Synthesis and anticancer activities of some thiazole derivatives

Article abstract of DOI:10.1080/10426500802446181

In this study, 2-substituted 4-[3/4-(4-arylthiazole-2-yl)aminophenyl] thiazole derivatives and 2-[4-[2-substituted 4-methylthiazole-5-yl]thiazole-2- yl]amino-5-arylidenethiazoline-4-one derivatives have been synthesized. The cytotoxic and/or growth inhibitory effects of the 16 selected compounds were evaluated in vitro against approximately 66 human tumor cell lines derived from nine neoplastic diseases. Some of the compounds were found to act as anticancer agents.

Full text of DOI:10.1080/10426500802446181

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Synthesis and Anticancer
Activities of Some Thiazole
Derivatives
Ismail Kayagil a & Seref Demirayak a
a Anadolu University, Faculty of Pharmacy,
Department of Pharmaceutical Chemistry, Eskisehir,
Turkey
Version of record first published: 04 Sep 2009.
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Activities of Some Thiazole Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 184:9, 2197-2207
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Phosphorus, Sulfur, and Silicon, 184:2197–2207, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802446181
Synthesis and Anticancer Activities of Some Thiazole
Derivatives
Ismail Kayagil and Seref Demirayak
Anadolu University, Faculty of Pharmacy, Department of
Pharmaceutical Chemistry, Eskisehir, Turkey
In this study, 2-substituted 4-[3/4-(4-arylthiazole-2-yl)aminophenyl]thiazole
derivatives and 2-[4-[2-substituted 4-methylthiazole-5-yl]thiazole-2-yl]amino-5-
arylidenethiazoline-4-one derivatives have been synthesized. The cytotoxic and/or
growth inhibitory effects of the 16 selected compounds were evaluated in vitro
against approximately 66 human tumor cell lines derived from nine neoplastic
diseases. Some of the compounds were found to act as anticancer agents.
Keywords Anticancer activity; poly-thiazole; thiazolone
INTRODUCTION
Since the initial isolation of the polypyrrole netropsin, I, in 1951 and
distamycin, II, in 1964, the interest in this class of compounds has
been increased.1 These natural antibiotics showed anticancer and an-
tiviral activities by DNA binding.2 Bleomycins, a group of anticancer
antibiotics, also have a bithiazole moiety along with the imidazole and
pyrimidine ring systems.3
The above observations created the interest for the synthesis of some
analogues of netropsin and distamycin, in which the pyrrole rings were
replaced by benzene, pyridine, thiophene, thiazole, imidazole, pyrazole,
or triazole, to study their anticancer and antiviral activities.4−13 The
studies on the anticancer activity of thia-net, III, which is a thiazole-
containing analogue of netropsin have been popular recently.2
Received 12 June 2008; accepted 1 September 2008.
Authors are grateful to V. L. Narayanan and J. P. Bader of the National Institutes of
Health, Bethesda, Maryland, USA, for anticancer screening.
Address correspondence to Seref Demirayak, Department of Pharmaceutical Chem-
istry, Faculty of Pharmacy, Anadolu University, 26470, Eskisehir, Turkey. E-mail:
sdemiray@anadolu.edu.tr
2197

2198
I. Kayagil and S. Demirayak
We are now reporting on the syntheses of some new compounds that
possess two or three thiazole ring residues along with their anticancer
activities.
RESULTS AND DISCUSSION
Chemistry
The synthesis of the title thiazole derivatives was accomplished with
the sequence of reactions depicted in Scheme 1. To prepare the novel
compounds, we have applied the known synthetic routes with mi-
nor modifications.14,15 The first two groups of the compounds are
2-substituted 4[3/4-(4-arylthiazole-2-yl)aminophenyl]thiazole deriva-
tives 4a–l and 7a–l, which are isomers of each other. Reaction of 2-
bromo-3ꢀ/4ꢀ-acetylaminoacetophenone with the suitable thioamides in
benzene afforded 2-substituted 3/4-acetylaminophenylthiazoles. These
crude derivatives were hydrolyzed with an aqueous hydrochloric acid
solution to afford the corresponding amine derivatives 2a–b. Then,
the amino compounds were treated with ammonium thiocyanate in
hydrochloric acid solution, followed by reaction with the suitable 4ꢀ-
substituted 2-bromoacetophenones to afford the target compounds 4a–l
or 7a–l (see Table I).
SCHEME 1
The third group includes 2-[4-[2-substituted 4-methylthiazole-5-
yl]thiazole-2-yl]amino-5-arylidenethiazoline-4-one derivatives 13a–h
(Table I). These compounds were obtained by following the common
reaction conditions, which have been described in the literature.14,15
Reaction of 3-chloropentan-2,4-dione with the suitable thioamides

