 Hz, CH2), 3.92 (t, 2H, J ¼ 12.0 Hz, CH2), 7.34e7.45 (m, 3H,
Ar-H), 7.64 (s, 1H, thiazole-H), 7.89 (d, 2H, J ¼ 7.5 Hz, Ar-H), 12.42
(brs, 1H, NH). 13C NMR
d 16.4, 51.2, 51.4, 61.3, 68.4, 68.6, 113.1, 132.7,
(brs, 1H, NH). 13C NMR
d
40.1, 108.1, 125.5, 125.6, 127.8, 128.7, 134.2,
166.3, 173.4. MS m/z (%): 241 (31.8, Mþ). 52: 1H NMR (DMSO-d6)
148.8, 157.6, 168.4. MS m/z (%): 266 (0.43, Mþ).
d
1.32 (d, 3H, J ¼ 5.0 Hz, CH3), 2.34 (s, 3H, CH3), 2.60 (t, 4H,
J ¼ 5.0 Hz, morpholine-H), 3.29 (t, 4H, J ¼ 5.0 Hz, morpholine-H),
4.1.6. 2- or 3-(Substituted amino)-N-(4-phenyl-thiazol-2-yl)-
acetamide or propanamide (38e42)
To a stirred solution of 36, 37 (0.01 mol) in dry toluene (50 ml),
the appropriate amine (0.04 mol) was added dropwise. The reaction
mixture was heated under reflux for 3e5 h. and continued as
mentioned under compounds 9e23, (Table 1). 39: 1H NMR (DMSO-
4.01 (q, 1H, CH), 7.25 (s, 1H, Ar-H), 8.05 (brs, 1H, NH). 13C NMR
d
12.4, 16.8, 51.3, 51.4, 62.0, 68.7, 68.8, 112.9, 133.0, 166.2, 174.0. MS
m/z (%): 255 (24.5, Mþ). 53: 1H NMR (DMSO-d6)
d
1.15 (d, 3H,
J ¼ 7.0 Hz, CH3), 2.10 (t, 4H, J ¼ 5.5 Hz, piperazine-H), 2.27 (s, 3H,
CH3), 2.48 (t, 4H, J ¼ 5.5 Hz, piperazine-H), 3.41e3.44 (q, 1H, CH),
7.17 (d, 1H, J ¼ 3.5 Hz, Ar-H), 7.43 (d, 1H, J ¼ 4.0 Hz, Ar-H), 11.62 (brs,
d6)
H), 7.21e7.48 (m, 5H, Ar-H), 7.65 (s, 1H, thiazole-H), 11.81 (brs, 1H,
NH). MS m/z (%): 316 (7.3, Mþ). 41: 1H NMR (DMSO-d6)
2.69 (s, 4H,
d
2.10 (s, 3H, CH3), 2.54(s, 2H, CH2), 2.62e2.83(m, 8H, piperazine-
1H, NH). MS m/z (%): 254 (2.2, Mþ). 54: 1H NMR (DMSO-d6)
d 1.22
(d, 3H, J ¼ 4.5 Hz, CH3), 1.46 (s, 3H, CH3), 2.21 (t, 4H, J ¼ 7.4 Hz,
piperazine-H), 2.42 (s, 3H, CH3), 2.55 (t, 4H, J ¼ 7.2 Hz, piperazine-
H), 3.39e3.48 (q, 1H, CH), 7.17 (s, 1H, Ar-H), 10.92 (brs, 1H, NH).
d
piperazine-H), 3.17 (s, 4H, piperazine-H), 3.39 (s, 2H, CH2), 6.78 (t,
1H, J ¼ 14.0 Hz, Ar-H), 6.95 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.21 (t, 2H,
J ¼ 15.5 Hz, Ar-H), 7.33 (t, 1H, J ¼ 14.5 Hz, Ar-H), 7.43 (t, 2H,
J ¼ 15.0 Hz, Ar-H), 7.65 (s, 1H, thiazole-H), 7.92 (d, 2H, J ¼ 7.0 Hz, Ar-
13C NMR
d
17.2, 17.5, 45.9, 51.2, 51.4, 54.9, 55.0, 61.2, 109.3, 145.3,
166.4, 175.3. MS m/z (%): 268 (13.1, Mþ). 55: 1H NMR (DMSO-d6)
d
1.26 (d, 3H, J ¼ 10.0 Hz, CH3), 2.69 (d, 4H, J ¼ 5.0 Hz,
H), 11.99 (brs, 1H, NH). 13C NMR
d
39.5, 48.2, 52.5, 60.0, 62.9, 108.1,
piperazine-H), 3.14 (d, 4H, J ¼ 4.9 Hz, piperazine-H), 3.55e3.57 (m,
1H, CH), 6.76 (t,1H, J ¼ 15.0 Hz, Ar-H), 6.90 (d, 2H, J ¼ 5.0 Hz, thiazole-
H), 7.19 (m, 3H, Ar-H), 7.45 (d,1H, J ¼ 5.0 Hz, Ar-H),11.88 (brs,1H, NH).
