Synthesis and Cytotoxicity in Vitro of N-Aryl-4-(Tert-butyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amine

Article abstract of DOI:10.1002/jccs.201400395

A series of novel N-aryl-4-(tert-butyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amines were synthesized in a green way. H₂O₂-NaBr Brominating circulatory system was used in the synthesis of the key intermediate in a mild condition. All of the target compounds were confirmed by¹H NMR and elemental analysis and tested for their cytotoxicity against two different human cancer cell lines. The cytotoxicity assay revealed that some of the title compounds showed moderate to strong cytotoxic activities. Compound 2i was the most potent compound with the IC₅₀ values of 9 μMagainst Hela cells and 15 μMagainst Bel-7402 cells, respectively.

Full text of DOI:10.1002/jccs.201400395

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis and Cytotoxicity in Vitro of N-Aryl-4-(tert-butyl)-5-(1H-1,2,4-triazol-1-
yl)thiazol-2-amine
Jiao Ye,* Meng-Wu Xiao, Xuan-Qing Xie, Shen-Yi Qiu, Ming-Chong Dai, Wan Li, Fang Shen and
Ai-Xi Hu*
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
(Received: Sept. 19, 2014; Accepted: May 13, 2015; Published Online: Jun. 5, 2015; DOI: 10.1002/jccs.201400395)
A series of novel N-aryl-4-(tert-butyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amines were synthesized in a
2 2
green way. H O -NaBr Brominating circulatory system was used in the synthesis of the key intermediate
1
in a mild condition. All of the target compounds were confirmed by H NMR and elemental analysis and
tested for their cytotoxicity against two different human cancer cell lines. The cytotoxicity assay revealed
that some of the title compounds showed moderate to strong cytotoxic activities. Compound 2i was the
most potent compound with the IC50 values of 9 mM against Hela cells and 15 mM against Bel–7402 cells,
respectively.
Keywords: Thiazole derivatives; Triazole; Bromination; Synthesis; Cytotoxicity.
INTRODUCTION
Thiazole derivatives, as a class of well known ni-
Scheme 1 Synthetic route of the target compounds 2
trogen-containing heterocyclic compounds, have been
studied extensively due to their numerous of pharmaco-
,2
logical applications and varied biological activities,
1
3
such as antimicrobial, anti-inflammatory, antihy-
-5
6
7
pertensive, antifungal,
8-10
11-13
antibacterial
and anti-
1
4-16
HIV.
In recent years, a considerable effort has been
made to develop new anti-cancer drugs based on thi-
azole. U.G. Bhat reported that thiazole antibiotics can in-
1
7
duce apoptosis in human cancers. S. Back discovered
RESULTS AND DISCUSSION
that 4-aryl-2-substituted aniline-thiazole analogs can in-
1
hibit the growth of human prostate cancer LNCap cells.
Chemistry
8
To the best of our knowledge, this is a new method for
the synthesis of 2-aminothiazole. Generally, bromine was
used as brominating agent in the synthesis of the key inter-
mediate 4, but the process was fraught with problems of
handling and low atom efficiency of substitution reactions.
Zhengyue Ma found that 1,3-thiazolidin-4-ones have a
good inhibitory effect against gastric cancer (SGC-
7
901), cervical cancer cells (Hela) and lung cancer cells
1
9
(
A-549).
Inspired by these reports, we have previously syn-
thesized various N-aryl-5-benzyl-4-(tert-butyl)thiazol-
-amines (1) and found that they were effective in cyto-
Although bromination reaction with H
2
has been reported,
2
O
2
-NaBr system
1-23
there is no a clear way to recycling
2
the bromide which produced from the reaction. Only solv-
ing this key issue may reduce the affection to our environ-
2
0
toxicity. To search for additional promising active
compounds, we continued our effort to modify the struc-
ture of compound 1 by replacement of the substituted
benzyl with triazole. Hereon, several novel N-aryl-4-
2 2
ment fundamentally. For this reason, we explored H O -
NaBr brominating circulatory system, and the recycling of
bromine in the synthesis process of compounds 2 is de-
picted in Scheme 2. In this system, compound 3 was
brominated to a–bromoketones 4 in excellent yield. After
work-up, compound 4, without further purification, was
carried forward to react with N-arylthiourea in ethanol to
(
(
tert-butyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amines
2) were synthesized (Scheme 1) and their cytotoxic ac-
tivities were evaluated against two human cancer cell
lines.
