Synthesis of new thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives as potent analgesic and anti-inflammatory agents

Article abstract of DOI:10.1007/s00044-013-0697-y

A series of thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones were synthesized and evaluated for their analgesic and anti-inflammatory activities. The structures of these compounds were supported by FT-IR, ¹HNMR, and Mass spectra. All of the final comp

Full text of DOI:10.1007/s00044-013-0697-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:948–957
DOI 10.1007/s00044-013-0697-y
ORIGINAL RESEARCH
Synthesis of new thiazolo[3,2-b][1,2,4]triazole-6(5H)-one
derivatives as potent analgesic and anti-inflammatory agents
•
Mohammad Javad Assarzadeh Ali Almasirad
•
•
Abbas Shafiee Mansur Nassiri Koopaei
•
Mohammad Abdollahi
Received: 11 May 2013 / Accepted: 7 August 2013 / Published online: 21 August 2013
Ó Springer Science+Business Media New York 2013
Abstract
6(5H)-ones were synthesized and evaluated for their anal-
A
series of thiazolo[3,2-b][1,2,4]triazole-
These compounds non-selectively inhibit the two cyclo-
oxygenase (COX1 and COX2) isoforms. However, their
clinical use is often limited by prevalent side effects such
as ulceration and gastrointestinal hemorrhage (Smith et al.,
1998; Warner et al., 1999; Abu-Hashem and Gouda, 2011;
Schoen and Vender, 1989; Tiryaki et al., 2012). So
development of new analgesic and anti-inflammatory
compounds with a safer profile of activity and acceptable
potency and efficacy is still an important issue. In the
previous study we described the synthesis of aryl hydra-
zone derivatives of 2-phenoxybenzoic acid 1 which showed
potent analgesic and anti-inflammatory activities (Almasi-
rad et al., 2006).
gesic and anti-inflammatory activities. The structures of
1
these compounds were supported by FT-IR, HNMR, and
Mass spectra. All of the final compounds showed potent
analgesic activity and the best compound 9d was 2.4 times
more potent than mefenamic acid as the reference drug. In
addition, most of them showed comparable or better anti-
inflammatory activity in comparison with mefenamic acid
and indomethacin. Moreover, compounds 9d, 9e, 9g, 9h,
9i, 9k, 9n, and 9o did not exhibit any significant ulcero-
genic activity.
Keywords Analgesic agents ꢀ
Anti-inflammatory activity ꢀ Thiazolo-triazole ꢀ
Ulcerogenic activity
In addition, compounds having thiazolo[3,2-b][1,2,4]
triazole-6(5H)-ones 2 have been reported to exhibit anti-
bacterial and antifungal (Pignatello et al., 1991; Shafiee
et al., 1998), anticancer (Lesyk et al., 2007), anti-inflam-
matory, and analgesic activities (Tozkoparan et al., 1999,
˘
2000; Berk et al., 2001; Dogdas¸ et al., 2007).These find-
Introduction
ings prompted us to design and synthesize new compounds
(9a–9o) by molecular hybridization of previously described
derivatives 1 and 2, in order to investigate the possible
pharmacophoric contribution of both the 2-phenoxyphenyl
and thiazolo-triazole moieties in the analgesic and anti-
inflammatory activities (Fig. 1).
Non-steroidal anti-inflammatory drugs (NSAIDS) are the
first-line drugs for the treatment of pain and inflammation.