Activities of Some Thiazole Derivatives
2199
SCHEME 2
has afforded 2-substituted 4-methyl-5-acetylthiazoles 8a–b. During
the reactions between 3-chloropentan-2,4-dione and thioamides, it is
obvious that both of the carbonyl groups can take place in the cy-
clization reactions. However, this regioselectivity does not cause the

2200
I. Kayagil and S. Demirayak
TABLE I Some Characteristics of the Compounds
Analyses Calc./Found (%)
mp Yield
Molecular
formula
Comp.
R
Rꢀ
(◦C) (%)
C
H
N
S
4a
CH3
H
188
178
122
224
218
72
75
82
85
80
77
65
71
80
88
63
67
70
72
78
83
76
79
68
71
75
80
C19H15N3S2
C20H17N3S2
C20H17N3OS2
65.30 4.33 12.02 18.35
64.96 4.67 11.86 18.06
66.08 4.71 11.56 17.64
66.75 5.02 11.91 17.74
63.30 4.52 11.07 16.90
63.56 4.92 10.87 17.20
4b
4c
4d
4e
4f
CH3 CH3
CH3 OCH3
CH3 Cl
C19H14ClN3S2 59.44 3.68 10.94 16.70
59.55 3.46 11.12 16 85
C19H14N4O2S2 57.85 3.58 14.20 16.26
58.05 4.11 14.47 16.11
C21H18N4OS2
C24H17N3S2
C25H19N3S2
C25H19N3OS2
CH3 NO2
CH3 NHCOCH3 209
62.05 4.46 13.78 15.77
61.85 4.35 14.04 16.12
70.04 4.16 10.21 15.58
69.85 4.16 10.25 15.62
70.56 4.50 9.87 15.07
70.45 4.67 9.44 14.93
68.00 4.34 9.52 14.52
67.75 4.02 9.55 14.64
4g
4h
4i
C6H5
H
159
225
193
231
224
C6H5 CH3
C6H5 OCH3
C6H5 Cl
4j
C24H16ClN3S2 64.63 3.62 9.42 14.38
64.89 4.34 9.32 14.22
C24H16N4O2S2 63.14 3.53 12.27 14.05
62.84 3.82 12.67 14.15
C26H20N4OS2
C19H15N3S2
C20H17N3S2
C20H17N3OS2
4k
4l
C6H5 NO2
C6H5 NHCOCH3 241
66.64 4.30 11.96 13.68
66.45 4.18 12.20 13.74
65.30 4.33 12.02 18.35
65.71 4.56 12.24 18.77
66.08 4.71 11.56 17.64
54.75 4.67 11.77 17.72
63.03 4.52 11.07 16.90
62.90 4.55 11.12 17.12
7a
7b
7c
7d
7e
7f
CH3
H
172
147
129
164
194
CH3 CH3
CH3 OCH3
CH3 Cl
C19H14ClN3S2 59.44 3.68 10.94 16.70
59.45 3.75 11.21 16.90
C19H14N4O2S2 57.85 3.58 14.20 16.26
58.15 3.68 14.22 16.26
C21H18N4OS2
C24H17N3S2
C25H19N3S2
C25H19N3OS2
CH3 NO2
CH3 NHCOCH3 111
62.05 4.46 13.78 15.77
61.96 4.50 13.80 15.80
70.04 4.16 10.21 15.58
70.14 4.22 10.44 15.80
70.56 4.50 9.87 15.07
70.60 5.60 10.10 14.90
68.00 4.34 9.52 14.52
68.41 4.32 9.68 14.60
7g
7h
7i
C6H5
H
202
227
197
139
C6H5 CH3
C6H5 OCH3
C6H5 Cl
7j
C24H16ClN3S2 64.63 3.62 9.42 14.38
64.68 3.70 9.45 14.44
(Continued on next page)