*
Corresponding author. Tel: +86 0731-88822286; Fax: +86 0731-88713642; Email: yejiao@hnu.edu.cn; axhu@hnu.edu.cn
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201400395
J. Chin. Chem. Soc. 2015, 62, 627-631
© 2015 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
627

Article
Ye et al.
produce N-aryl-4-(tert-butyl)-5-(1H-1,2,4-triazol-1-yl)thi-
azol-2-amine hydrobromides, which were converted to
free-bases 2a-2q by neutralization with sodium hydrogen
carbonate. The overall yield of compounds 2 (based on 3) is
ternal standard. The elemental analysis were carried out on a
VARIO EL III instrument.
Synthesis: As described in Scheme 1, compounds 2 were
synthesized from the reaction of a–bromoketones (4) and N-
arylthiourea (6), while benzoyl arylthiourea (5) and N-aryl-
5
4-90% (Table 1). At the same time, sodium bromide can
be reused as the bromine source in the next run. The
-NaBr brominating circulatory system we explored
2
4
thiourea 6 were prepared according to the literature method.
H
2
O
2
Synthesis of 1-bromo-3,3-dimethyl-1-(1H-1,2,4-triazol-
1-yl)butan-2-one (4): Sodium bromide (6.6 mmol), water (6.0
mL) and concentrated sulfuric acid (0.3 mL) were added in se-
quence to a solution of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-
successfully solved the problem of the bromine handling.
The process is atom economic and environmental friendly.
1
In addition, all the new compounds were confirmed by H
NMR spectroscopy and elemental analysis.
4
yl)butan-2-one (3, 6.0 mmol) in CCl (40.0 mL). The mixture was
heated to 65 °C, then, 30% hydrogen peroxide (3.6 mL) was
Table 1. The reaction results for the synthesis of compounds 2
Scheme 2 Recycling of bromine in the synthesis of
compounds 2
Compd.
Y
H
m.p. (°C) Yield (%)
2
2
2
2
2
2
2
2
a
b
c
d
e
f
187-189
140-141
128-130
193-195
122-124
156-159
200-202
148-150
168-170
141-143
229-232
170-172
194-196
166-168
195-198
227-229
145-147
67
83
85
63
66
54
60
90
60
58
81
67
86
73
63
74
86
4-CH
3
2-CH
3
O
2-F
2-Cl
3-Cl
4-Cl
3-Br
g
h
Cytotoxicity in vitro
2i
3-CF
3
2
2
2
2
2
2
2
2
j
2-NO
2
2
The compounds 2a-2q were tested cytotoxic activi-
ties against two cancer cell lines: Hela (cervix cancer) and
Bel-7402 (liver cancer), and the IC50 values of some active
compounds were compared to Cisplatin (Table 2). Com-
pouds 2h, 2i, 2o and 2q showed moderate to strong cyto-
toxic activities against Hela cell line with IC50 values of 25,
k
l
4-NO
2,4-diCH
2,6-diCH
3,4-diCH
3
3
3
m
n
o
p
q
3-Cl-4-F
2-Cl-4-NO
2
9
, 25 and 22 mM, respectively, which were close to that of
2,3-CH=CH-CH=CH
Cisplatin (IC50 20 mM). Meanwhile, they also exhibited po-
tent cytotoxic activities against Bel-7402 cell line with IC50
values of 29, 15, 37 and 33 mM, respectively, which were
equivalent to that of Cisplatin (IC50 30 mM). Among them,
compound 2i, with meta-electron-withdrawing group (3-
Table 2. Cytotoxic activities of selected compounds against Hela
and Bel–7402 cells
IC50 (mM)
Compd.
Y
CF
3
) on the phenyl ring, is the most potent compound,
Hela
95
Bel–7402
ND
41
which may be a good candidate for further study in vitro
against a broad panel of human cancer cell lines.
2b
2c
4-CH
3
2-CH
O
59
3
2
2
2
2
2
2
e
h
i
2-Cl
3-Br
75
ND
29
25
EXPERIMENTAL
3-CF3
9
15
Materials and Instruments: All solvents were of reagent
grade. All chemicals were analytical reagents and used directly
without further purification. Melting point was measured on an
X-4 electrothermal digital melting point apparatus and uncor-
j
2-NO2
274
445
25
583
687
37
n
o
3,4-diCH
3
3-Cl-4-F
1
rected. The H NMR spectra were recorded on a VARIAN
2q
2,3-CH=CH-CH=CH
22
33
Cisplatin
20
30
3
INOVA-400 spectrometer (400 MHz) in CDCl with TMS as in-
628
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis and Cytotoxicity of Thiazol-2-amines
added dropwise during 2 h. The mixture continued to react for 30
1H), 7.62 (bs, 1H), 8.11 (s, 1H), 8.28 (s, 1H). Anal. Calc. for
min, poured into NaHCO
3
aqueous solution (40.0 mL), and ex-
15 5
C H16ClN S: C, 53.97, H, 4.83, N, 20.98 found: C, 53.91, H,
tracted with dichloromethane (3 ´ 10 mL). The organic phase was
4.83, N, 21.02. 4-(tert-Butyl)-N-(4-chlorophenyl)-5-(1H-1,2,4-
washed with saturated NaCl solution, dried over anhydrous
triazol-1-yl)thiazol-2-amine (2g): Reaction time: 1.0 h, yield:
1
60%, m.p. 200-202 °C; H NMR (400 MHz, CDCl
Na
2
SO
4
, and evaporated in vacuum to give compound 4 as an oil.