M. J. Assarzadeh ꢀ A. Almasirad (&) ꢀ M. N. Koopaei
Department of Medicinal Chemistry, Pharmaceutical Sciences
Branch, Islamic Azad University, 19419 Tehran, Iran
e-mail: almasirad.a@iaups.ac.ir; almasial@sina.tums.ac.ir
Results and discussion
A. Shafiee
Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, 14174 Tehran, Iran
Chemistry
The designed compounds were synthesized as outlined in
Schemes 1 and 2. Hydrazide 5 was prepared as described
previously (Almasirad et al., 2006, 2004). 5-(2-Phenoxy-
phenyl)-2H-1,2,4-triazole-3(4H)-thione, 7 was prepared via
M. Abdollahi
Department of Pharmacology and Toxicology, Faculty of
Pharmacy and Pharmaceutical Sciences Research Center, Tehran
University of Medical Sciences, 14174 Tehran, Iran
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Med Chem Res (2014) 23:948–957
949
Fig. 1 Design of target
compounds
O
C
O
H
Ar
N
N
C
H
N
N
Ar
O
S
Ar'
N
1
2
O
N
N
Ar
S
N
O
9a-9o
Scheme 1 a CH3OH, H2SO4,
reflux; b NH2NH2H2O, rt;
c KSCN, HCl, reflux; d NaOH,
reflux
O
O
O
C
O
C
NH2
CH3
N
O
OH
H
b
a
O
O
5
3
4
c
O
C
NH
N
H
N
S
S
N
C
d
N
H
H
NH2
O
O
6
7
123

950
Med Chem Res (2014) 23:948–957
O
NH
3
N
5
6
6'
S
5
N
N
5'
4'
6'
3'
2
N
1'
5'
4'
1'
2'
H
Ar
S
8
N
2'
O
1''
3'
O
1''
2''
3''
6''
5''
a
6''
5''
Ar-CHO
2''
3''
4''
4''
9a-o
8
7
4'''
7'''
3"'
5'''
2"'
3'''
2'''
3'''
3'''
4'''
5'''
8'''
5'''
6'''
2'''
Ar =
R
4'''
5'''
2'''
4"'
1'''
1'''
6'''
X
N
9'''
6'''
X= O, S
9m-9n
COCH3
9a-9k
9l
9o
Scheme 2 a ClCH2COOH, CH3COOH, (CH3CO)2O, NaOAc, reflux
Table 1 Physical properties of compounds 9a–9o
O
N
N
Ar
S
N
O
Compound no
Ar
Recrystallization solvent
Yield (%)
Mp (°C)
Formulaa
9a
9b
9c
9d
9e
9f
Phenyl
Ethanol
Ethanol
Methanol
Ethanol
Methanol
Ethanol
Ethanol
Ethanol
Ethanol
Methanol
Methanol
Ethanol
Ethanol
Ethanol
Ethanol
64
57
73
66
73
69
86
76
53
86
73
58
94
73
68
169–172
238–241
222–223
194–197
200–203
205–207
216–219
188–191
223–225
220–223
220–221
190–192
207–209
194–195
233–235
C23H15N3O2S
4-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
4-Nitrophenyl
4-Methylphenyl
4-Methoxyphenyl
4-Methylthio
C
C
C
C
C
C
C
23H14FN3O2S
23H14ClN3O2S
23H14BrN3O2S
23H14N4O4S
24H17N3O2S
24H17N3O3S
24H17N3O2S2
9g
9h
9i
4-Acetoxyphenyl
4-N,N-Dimethylaminophenyl
3,5-Di-t-Bu-4 hydroxy
Styryl
C25H17N3O4S
9j
C
C
C
C
C
25H20N4O2S
31H31N3O3S
25H17N3O2S
21H13N3O3S
21H13N3O2S2
9k
9l
9m
9n
9o
a
2-Furyl
2-Thienyl
1-Acetyl-2-indolyl
C27H18N4O3S
All compounds were analyzed for C, H, N. Analytical results obtained for these elements were within 0.4 % of the calculated value for the formula shown
123

Med Chem Res (2014) 23:948–957
951
Table 2 Analgesic effect of
compounds (9a–9o) in the
abdominal constrictions induced
by acetic acid in mice
Compound
Constriction no (mean SEM)a
Inhibition (%)b
Relative activityc
Control
112.3 10.5
67.0 7.5
19.8 7.3
30.4 11
15.8 4.3
03.6 1.2
27.0 4.07
19.2 1.6
62.0 6.4
18.8 6.4
14.7 2.8
22.4 8.2
5.5 1.90
24.2 6.1
25.0 3.6
22.3 3.3
16.5 2.6
–
–
Mefenamic acid
40.3
82.3
73
1***
9a
9b
9c
9d
9e
9f
2.04***
1.81***
2.13***
2.39***
1.89***
2.06***
1.11***
2.06***
2.15***
1.99***
2.35***
1.95***
1.93***
1.99***
2.12***
85.9
96.7
76.0
83.0
44.8
83.2
86.9
80.0
95.0
78.4
77.7
80.1
85.3
a
9g
9h
9i
Number of animals in each
group n = 6; compounds were
administered at the dose of
30 mg/kg
9j
b
Percentage of inhibition
obtained by comparison with
vehicle control group
9k
9l
c
9m
9n
9o
Analgesic activity relative to
mefenamic acid; differed from
control group ***p \ 0.001
significant from control
reaction of 5 with potassium thiocyanate and hydrochloric
acid followed by cyclization of intermediate 6 with aque-
ous sodium hydroxide (Almasirad et al., 2007).
electron withdrawing substituents were slightly preferred
over electron donating ones. Moreover, introduction of an
electron withdrawing and lipophilic substituent such as
bromine resulted in compound 9d with a considerably
improved analgesic activity (96 % inhibition) relative to
the unsubstituted derivative 9a (82 % inhibition).