Activities of Some Thiazole Derivatives
2201
TABLE I Some Characteristics of the Compounds Continued
Analyses Calc./Found (%)
mp Yield
(◦C) (%)
Molecular
formula
Comp.
R
Rꢀ
C
H
N
S
7k
C6H5 NO2
187
65
67
78
77
81
86
63
61
74
79
C24H16N4O2S2
C26H20N4OS2
C18H14N4OS3
C19H16N4OS3
C19H16N4O2S3
63.14 3.53 12.27 14.05
63.22 3.45 12.33 14.20
66.64 4.30 11.96 13.68
66.88 4.28 12.04 13.72
54.25 3.54 14.06 24.14
54.35 3.60 14.20 24.20
55.32 3.91 13.58 23.32
55.82 3.85 13.66 23.40
53.25 3.76 13.07 22.45
53.50 3.90 13.22 22.85
7l
C6H5 NHCOCH3 226
13a
13b
13c
13d
13e
13f
13g
13h
CH3
H
271
257
266
287
259
243
218
276
CH3 CH3
CH3 OCH3
CH3 Cl
C18H13ClN4OS3 49.93 3.03 12.94 22.22
50.14 3.12 13.12 21.98
C6H5
H
C22H16N4OS3
C23H18N4OS3
C23H18N4O2S3
59.98 3.50 12.16 20.88
60.10 3.60 12.18 21.00
60.74 3.82 11.80 20.27
60.55 3.92 12.00 20.30
58.75 3.70 11.42 19.61
58.95 3.81 11.60 19.65
C6H5 CH3
C6H5 OCH3
C6H5 Cl
C22H15ClN4OS3 55.80 3.05 11.32 19.43
55.92 2.95 11.53 19.50
different products because of the symmetry of 3-chloropentan-
2,4-dione. The compounds 8a–b were reacted with bromine
to afford the corresponding bromoacetyl derivatives. They were
then treated with thiourea to give 2-substituted 4-methyl-5-(2-
aminothiazole-4-yl)thiazoles 10a–b. The aminothiazoles were reacted
with chloroacetylchloride in tetrahydrofuran in the presence of tri-
ethylamine, followed by reaction with ammonium thiocyanate in
ethanol to afford 2-[4-(2-substituted 4-methylthiazole-5-yl)thiazole-2-
yl]aminothiazoline-4-ones 12a–b as starting materials. Finally, the
2-aminothiazoline-4-one derivatives were heated with a suitable aro-
matic aldehyde in acetic acid in the presence of sodium acetate to give
the target compounds 13a–h.
Pharmacology
The compounds selected by the National Cancer Institute (NCI) and
their preliminary anticancer test results as growth percent values ob-
tained against BC, NSCLC, and CNSC cells are given in Table II. It was