3
) d 1.16 (s,
General procedure for synthesis of N-aryl-4-(tert-
9H), 7.33 (m, 4H), 8.09 (s, 1H), 8.26 (s, 1H). Anal. Calc. for
15 5
C H16ClN S: C, 53.97, H, 4.83, N, 20.98 found: C, 54.02, H,
butyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amine (2): A suspen-
sion of compound 4 and N-arylthiourea 6 (5 mmol) in EtOH (30.0
mL) was heated at reflux (monitored by thin-layer chromatogra-
4.83, N, 20.95. 4-(tert-Butyl)-N-(3-bromophenyl)-5-(1H-1,2,
4-triazol-1-yl)thiazol-2-amine (2h): Reaction time: 1.0 h, yield:
1
90%, m.p. 148-150 °C; H NMR (400 MHz, CDCl
phy). Then the mixture was cooled and poured into NaHCO
3
3
) d 1.16 (s,
aqueous solution. The resultant precipitate was filtered off and
purified by recrystallization from ethanol to obtain the target
compounds. The filtrate was evaporated to give the recovered so-
dium bromide, which was reused for the next run. 4-(tert-Butyl)-
N-phenyl-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amine (2a): Reac-
9H), 7.17 (bs, 1H), 7.21-7.28 (m, 3H), 7.64 (d, J = 1.2 Hz, 1H),
8.09 (s, 1H), 8.26 (s, 1H). Anal. Calc. for C15 S: C, 47.62,
H
16BrN
5
H, 4.26, N, 18.51 found: C, 47.58, H, 4.27, N, 18.54. 4-(tert-
Butyl)-5-(1H-1,2,4-triazol-1-yl)-N-(3-(trifluorometh-yl)phenyl)
thiazol-2-amine (2i): Reaction time: 1.5 h, yield: 60%, m.p.
1
168-170 °C; H NMR (400 MHz, CDCl
1
tion time: 1.0 h, yield: 67%, m.p. 187-189 °C; H NMR (400
3
) d 1.17 (s, 9H), 7.32-7.56
MHz, CDCl
3
) d 1.17 (s, 9H), 1.83 (bs, 1H), 7.11-7.40 (m, 5H),
.09 (s, 1H), 8.26 (s, 1H). Anal. Calc. for C15 S: C, 60.18, H,
.72, N, 23.39 found: C, 60.25, H, 5.73, N 23.42. 4-(tert-Butyl)-
(m, 4H), 7.89 (bs, 1H), 8.10 (s, 1H), 8.27 (s, 1H). Anal. Calc. for
16 16 3 5
C H F N S: C, 52.31, H, 4.39, N, 19.06 found: C, 52.25, H,
8
5
H
17
N
5
4.38, N, 19.09. 4-(tert-Butyl)-N-(2-nitrophenyl)-5-(1H-1,2,4-
N-(4-methylphenyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amine
1
2b): Reaction time: 1.0 h, yield: 83%, m.p. 140-141 °C; H NMR
triazol-1-yl)thiazol-2-amine (2j): Reaction time: 1.5 h, yield:
1
58%, m.p. 141-143 °C; H NMR (400 MHz, CDCl
(
3
) d 1.20 (s,
(
400 MHz, CDCl
H), 7.21 (d, J = 8.8 Hz, 2H), 8.08 (s, 1H), 8.24(s, 1H). Anal.