The treatment of 6 with chloroacetic acid and different
aromatic aldehydes in the presence of sodium acetate, acetic
acid, and acetic anhydride gave final derivatives (9a–9o)
¨
(Table 1) (Uzgoren-Baran et al., 2012). In the FT-IR
In vivo anti-inflammatory evaluation of 9a–9o was
carried out by carrageenan-induced rat paw edema test
(Rineh et al., 2007; Calıskan et al., 2013). According to the
results, except for compounds 9a, 9f, 9j, and 9m all of
them were active anti-inflammatory agents (48–82 %
inhibition) after 4 h (Table 3). The anti-inflammatory
activity of compounds 9e, 9g, 9h, 9i, 9k, and 9n was more
than that of mefenamic acid and the activity of 9e, 9g, and
9n was comparable to indomethacin. Bioisosteric replace-
ment of phenyl ring 9a with thienyl 9n confers significantly
higher activity during all time intervals than 9a. Compound
9f bearing a 4-methyl moiety as a more lipophilic electron
donating group in comparison to methoxy in 9g showed
lower activity. It can be concluded by comparison of 9g
with 9h, 9i and 9j that adding bulky electron donating
groups can deteriorate the activity and resulted in less
active compounds. The good activity of compounds 9e and
9g can be deduced by a possible hydrogen bond formation
between the oxygens of OCH3 or NO2 groups with the
binding site of the receptor. Finally, the elucidation of anti-
inflammatory results again emphasizes that both electron
donating and electron withdrawing groups on benzyliden
moiety can result in potent derivatives in this series of
compounds.
spectrum of target compounds strong C=O stretching band
at 1725–1750 was observed which is an evidence for the
ring closure. The Z conformation of the exocyclic double
bound in the 5th position of thiazolotriazole ring system
1
was confirmed on the basis of H-NMR spectroscopy. The
1H-NMR spectra of compounds 9a–9o showed only one
kind of =CH proton that is deshielded by the adjacent car-
bonyl moiety to the higher chemical shift values
(8.11–8.18 ppm) than the expected ones for E isomers.
Pharmacology
The analgesic activity was evaluated by acetic acid-
induced writhing assay and results are shown in Table 2
(Almasirad et al., 2006; Moradi et al., 2010; Tozkoparan
et al., 2012). All of the target compounds induced signifi-
cant reduction in the writhing response in comparison with
control and except for compound 9g all of them were more
effective than mefenamic acid. The best compound 9d was
2.4 times more effective than mefenamic acid. The results
showed that different substituted phenyl or heteroaromatic
rings at 5th position of the thiazole ring caused a noticeable
analgesic activity. Both the electron withdrawing and
donating groups on the 4th position of benzylidene ring of
compounds (9b–9k) lead to potent compounds, but
The compounds 9d, 9e, 9g, 9h, 9i, 9k, 9n, and 9o as the
best derivatives, in analgesic or anti-inflammatory tests,
123

952
Med Chem Res (2014) 23:948–957
Table 3 Anti-inflammatory activity of the compounds in a carra-
geenan-induced hind paw edema model in rat
Table 3 continued
Compound
Time
(h)a
Thickness
variation (mm)b
Inhibition
(%)c
Compound
Control
Time
(h)a
Thickness
variation (mm)b
Inhibition
(%)c
9i
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1.08 0.12
1.20 0.13
1.34 0.07
0.88 0.09
1.54 0.30
2.04 0.32
2.04 0.32
1.68 0.34
1.10 0.08
1.10 0.12
1.32 0.18
1.04 0.09
1.23 0.18
2.20 0.29
2.05 0.18
1.34 0.24
1.50 0.23
2.14 0.17
2.32 0.16
1.88 0.18
1.08 0.22
1.14 0.22
0.86 0.27
0.44 0.13
1.20 0.16
1.84 0.18
1.74 0.18
1.34 0.18
48.5*
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
2.10 0.28
2.46 0.13
2.70 0.2
2.62 0.24
0.38 0.14
0.76 0.19
0.68 0.26
0.36 0.15
0.66 0.27
1.24 0.27
1.10 0.25
1.08 0.18
1.74 0.16
2.62 0.25
1.82 0.32
1.72 0.2
1.62 0.10
2.34 0.1
1.92 0.14
1.22 0.15
1.80 0.11
2.26 0.15
1.92 0.3
1.18 0.16
1.46 0.16
2.08 0.21
2.04 0.05
1.36 0.14
0.52 0.2
0.64 0.33
0.54 0.31
0.38 0.21