2202
I. Kayagil and S. Demirayak
TABLE II The Preliminary Test Results
The growth percentage
BC
NSCLC
CNS
Compounds
Conc. (Molar)
MCF7
NCI-H460
SF-268
4c
4d
4f
4i
4j
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
5 × 10−5
43
101
123
121
95
49
39
25
2
49
38
53
138
124
81
42
99
110
120
85
70
20
5
0
70
7
12
122
120
61
83
80
96
106
108
105
100
82
26
24
100
51
81
4l
7c
7d
7f
7i
7j
7l
13c
13d
13g
13h
98
97
71
85
91
reported that the compounds 4c, 4l, 7c, 7d, 7f, 7j, and 7l have the re-
markable inhibition values for BC and NSCLC, and that 7d, 7f, and 7j
have remarkable inhibition values for CNS. These compounds, except
4c, were accepted for the further screening tests. In this step, the se-
lected six compounds were evaluated in vitro against 66 human tumor
cell lines derived from nine neoplastic diseases (see the Experimental
section), and the detailed test results are given in Table III.
TABLE III Log10 GI50 Values
Comp.
L
NSCLC CC CNSC
M
OC
RC
PC
BC MG MID
4l
7c
7d
7f
7j
7l
A
−4.66 −4.38 −4.45 −4.77 −4,74 −4.83 −4.80 −4.57 −4.79
−6.54 −6.13 −6.21 −5.85 −6.01 −6.12 −5.70 −5.76 −5.92
−4.81 −5.10 −4.99 −4.98 −5.06 −4.93 −4.99 −5.03 −4.98
−5.35 −5.47 −6.64 −5.70 −6.12 −5.76 −5.68 −5.35 −5.96
−4.90 −4.95 −5.00 −4.97 −5.10 −4.81 −4.92 −5.14 −4.93
−4.55 −4.58 −4.70 −4.69 −4.93 −4.55 −4.79 −4.74 −4.66
−5.48 −5.17 −5.11 −5.12 −5.08 −5.18 −4.99 −4.49 −4.79
−6.39 −6.20 −6.14 −6.18 −6.08 −6.45 −6.17 −6.41 −6.05
−4.75
−6.02
−4.99
−5.81
−4.96
−4.69
−5.09
−6.20
B
A: Melphalan, B: Cis-Diaminodichloroplatinum.

Activities of Some Thiazole Derivatives
2203
According to the test method, it is stated that the compounds hav-
ing log10 GI50 (GI50: growth inhibition of 50%) values greater than –4
are considered as inactive. It can be seen that all of our compounds’
log10 GI50 values are smaller than –4. Therefore, we may conclude
that all of our compounds provide a notable activity level. Melpha-
lan and cis-diaminodichloroplatinum, which are the commonly used
clinical chemotherapeutic agents, were used as standard compounds
for the test. When the mean graph midpoint (MG-MID) values of the
compounds melphalan and cis-diaminodichloroplatinum, i.e., –5.09 and
–6.20 respectively, are considered, it is observed that our com-
pounds provide high activity levels. The MG-MID value of the
compound 7c is almost equal that of the control compound cis-
diaminodichloroplatinum. In a similar manner, the activity values of
the compounds 7c and 7f are higher than that of the other control
compound melphalan. When these data are examined according to
their activity against various cancer types, it is observed that both
the standard and the tested compounds are effective against leukemia
for 7c and colon cancer for 7c and 7f in lower concentrations. The
most noteworthy compound is 7f, which is even more active than cis-
diaminodichloroplatinum against colon cancer. It is noticeable that
all of the compounds, except 4l, under detailed investigation are 1,3-
isomers between compounds 4 and 7. Another noticeable point is that
the compounds 13 have the lowest activity values.
EXPERIMENTAL
Chemistry
Melting points were determined by using an Electrothermal 9100
digital melting point apparatus and were uncorrected. Spectro-
scopic data were recorded on the following instruments: FTIR: Schi-
madzu 8400S Spectrophotometer; 1H NMR: Bruker DPX 400 NMR
spectrometer. The starting compounds 5-(3/4-aminophenyl)thiazoles
2a,b and 5a,b.16−18 1-[4-(2-substituted thiazole-5-yl)phenyl]thioureas
3a,b,16 2-substituted 4-methyl-5-acetylthiazoles 8a–b,19 2-substituted
4-methyl-5-(2-bromoacetyl)thiazoles 9a–b,20 and 4-(2-substituted 4-
methythiazole-2-yl)-2-aminothiazoles 10a,b20,21 were obtained accord-
ing to the methods in the literature. The starting compounds
6a,b,11a,b, and12a,b were prepared and used according to the steps
in this section without any structural identifications. Some char-
acteristics were shown in Table I. The spectral analyses data for