Calc. for C16 S: C, 61.31, H, 6.11, N, 22.34 found: C, 61.37,
H, 6.11, N, 22.30. 4-(tert-Butyl)-N-(2-methoxyphenyl)-5-(1H-
3
) d 1.17 (s, 9H), 2.34 (s, 3H), 7.17 (d, J = 8.8 Hz,
9H), 7.08-7.13 (m, 1H), 7.65-7.70 (m, 1H), 8.12 (s, 1H), 8.29 (dd,
2
J = 1.6 Hz, J = 8.8 Hz, 1H), 8.29 (s, 1H), 8.74 (dd, J = 1.6 Hz, J =
H
19
N
5
16 6 2
8.8 Hz, 1H), 10.68 (bs, 1H). Anal. Calc. for C15H N O S: C,
52.31, H, 4.68, N, 24.40 found: C, 52.36, H, 4.68, N, 24.38. 4-
(tert-Butyl)-N-(4-nitrophenyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-
1
,2,4-triazol-1-yl)thiazol-2-amine (2c): Reaction time: 1.0 h,
1
yield: 85%, m.p. 128-130 °C; H NMR (400 MHz, CDCl
3
) d 1.17
2-amine (2k): Reaction time: 2.0 h. yield: 81%, m.p. 229-232 °C;
1
(
s, 9H), 3.92 (s, 3H), 6.92 (dd, J = 2.0 Hz, J = 7.6 Hz, 1H),
.97-7.03 (m, 2H), 7.70 (bs, 1H), 7.93 (dd, J = 2.0 Hz, J = 7.6 Hz,
H), 8.09 (s, 1H), 8.25 (s, 1H). Anal. Calc. for C16 OS: C,
3
H NMR (400 MHz, CDCl ) d 1.19 (s, 9H), 7.60 (d, J = 9.2 Hz,
6
1
5
4
2H), 7.67 (bs, 1H), 8.12 (s, 1H), 8.26 (d, J = 9.2 Hz, 2H), 8.29 (s,
1H). Anal. Calc. for C15 S: C, 52.31, H, 4.68, N, 24.40
H
19
N
5
16 6 2
H N O
8.34, H, 5.81, N, 21.26 found: C, 58.26, H, 5.80, N, 21.29.
found: C, 52.37, H, 4.69, N, 24.36. 4-(tert-Butyl)-N-(2,4-
dimethylphenyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amine
-(tert-Butyl)-N-(2-fluorophenyl)-5-(1H-1,2,4-triazol-1-yl)
1
(2l): Reaction time: 0.5 h, yield: 67%, m.p. 170-172 °C; H NMR
thiazol-2-amine (2d): Reaction time: 5.0 h, yield: 63%, m.p.
1
93-195 °C; H NMR (400 MHz, CDCl
1
3
) d 1.10 (s, 9H), 7.03-7.30
(400 MHz, CDCl
(s, 3H), 7.06-7.12 (m, 3H), 8.07 (s, 1H), 8.23 (s, 1H). Anal. Calc.
S: C, 62.36, H, 6.46, N, 21.39 found: C, 62.30, H,
3
) d 1.15 (s, 9H), 1.85 (bs, 1H), 2.23 (s, 3H), 2.25
(
(
m, 3H), 8.22 (s, 1H), 8.42 (t, J = 8.0 Hz, 1H), 8.93 (s, 1H), 10.17
bs, 1H). Anal. Calc. for C15 S: C, 56.76, H, 5.08, N, 22.07
H
16FN
5
21 5
for C17H N
found: C, 56.81, H, 5.08, N, 22.02. 4-(tert-Butyl)-N-(2-chloro-
phenyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amine (2e): Reac-
1
tion time: 2.0 h, yield: 66%, m.p. 122-124 °C; H NMR (400
6.46, N, 21.43. 4-(tert-Butyl)-N-(2,6-dimethylphenyl)-5-(1H-
1,2,4-triazol-1-yl)thiazol-2-amine (2m): Reaction time: 1.0 h,
1
yield: 86%, m.p. 194-196 °C; H NMR (400 MHz, CDCl
3
) d 1.13
MHz, CDCl
3
) d 1.18 (s, 9H), 7.02 (t, J = 8.0 Hz, 1H), 7.30 (t, J =
.0 Hz, 1H), 7.42 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.52 (bs, 1H),
.08 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.27 (s, 1H).