1.66 0.25
1.76 0.13
2.40 0.14
2.00 0.17
0.32 0.23
1.37 0.34
0.77 0.31
0.47 0.22
1.20 0.11
1.40 0.14
1.14 0.11
0.88 0.17
–
51.2*
–
50.37
–
66.41***
26.66
–
9j
9k
9l
Indomethacin
81.9***
69.1***
74.8***
86.25***
68.5***
49.59*
59.25***
58.77***
17.14
17.07
24.44
35.87
47.6*
Mefenamic acid
55.28**
51.11
60.30***
41.4
9a
9b
9c
9d
9e
9f
10.56
6.5
24.07
32.6
48.85***
28.57
34.35
9m
9n
9o
a
22.8
13
4.87
14.07
28.88
28.24
53.43***
14.28
48.5 *
53.6**
68.14***
83.2***
42.8
8.1
28.88
54.96***
30.4
25.2
15.44
35.55
24.44
48.85***
48.09**
75.23***
73.9***
80***
85.49***
20.9
Time after carrageenan injection (0.1 mg/paw)
b
Number of animals in each group n = 6; compounds were
administered at the dose of 30 mg/kg
c
Percentage of inhibition obtained by comparison with vehicle;
results are expressed as mean SEM, *p \ 0.05; **p \ 0.01;
***p \ 0.001 significant from control
28.45
11.11
were evaluated for their acute ulcerogenic activity. A sig-
nificant reduction in ulcerogenic activity with the stomach
ulceration score between 0.00 0.00 and 0.33 0.21 was
observed in the tested compounds. However, the standard
drug indomethacin showed a high score of 1.60 0.33 as
shown in Table 4. In contrast, none of the synthesized
derivatives induced significant ulceration in comparison to
control. According to some reports their low ulcerogenic
properties may be as a result of anti-oxidative activity in
thiazolo-triazole-5-ones (Aktay et al., 2005).
23.66
9g
9h
84.7***
44.3
71.48***
82.06***
42.8
43.08
57.7***
66.4***
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Med Chem Res (2014) 23:948–957
953
(KBr disks). Elemental analyses were carried out with a
Perkin-Elmer Model 240-c apparatus (Perkin Elmer, Nor-
walk, CT, USA). The results of the elemental analyses were
within 0.4 % of theoretical values for C, H, and N.
Table 4 Ulcerogenic activity screening of the selected compounds in
rat
Compound
Dose (mg/kg) p.o
Stomach ulceration score
(mean SEM)
Control
0.00 0.00
1.60 0.33*
0.00 0.00
0.00 0.00
0.00 0.00
0.16 0.10
0.16 0.10
0.00 0.00
0.33 0.21
0.25 0.11
Synthesis of 5-(2-phenoxyphenyl)-2H-1,2,4-triazole-
3(4H)-thione (7)
Indomethacin
90
90
90
90
90
90
90
90
90
9d
9e
9g
9h
9i
A suspension of compound 5 (5 g, 22 mmol), potassium
thiocyanate (9.9 g, 110 mmol), and hydrochloric acid
(21 ml) in water (450 ml) was refluxed for 19 h. After
cooling, the resulting thiosemicarbazide 6 was removed by
filtration and washed with water. It was dissolved in 4 %
sodium hydroxide solution (15 ml) and refluxed for 5 h. The
mixture was cooled and acidified by hydrochloric acid to pH
5–6 and the resulting precipitate was filtered and crystallized
from ethanol to give 3.6 g (77 %) of 7 as a white solid. IR
(KBr): t cm-1 3095(NH), 3059(CH, aromatic), 2575(weak,
9k
9n
9o
*p \ 0.001 significant from control
Conclusions
1
SH), 1224(C=S); H-NMR (400 MHz, DMSO-d6): d ppm
New thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones with 2-phen-
oxyphenyl and different aryliden and heteroaryliden moie-
ties were synthesized and their analgesic and anti-inflam-
matory activities were screened in vivo by writhing and
carrageenan-induced rat paw edema tests. Results revealed
that most of them were more potent analgesic agents than
mefenamic acid and most of the final products showed
significant anti-inflammatory activity in comparison to
control and in some cases, pharmacological properties of
compounds 9g–9i, 9k, and 9n were comparable or better
than indomethacin and mefenamic acid as the reference
drugs. The synthesized compounds showed better profile of
activities in comparison to the previously described thiazolo-
triazoles (Tozkoparan et al., 2000; 1999). Acute ulcerogenic
activity of the selected derivatives was evaluated and it can
be concluded from the results that the gastrointestinal safety
profile of the designed compounds was better than indo-
methacin and comparable to control.