2204
I. Kayagil and S. Demirayak
prototypes of final compounds 4a–l, 7a–l, and 13a–h are given
below.
General Method for the Preparation of 2-Substituted
4[3/4-(4-arylthiazole-2-yl)aminophenyl]thiazole Derivatives
4(a–l) and 7(a–l)
A mixture of 1-[3-(2-substituted thiazole-4-yl)phenyl]thiourea or 1-[4-
(2-substituted thiazole-5-yl)phenyl]thiourea derivatives (5 mmol) and
a suitable 2-bromoacetophenone (5.5 mmol) in ethanol (50 mL) was
refluxed for 4 h. The cooled mixture was filtered and recrystallized
from ethanol.
1
4a: IR (KBr) νmax (cm−1): 3347 (N H), 1614–1443 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 2.71 (3H, s, CH3), 7.31–7.35 (1H,
m, Ar-H), 7.38 (1H, s, thiazole C4-H), 7.43–7.47 (2H, m, Ar-H), 7.78 (1H,
s, thiazole C4-H), 7.80 (2H, d, J = 8.73 Hz, Ar-H), 7.94 (2H, d, J = 8.49
Hz, Ar-H), 7.96 (2H, d, J = 7.12 Hz, Ar-H), 10.43 (1H, s, NH).
1
4b: IR (KBr )νmax (cm−1): 3354 (N H), 1614–1442 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 2.32 (3H, s, CH3), 2.70 (3H, s,
CH3), 7.24 (2H, d, J = 8.74 Hz, Ar-H), 7.28 (1H, s, Thiazole C4-H), 7.75
(1H, s, Thiazole C4-H), 7.78 (2H, d, J = 8.61 Hz, Ar-H), 7.82 (2H, d, J =
8.68 Hz, Ar-H), 7.91 (2H, d, J = 8.55 Hz, Ar-H), 10.39 (1H, s, NH).
1
4d: IR (KBr) νmax(cm−1): 3346 (N H), 1616–1462 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 2.71 (3H, s, CH3), 7.44 (1H, s,
thiazole C4-H), 7.50 (2H, d, J = 8.79 Hz, Ar-H), 7.78 (1H, s, thiazole
C4-H), 7.80 (2H, d, J = 8.60 Hz, Ar-H), 7.94 (2H, d, J = 8.65 Hz, Ar-H),
7.97 (2H, d, J = 8.50 Hz, Ar-H), 10.45 (1H, s, NH).
4f: IR (KBr )νmax (cm−1): 3362 (N H), 1672 (C O), 1610–1472 (C N,
1
C C), H NMR (400 MHz) (DMSO-d6)δ (ppm): 2.08 (3H, s, COCH3),
2.71 (3H, s, CH3), 7.23 (1H, s, thiazole C4-H), 7.67 (2H, d, J = 8.61 Hz,
Ar-H), 7.75 (1H, s, thiazole C4-H), 7.80 (2H, d, J = 8.74 Hz, Ar-H), 7.88
(2H, d, J = 8.58 Hz, Ar-H), 7.93 (2H, d, J = 8.65 Hz, Ar-H), 10.05 (1H,
s, CONH), 10.40 (1H, s, NH).
1
4g: IR (KBr) νmax (cm−1): 3380 (N H), 1614–1433 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 7.31–7.35 (1H, m, Ar-H), 7.39 (1H,
s, thiazole C4-H), 7.44–7.47 (2H, m, Ar-H), 7.51–7.57 (3H, m, Ar-H), 7.89
(2H, d, J = 8.76 Hz, Ar-H), 7.97 (2H, d, J = 8.33 Hz, Ar-H), 8.03–8.08
(5H, m, Ar-H, thiazole C4-H), 10.59 (1H, s, NH).
1
4h: IR (KBr )νmax (cm−1): 3382 (N H), 1614–1433 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 2.35 (3H, s, CH3), 7.27 (2H, d,
J:8.08 Hz, Ar-H), 7.31 (1H, s, thiazole C4-H), 7.55 (3H, d, J = 7.57 Hz,