S: C, 53.97, H, 4.83, N, 20.98 found:
C, 54.05, H, 4.83, N, 20.94. 4-(tert-Butyl)-N-(3-chlorophenyl)-
(s, 9H), 2.35 (s, 6H), 6.75 (bs, 1H), 7.12-7.18 (m, 3H), 8.02 (s,
1H), 8.20 (s, 1H). Anal. Calc. for C17 S: C, 62.36, H, 6.46, N,
8
8
21 5
H N
21.39 found: C, 62.30, H, 6.47, N, 21.42. 4-(tert-Butyl)-N-
(3,4-dimethylphenyl)-5-(1H-1,2,4-triazol-1-yl)thiazol-2-amine
1
(2n): Reaction time: 0.5 h, yield: 73%, m.p. 166-168 °C; H NMR
Anal. Calc. for C15H16ClN
5
5
1
1
-(1H-1,2,4-triazol-1-yl)thiazol-2-amine (2f): Reaction time:
1
.5 h, yield: 54%, m.p. 156-159 °C; H NMR (400 MHz, CDCl
(400 MHz, CDCl
7.04-7.12 (m, 3H), 7.15 (bs, 1H), 8.07 (s, 1H), 8.23 (s, 1H). Anal.
Calc. for C17 S: C, 62.36, H, 6.46, N, 21.39 found: C, 62.26,
3
) d 1.15 (s, 9H), 2.23 (s, 3H), 2.25 (s, 3H),
3
) d
.16 (s, 9H), 7.03-7.06 (m, 1H), 7.22-7.29 (m, 2H), 7.50-7.51 (m,
21 5
H N
J. Chin. Chem. Soc. 2015, 62, 627-631
© 2015 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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629

Article
Ye et al.
H, 6.45, N, 21.43. 4-(tert-Butyl)-N-(3-chloro-4-fluorophenyl)-
ACKNOWLEDGEMENTS
5
1
1
1
-(1H-1,2,4-tria-zol-1-yl)thiazol-2-amine (2o): Reaction time:
1
.5 h, yield: 63%, m.p. 195-198 °C; H NMR (400 MHz, CDCl
We gratefully acknowledge the National Natural Sci-
ence Foundation Emergency Project of China (No.
21442014) and the Natural Science Foundation of Hunan
Province (No. 12jj3012) for financial support.
3
) d
.11 (s, 9H), 7.37-7.48 ( m, 2H), 8.08 (dd, J = 2.4 Hz, J = 6.8 Hz,
H), 8.23 (s, 1H), 8.94 (s, 1H), 10.58 (bs, 1H). Anal. Calc. for
C
15
H
15ClFN
5
S: C, 51.21, H, 4.30, N, 19.91 found: C, 51.29, H,
4
.31, N, 19.94. 4-(tert-Butyl)-N-(2-chloro-4-nitrophenyl)-5-
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were measured cytotoxic activities against two human cancer cell
lines including Hela (cervix cancer) and Bel-7402 (liver cancer)
by the MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetra-
2
5
zolium bromide) assay with Cisplatin as the positive control.
MTT solution (10.0 mL/well) in RPMI-1640 (Sigma, St. Louis,
MO) was added after the cells were treated with the title com-
pound (concentration ranging from 0 to 0.5 mM) for 48 h, and then
1
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2
1
2
the cells were further incubated for 4 h at 37 °C in 5% CO incuba-
6
tor. The purple formazan crystals were dissolved in 100.0 mL
DMSO and well-mixed. The absorbance of each well at 570 nm
was measured by Multiskan MK3 microplate reader. The assay
was performed three times in the same manner, and the IC50 (50%
inhibition) was calculated by SPSS statistical software.
12. Lu, X. Y.; Liu, X. B.; Wan, B. J.; Scott, G. F.; Chen, L. L.;
Zhou, C. L.; You, Q. D. Eur. J. Med. Chem. 2012, 49,
1
64-171.
1
1
1
1
3. Chigarambatla, K.; Rao, N. G. R.; Nayak, B. S.; Sonar, V. N.
J. Adv. Sci. Res. 2013, 4, 01-05.
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5
2-58.
CONCLUSIONS
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1995, 60, 7927-7933.
In summary, a series of novel N–aryl–4-(tert-butyl)-
6. Frank, W. B.; Amanda, S. C.; Marita, H. S.; Richard, J.; Nils,
G. J.; Christopher, L. J.; Micheal, D. K.; Peter, L.; John, M.
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5
-(1H-1,2,4-triazol-1-yl)thiazol-2-amines were synthe-
sized from 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-
-one. H -NaBr Brominating circulatory system was
2
2 2
O
used in the synthesis of the key intermediate 1-bromo-3,3-
dimethyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-one, and the
sodium bromide was recovered and reused. The process is
efficient, low toxicity and high atom economy. The cyto-
toxicity assay showed that some of the title compounds ex-
hibited moderate to strong cytotoxic activities against Hela
and Bel-7402 cell lines, while compound 2i was the most
potent compound and could be used as a lead compound for
further study.
4
929-4936.
1
7. Bhat, U. G.; Halasi, M.; Gartel, A. L. Plos One. 2009, 4,
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1
2
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