13.60(s, 1H, NH), 13.40(s, 1H, NH), 7.75(d, J = 8.0 Hz, 1H,
H-6), 7.40–7.16(m, 4H, H-4, H-5, H-30 and H-50),
7.01–6.93(m, 2H, H-3 and H-40), 6.82(d, J = 8.2 Hz, 2H,
H-20 and H-60); 13CNMR(400 MHz, CDCl3): d ppm 167.21
(C-3), 150.19(C-5), 151.41(C-100), 150.48(C-20), 129.99
(C-40), 129.33(C-300and C-500), 126.40(C-60), 123.03(C-50),
122.05(C-400), 117.79(C-30),117.42(C-200 and C-600), 110.43
(C-10); MS: m/z (%) 269 (M?, 100),196 (13), 181 (9), 77(27),
51(18); Anal. Calcd. for C14H11N3OS: C, 62.43; H, 4.12; N,
15.60. Found: C, 62.18; H, 4.14; N, 15.65.
General procedure for the preparation of 5-benzylidene-
2-(2-phenoxyphenyl) thiazolo[3,2-b][1,2,4]triazol-
6(5H)-one derivatives (9a–9o)
A mixture of 0.5 g (1.86 mmol) of 7, 0.26 g (2.74 mmol)
of chloroacetic acid, 1.86 mmol of various aromatic alde-
hydes, and 0.26 g (3.17 mol) of anhydrous sodium acetate
was refluxed in 3.72 ml of acetic anhydride and 5 ml of
acetic acid for 18 h. The precipitate was filtered and
washed with diethyl ether and then crystallized from a
suitable solvent. In some cases, several recrystallizations
were required to remove unwanted materials. Melting
points, crystallization solvents, and yields for (9a–9o) are
reported in Table 1.
Experimental
Chemicals were purchased from Merck Chemical Company
(Tehran, Iran). 2-Phenoxybenzoic acid was purchased from
Sigma-aldrich chemical Co. Melting points were taken on a
Kofler hot-stage apparatus (Reichert, Vienna, Austria) and
1
are uncorrected. H-NMR spectra were obtained using a
(5Z)-5-Benzylidene-2-(2-phenoxyphenyl)[1,3]thiazolo[3,2-
Bruker FT-400 spectrometer (Bruker, Rheinstetten, Ger-
many) and 13C-NMR were obtained using a Bruker FT-500
spectrometer (Bruker, Rheinstetten, Germany). Tetramethyl
silane was used as an internal standard. Mass spectra were
obtained using a 5973 Network Mass Selective Detector at
70 eV (Agilent Technology).The FT-IR spectra were
obtained using a Shimadzu FT-IR 8400S spectrographs
b][1,2,4]triazol-6(5H)-one (9a)
Yellow crystals, IR (KBr): t cm-1 3050(C–H, aromatic),
1
1740(C=O); H-NMR (400 MHz, CDCl3): d ppm 8.21(s,
1H, CH=), 8.13(dd, J = 8.0,1.6 Hz, 1H, H-60), 7.63–7.03
(m, 13H, aromatic); 13CNMR(400 MHz, CDCl3): d ppm
176.81(C-6), 162.30(C-8), 155.71(C-2), 151.70(C-100),
123

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Med Chem Res (2014) 23:948–957
150.93(C-20), 140.63(C-5), 134.20(C-1000), 134.02(C-alken),
130.50(C-40), 129.11(C-300 and C-500), 128.07(C-3000 and
C-50000), 127.90(C-4000), 127.08(C-60), 126.91(C-2000 and C-6000),
124.41(C-50), 121.10(C-10), 120.33(C-400), 119.25(C-30),
118.67(C-200 and C-600); MS: m/z (%) 397(M?, 100), 267(14),
195(12), 77(41), 51(18); Anal. Calcd. for C23H15N3O2S: C,
69.50; H, 3.80; N, 10.57. Found: C, 69.22; H, 3.49; N, 10.75.