Activities of Some Thiazole Derivatives
2205
Ar-H), 7.86 (4H, d, J = 8.40 Hz, Ar-H), 8.05 (1H, s, thiazole C4-H), 8.07
(4H, d, J = 8.57 Hz, Ar-H), 10.45 (1H, s, NH).
1
4k: IR (KBr) νmax(cm−1): 3378 (N H), 1612–1438 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 7.51–7.57 (3H, m, Ar-H, thiazole
C4-H), 7.79 (1H, s, thiazole C4-H), 7.89 (2H, d, J = 8.70 Hz, Ar-H),
8.03–8.08 (5H, m, Ar-H), 8.22 (2H, d, J = 8.92 Hz, Ar-H), 8.32 (2H, d, J
= 8.92 Hz, Ar-H), 10.79 (1H, s, NH).
1
7a: IR (KBr )νmax (cm−1): 3280 (N H), 1618–1470 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 2.77 (3H, s, CH3), 7.33–7.47 (5H,
m, Ar-H, thiazole C4-H), 7.51 (1H, d, J = 7.75 Hz, Ar-H), 7.66, 7.68 (1H,
dd, J = 1.98, 2.00 Hz, J = 7.96 Hz, Ar-H), 7.87 (1H, s, thiazole C4-H),
8.02 (2H, d, J = 7.37 Hz, Ar-H), 8.64 (1H, d, J = 1.55 Hz, Ar-H), 10.41
(1H, s, NH).
1
7c: IR (KBr) νmax (cm−1): 3276 (N H), 1617–1468 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 2.77 (3H, s, CH3), 3.80 (3H, s,
OCH3), 7.00 (2H, d, J = 8.81 Hz, Ar-H), 7.18 (1H, s, thiazole C4-H),
7.37–7.42 (2H, m, Ar-H), 7.49–7.52 (1H, m, Ar-H), 7.67, 7.69 (1H, dd, J
= 1.54, 1.52 Hz, J:8.01 Hz, Ar-H), 7.87 (1H, s, thiazole C4-H), 7.94 (2H,
d, J = 8.78 Hz, Ar-H), 10.41 (1H, s, NH).
1
7e: IR (KBr) νmax (cm−1): 3283 (N H), 1618–1474 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 2.77 (3H, s, CH3), 7.41 (1H, t, J =
7.86 Hz, thiazole C4-H), 7.54 (1H, d, J = 7.73 Hz, Ar-H), 7.67, 7.69 (1H,
dd, J = 1.79, 1.80 Hz, J = 7.99 Hz, Ar-H), 7.78 (1H, s, Ar-H), 7.89 (1H,
s, Thiazole C4-H), 8.24 (2H, d, J: = 8.83 Hz, Ar-H), 8.30 (2H, d, J = 8.84
Hz, Ar-H), 8.55 (1H, s, Ar-H), 10.53 (1H, s, NH).
1
7g: IR (KBr) νmax (cm−1): 3240 (N H), 1608–1471 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 7.33–7.46 (4H, m, Ar-H, thiazole
C4-H), 7.52–7.58 (3H, m, Ar-H), 7.60–7.64 (2H, m, Ar-H), 8.01 (2H, d, J
= 7.18 Hz, Ar-H), 8.05 = 8.08 (3H, m, Ar-H), 8.15 (1H, s, thiazole C4-H),
8.73 (1H, s, Ar-H), 10.47 (1H, s, NH).
1
7i: IR (KBr) νmax(cm−1): 3245 (N H), 1609–1469 (C N, C C), H
NMR (400 MHz) (DMSO-d6)δ (ppm): 3.77 (3H, s, OCH3), 6.93 (2H, d,
J:8.73 Hz, Ar-H), 7.21 (1H, s, thiazole C4-H), 7.41–7.45 (1H, m, Ar-H),
7.50–7.62 (4H, m, Ar-H), 7.94 (2H, d, J = 8.68 Hz, Ar-H), 8.03–8.08 (3H,
m, Ar-H), 8.15 (1H, s, Thiazole C4-H), 8.76 (1H, s, Ar-H), 10.43 (1H, s,
NH).
7l: IR(KBr) νmax(cm−1) : 3238 (N H), 1676 (C O), 1608–1473 (C N,
1
C C), H NMR (400 MHz) (DMSO-d6)δ (ppm): 2.08 (3H, s, COCH3),
7.26 (1H, s, thiazole C4-H), 7.44–7.62 (5H, m, Ar-H), 7.66 (2H, d, J =
8.70 Hz, Ar-H), 7.92 (2H, d, J = 8.64 Hz, Ar-H), 7.98–8.07 (3H, m, Ar-
H), 8.15 (1H, s, thiazole C4-H), 8.62 (1H, s, Ar-H), 10.06 (1H, s, CONH),
10.42 (1H, s, NH).