115.4, 118.8, 125.7, 127.8, 128.7, 128.9, 134.2, 148.8, 151.0, 157.4, 168.6.
MS m/z (%): 378 (2.31, Mþ).
13C NMR
d 12.7, 48.6, 48.8, 61.6, 78.6, 79.1, 113.4, 115.4, 118.8, 128.8,
4.1.7. N-(Thiazol-2-yl or 4-methyl-thiazol-2-yl)-2-chloro-
propanamide (45, 46)
137.5, 151.0, 157.5, 170.7. MS m/z (%): 316 (5.7, Mþ). 56: 1HNMR (DMSO-
d6)
d
1.18 (d, 3H, J ¼ 5.0 Hz, CH3), 2.30(s, 3H, CH3), 2.58(t, 4H, J ¼ 5.5 Hz,
A mixture of 2-aminothiazole (1) or 2-amino-4-methylthiazole
(43, 0.01 mol), 2-chloropropionyl chloride (44, 1.9 g, 1.4 ml,
0.015 mol), potassium carbonate (2.07 g, 0.015 mol) was stirred in
methylene chloride (50 ml) at room temperature for 36 h. The
solvent was then evaporated under reduced pressure. The residue
obtained was then suspended in large amount of chloroform then
neutralize with ammonia solution. Separate the organic layer and
continue as mentioned under compounds 5e8, (Table 1). 45: 1H
piperazine-H), 2.64 (t, 4H, J ¼ 5.0 Hz, piperazine-H), 3.28 (m, 1H, CH),
6.72 (t,1H, J ¼ 15 Hz, Ar-H), 6.87 (d, 2H, J ¼ 10 Hz, Ar-H), 7.10 (s,1H, Ar-
H), 7.15 (t, 2H, J ¼ 15.0 Hz, Ar-H), 11.60 (brs, 1H, NH). MS m/z (%): 330
(28.5, Mþ).
4.1.9. Ethyl 4-methyl-2-[2-chloro-propanamido]-thiazole-5-
carboxylate (57)
A solution of ethyl 2-amino-4-methylthiazole-5-carboxylate
(24, 1.8 g, 0.01 mol), potassium carbonate (2.07 g, 0.015 mol) in
dry toluene (50 ml) was stirred at room temperature, while 2-
chloropropionyl chloride (44, 1.9 g, 1.4 ml. 0.015 mol), was added
dropwise. The reaction mixture was heated under reflux for 4e6 h,
and continued as mentioned under compounds 5e8, (Table 1). 57:
NMR (DMSO-d6)
CH), 7.29 (d, 1H, J ¼ 5.0 Hz, Ar-H), 7.52 (d, 1H, J ¼ 4.9 Hz, Ar-H), 12.52
(brs, 1H, NH). 13C NMR
20.5, 62.9, 114.2, 138.7, 157.5, 167.4. MS m/z
(%): 190 (22.3, Mþ). 46: 1H NMR (DMSO-d6)
1.29 (s, 3H, CH3), 1.59
(d, 3H, J ¼ 5.0 Hz, CH3), 4.30e4.34 (q, 1H, CH), 7.46 (s, 1H, Ar-H),
11.95 (brs, 1H, NH). 13C NMR
11.1, 20.6, 120.1, 126.9, 156.0, 167.1,
173.3 MS m/z (%): 204 (15.2, Mþ).
d
1.63 (d, 3H, J ¼ 5.0 Hz, CH3), 4.80e4.83 (q, 1H,
d
d
d
1H NMR (DMSO-d6)
J ¼ 5.0 Hz, CH3), 2.37 (s, 3H, CH3), 4.12e4.15 (q, 2H, CH2CH3),
d
1.22 (t, 3H, J ¼ 20.0 Hz, CH2CH3), 1.62 (d, 3H,

S.M. El-Messery et al. / European Journal of Medicinal Chemistry 54 (2012) 615e625
625
4.21e4.23 (q, 1H, CH), 7.27 (brs, 1H, NH). 13C NMR
d 10.3, 11.2, 21.4,
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28.3, 62.3,101.4,150.1, 166.1,166.9,175.5. MS m/z (%): 276 (12.9, Mþ).