and C-5000), 131.74(C-2000 and C-6000), 130.60(C-40), 130.44(C-
4000), 128.91(C-300 and C-500), 127.88(C-60), 124.36(C-50),
121.14(C-400), 120.33(C-10), 119.22(C-30), 118.68(C-200 and
C-600); MS: m/z (%) 477(M??2, 8),475(M?, 8), 273(38),
71(50), 57(66), 43(100); Anal. Calcd. for C23H14BrN3O2S: C,
57.99; H, 2.96; N, 8.82. Found: C, 58.22; H, 2.81; N, 8.48.
(5Z)-5-(4-Nitrobenzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9e)
(5Z)-5-(4-Fluorobenzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9b)
Yellow crystals, IR (KBr): t cm-1 3054(CH, aromatic),
1739(C=O), 1518, 1346(NO2); 1H-NMR (400 MHz, CDCl3):
d ppm 8.39(d, J = 8.8 Hz, 2H, H-3000 and H-5000), 8.22(s, 1H,
CH=), 8.14(d, J = 6.8 Hz, 1H, H-60), 7.78(d, J = 8.8 Hz,
2H, H-2000 and H-6000), 7.46–7.04(m, 8H, aromatic);
13CNMR(400 MHz, CDCl3): d ppm 176.81(C-6), 160.93(C-
8), 154.44(C-2), 151.62(C-100), 151.00(C-20), 142.63(C-4000),
140.50(C-5), 139.70(C-1000), 134.14(C-alken), 130.49(C-40),
128.83(C-300 and C-500), 128.22(C-2000 and C-6000), 127.90(C-
60), 124.38(C-50), 121.29(C-10), 120.39(C-400), 119.98(C-3000
and C-5000), 119.22(C-30), 118.65(C-200 and C-600); MS: m/z
(%) 442(M?, 100), 269(47), 195 (16), 77 (46), 51 (29); Anal.
Calcd. for C23H14N4O4S: C, 62.44; H, 3.19; N, 12.66.Found:
C, 62.21; H, 3.49; N, 12.88.
Creamy crystals, IR(KBr): t cm-1 3071(CH, aromatic),
1740(C=O); 1H-NMR (400 MHz, CDCl3): d ppm 8.17(s, 1H,
CH=), 8.13(dd, J = 8.0, 2.0 Hz, 1H, H-60), 7.64–7.03(m, 13H,
aromatic); 13CNMR(400 MHz, CDCl3): d ppm 176.39(C-6),
160.68(C-8), 159.70(C-4000), 156.40(C-2), 151.41(C-100),
150.52(C-20), 140.52(C-5), 133.50(C-alken), 131.08(C-40),
129.98 (C-1000), 129.21(C-300 and C-500), 129.15(C-2000 and
C-6000), 128.18 (C-60), 124.33(C-50), 120.98(C-400), 120.31(C-
10), 119.09(C-30), 118.29(C-200 and C-600), 115.37(C-3000 and
C-5000); MS: m/z (%) 415(M?, 7), 277(28), 250(69), 148(97),
69(91), 57(84), 43(100); Anal. Calcd. for C23H14FN3C2S: C,
66.49; H, 3.40; N, 10.11. Found: C, 66.69; H, 3.59; N, 10.44.