2206
I. Kayagil and S. Demirayak
General Method for the Preparation of 2-[4-(2-Substituted 4-
Methylthiazole-5-yl)thiazole-2-yl]amino-5-arylydenethiazoline-
4-ones Derivatives 13(a–h)
A mixture of 2-[4-(2-substituted 4-methylthiazole-5-yl)thiazole-2-
yl]aminothiazoline-4-one derivative (5 mmol), a suitable 4-substituted
benzaldehyde (5.5 mmol) and sodium acetate (15 mmol) in acetic acid
(50 mL) was refluxed for 8 h. The cooled mixture was poured into ice
water. The precipitate was filtered and crystallized from ethanol.
13a: IR (KBr) νmax (cm−1): 3120 (N H), 1724, 1688 (C O), 1590–
1430 (C N, C C), 1H NMR (400 MHz) (DMSO-d6)δ (ppm): 2.45 (3H, s,
CH3), 2.82 (3H, s, CH3), 7.31 (1H, s, =CH-), 7.41–7.62 (5H, s, Ar-H),
8.15 (1H, s, thiazole C4-H), 10.45 (1H, s, NH).
13d: IR (KBr) νmax(cm−1): 3128 (N H), 1730, 1704 (C O), 1589–1423
(C N, C C), 1H NMR (400 MHz) (DMSO-d6)δ (ppm): 2.44 (3H, s, CH3),
2.80 (3H, s, CH3), 7.32 (1H, s, =CH-), 7.45 (2H, d, J = 8.62 Hz, Ar-H),
8.15 (1H, s, thiazole C4-H), 8.40 (2H, d, J = 8.64 Hz, Ar-H), 10.45 (1H,
s, NH).
13g: IR (KBr )νmax(cm−1): 3126 (N H), 1720, 1683 (C O), 1589–1461
(C N, C C), 1H NMR (400 MHz) (DMSO-d6)δ (ppm): 2.45 (3H, s, CH3),
7.12 (2H, d, J = 7.85 Hz, Ar-H), 7.32 (1H, s, =CH-), 7.42–7.50 (3H, m,
Ar-H), 7.85–7.95 (2H, m, Ar-H), 8.12 (1H, s, thiazole C4-H), 8.38 (2H,
d, J = 7.90 Hz, Ar-H), 10.43 (1H, s, NH).
Pharmacology
The cytotoxic and/or growth inhibitory effects of the compounds were
evaluated in vitro against approximately 66 human tumor cell lines
derived from nine neoplastic diseases, namely leukaemia (L), non-
small cell lung cancer (NSCLC), colon cancer (CC), central nervous
system cancer (CNSC), melanoma (M), ovarian cancer (OC), renal can-
cer (RC), prostate cancer (PC), breast cancer (BC). The evaluation
of anticancer activity was performed at the NCI of Bethesda, Mary-
land, USA, following the in vitro screening program, which is based
upon the use of multiple panels of 66 human tumor cell lines against
which our compounds were tested at 10-fold dilutions of five concen-
trations ranging from 10−4 to 10−8 M. The percentage growth was
evaluated spectrophotometrically versus controls not treated with test
agents. A 48 h continuous drug exposure protocol was followed, and
a sulforhodamine B (SRB) protein assay was used to estimate cell
growth.22,23

Activities of Some Thiazole Derivatives
2207
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