[3] M. Kuramoto, Y. Sakata, K. Terai, I. Kawasaki, J. Kunitomo, T. Ohishi,
T. Yokomizo, S. Takeda, S. Tanaka, Y. Ohishi, Preparation of leukotriene B(4)
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K.A. Kellar, J.G. Mulheron, R. Batorsky, U. Roongta, A. Kamath, P. Marathe,
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S.D. kimball, N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-
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4.1.10. Ethyl 4-methyl-2-[2-(substituted amino)-propanamido]-
thiazole-5-carboxylates (58e62)
To a stirred solution of 57 (2.76 g, 0.01 mol) in dry toluene
(50 ml), the appropriate amine (0.04 mol) was added dropwise. The
reaction mixture was heated under reflux for 3e5 h, and continued
as mentioned under compounds 9e23, (Table 1). 58: 1H NMR
(DMSO-d6)
CH3), 2.33 (m, 7H, 2CH2, CH3), 2.46 (s, 3H, CH3), 3.27e3.32 (m, 1H,
CH), 4.01e4.11 (q, 2H, CH2), 7.64 (brs, 1H, NH). 13C NMR
10.1, 11.3,
11.5, 12.6, 16.9, 29.3, 39.5, 40.2, 65.3, 101.9, 150.2, 165.3, 173.8, 174.6.
MS m/z (%): 313 (6.93, Mþ). 59: 1H NMR (DMSO-d6)
1.18 (m, 6H,
d
1.17 (t, 6H, J ¼ 5.0 Hz, CH2CH3), 1.19 (d, 3H, J ¼ 5.0 Hz,
d
d
CH3, CH2CH3), 2.01 (d, 3H, CH3), 2.33e2.46 (m, 10H, piperidine-H),
3.27e3.33 (m, 1H, CH), 4.11 (m, 2H, CH2CH3), 7.63 (brs, 1H, NH).
13C NMR
d
11.3, 12.1, 17.2, 24.3, 25.6, 25.8, 29.4, 51.2, 51.9, 62.4, 101.3,
149.9, 163.9, 175.2, 176.9. MS m/z (%): 325 (38.2, Mþ). 60: 1H NMR
(DMSO-d6) 1.17 (m, 3H, CH2CH3),1.18 (d, 3H, CH3),1.22 (s, 3H, CH3),
d
2.32 (m, 4H, morpholine-H), 2.55 (m, 4H, morpholine-H),
3.27e3.31 (m, 1H, CH), 4.13 (m, 2H, CH2CH3), 7.64 (brs, 1H, NH).
MS m/z (%): 327 (1.90, Mþ). 61: 1H NMR (DMSO-d6)
d 1.11 (m, 3H,
CH2CH3), 1.21 (d, 3H, CH3), 1.38 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.47
(m, 4H, piperazine-H), 2.52 (m, 4H, piperazine-H), 3.27e3.34 (m,
1H, CH), 4.46 (m, 2H, CH2CH3), 9.52 (brs, 1H, NH). MS m/z (%): 340
(19.5, Mþ). 62: 1H NMR (DMSO-d6)
d 1.19 (m, 3H, CH2CH3), 1.17 (d,
3H, CH3), 2.28 (s, 3H, CH3), 2.32 (m, 4H, piperazine-H), 2.74 (m, 4H,
piperazine-H), 3.30 (m,1H, CH), 4.29 (m, 2H, CH2CH3), 7.51e7.63 (m,
5H, Ar-H), 10.82 (brs, 1H, NH). MS m/z (%): 402 (25.7, Mþ).
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[1] W.O. Foye, T.L. Lemke, D.A. Williams, Principles of Medicinal Chemistry, forth
ed., Williams and Wilkins, Media, PA, USA, 2002, pp. 822.