(5Z)-5-(4-Chlorobenzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9c)
(5Z)-5-(4-Methylbenzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9f)
White crystals, IR (KBr): t cm-1 3055 (CH, aromatic),
1739(C=O); 1H-NMR (400 MHz, CDCl3): d ppm 8.15(s, 1H,
CH=), 8.13(dd,J = 7.6,1.6 Hz, 1H, H-60),7.56–7.03(m,12H,
aromatic); 13CNMR(400 MHz, CDCl3): d ppm 176.91(C-6),
160.90(C-8), 155.89(C-2), 151.62(C-100), 150.08(C-20),
140.55(C-5), 136.52(C-4000), 136.40(C-1000), 134.10(alken),
131.2(C-3000 and C-5000), 131.05(C-2000 and C-6000), 130.51(C-
40), 128.90(C-300 and C-500), 127.78(C-60), 124.30(C-50),
121.23(C-400), 120.36(C-10), 119.20(C-30), 118.64(C-200 and
C-600); MS: m/z (%) 433(M??2, 33), 431(100), 267(38),
195(30), 77(38), 51(22); Anal. Calcd. for C23H14ClN3O2S: C,
63.96; H, 3.27; N, 9.73. Found: C, 63.77; H, 2.99; N, 9.45.
Creamy crystals, IR(KBr): t cm-1 3083(CH, aromatic),
1733(C=O); H-NMR (400 MHz, CDCl3): d ppm 8.19 (s,
1
1H, CH=), 8.13(dd, J = 8.0,2.4 Hz, 1H, H-60), 7.51(d,
J = 8.4 Hz, 2H, H-2000 and H-6000), 7.46–7.03(m, 10H,
aromatic), 2.44(s, 3H, CH3); 13CNMR(400 MHz, CDCl3):
d ppm 176.39(C-6), 160.61(C-8), 156.44(C-2), 151.30(C-
100), 150.54(C-20), 140.59(C-5), 137.50(C-4000), 133.72(C-
alken), 132.09(C-1000), 131.09(C-40), 129.03(C-3000 and
C-5000), 128.72 (C-300 and C-500), 128.19(C-60), 126.32(C-
2000 and C-6000), 124.29(C-50), 121.00(C-400), 120.28(C-10),
119.10(C-30), 118.44(C-200 and C-600), 24.21(CH3); MS: m/
z (%)411(M?, 100), 395(10), 267(20), 195(21), 77(27),
51(12); Anal. Calcd. for C24H17N3O2S: C,70.05; H,4.16;
N, 10.21. Found: C, 70.29; H, 3.96; N, 9.98.
(5Z)-5-(4-Bromobenzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9d)
(5Z)-5-(4-Methoxybenzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9g)
Creamy crystals, IR (KBr): t cm-1 3053 (CH, aromatic),
1733(C=O); 1H-NMR (400 MHz, CDCl3): d ppm 8.12 (dd,
J = 8.0, 2.0 Hz, 1H, H-60), 8.11(s, 1H, CH=), 7.66(d,
J = 6.8 Hz, 2H, H-3000 and H-5000), 7.47–7.01(m, 10H,
aromatic); 13CNMR(400 MHz, CDCl3): d ppm 176.83(C-6),
160.90(C-8), 156.44(C-2), 151.63(C-100), 150.94(C-20),
140.54(C-5), 134.17(C-1000), 134.09(C-alken), 131.79(C-3000
Brown crystals, IR (KBr): t cm-1 3052 (CH, aromatic),
1
1733(C=O); H-NMR (400 MHz, CDCl3): d ppm 8.16(s,
1H, CH=), 8.13(dd, J = 8.0, 2.0 Hz, 1H, H-60), 7.58(d,
J = 8.8 Hz, 2H, H-2000 and H-6000), 7.46–7.03(m, 10H,
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Med Chem Res (2014) 23:948–957
955
aromatic), 3.89(s, 3H, CH3); 13CNMR(400 MHz, CDCl3):
d ppm 176.28(C-6), 160.59(C-8), 159.91(C-5000), 156.31(C-
2), 151.69(C-100), 150.46(C-20), 140.49(C-5), 133.75(C-al-
ken), 131.07(C-40), 129.21(C-300 and C-500), 127.44(C-1000
and C-6000), 127.29(C-1000), 127.08(C-60), 124.35(C-50),
121.00(C-400), 120.39(C-10), 118.99(C-30), 118.17(C-200
and C-600), 114.31(C-3000 and C-5000), 55.98(CH3); MS: m/z
(%) 427(M?, 100), 267(18), 195(25), 77(22), 51(13); Anal.
Calcd. for C24H17N3O3S: C, 67.43; H, 4.01; N, 9.83.
Found: C, 67.56; H, 4.33; N, 9.52.
J = 7.6,1.6 Hz, 1H, H-60), 8.11(s, 1H, CH=), 7.51(d,
J = 9.2 Hz, 2H, H-2000 and H-6000), 7.40–7.02(m, 8H, aro-
matic), 6.75(d, J = 8.8 Hz, 2H, H-3000 and H-5000), 3.11(s,
6H, CH3); 13CNMR(400 MHz, CDCl3): d ppm 176.49(C-
6), 159.8(C-8), 155.61(C-2), 151.40(C-100), 150.79(C-20),
145.81(C-4000), 140.22(C-5), 133.91(C-alken), 130.01(C-
40), 129.04(C-300 and C-500), 128.04(C-60), 127.91(C-2000
and C-6000), 126.44(C-1000), 124.26(C-50), 121.01(C-400),
120.69(C-10), 119.21(C-30), 118.43(C-200 and C-600),
118.06(C-3000 and C-5000), 39.31(CH3); MS: m/z (%) 440
(M?, 9), 69(94), 56(62), 43(100); Anal. Calcd. for
C25H20N4O2S: C, 68.16; H, 4.58; N, 12.72. Found: C,
68.36; H, 4.38; N, 12.49.
(5Z)-5-[4-(Methylsulfanyl)benzylidene]-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9h)
(5Z)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9k)
Yellow crystals, IR (KBr): t cm-1 3048(CH, aromatic),
1730(C=O); H-NMR (400 MHz, CDCl3): d ppm 8.14(m,
1
2H, H-60 and CH=), 7.53–7.03(m, 12H, aromatic), 2.54(s,
3H, CH3); 13CNMR(400 MHz, CDCl3): d ppm 176.20(C-
6), 160.52(C-8), 156.49(C-2), 151.30(C-100), 150.54(C-20),
140.68(C-5), 136.40(C-4000), 132.98(C-alken), 132.39(C-
1000), 131.42(C-40), 129.42(C-300 and C-500), 127.64(C-60),
126.93(C-3000 and C-5000), 126.32 (C-2000 and C-6000),
124.21(C-50), 121.98(C-400), 121.01(C-10), 118.22(C-30),
117.93(C-200 and C-600), 14.03(CH3); MS: m/z (%) 443(M?,
7), 411(9), 271(20), 151(23), 138(33), 69(100), 57(91);
Anal. Calcd. for C24H17N3O2S2: C, 64.99; H, 3.86; N, 9.47.
Found: C, 65.23; H, 4.07; N, 9.22.
White crystals, IR (KBr): t cm-1 3595(OH non-bonded),
3400(OH bonded), 3061(CH, aromatic), 1735(C=O); H-
1
NMR (400 MHz, CDCl3): d ppm 8.17(s, 1H, CH=),
8.14(dd, J = 7.6, 1.6 Hz, 1H, H-60), 7.48(s, 2H, H-2000 and
H-600),7.43–7.02(m, 8H, aromatic), 5.83(bs, 1H, OH),
1.49(s, 18H, CH3); 13CNMR(400 MHz, CDCl3): d ppm
176.87(C-6), 160.73(C-8), 155.84(C-2), 151.60(C-100),
150.03(C-20), 140.70(C-4000), 140.62(C-5), 139.50(C-3000
and C-5000), 134.08(C-alken), 130.52(C-40), 128.91(C-300
and C-500), 127.80 (C-60)0,00 126.33(C-1000), 124.32(C-50),
121.14(C-400), 121.03(C-2
and C-6000), 120.30(C-10),
4-{(Z)-[6-Oxo-2-(2-phenoxyphenyl)[1,3]thiazolo[3,2-
119.25(C-30), 118.71(C-200 and C-600), 32.49(CH3),
31.91(C–CH3); MS: m/z (%), 525(M?, 100), 269(9),
196(19), 77(22); Anal. Calcd. for C31H31N3O3S: C, 70.83;
H, 5.94; N, 7.99. Found: C, 71.18; H, 5.66; N, 8.15.
b][1,2,4]triazol-5(6H)-ylidene]methyl}phenyl acetate (9i)
Creamy crystals, IR (KBr): t cm-1 3062(CH, aromatic),
1760,1750, (C=O); 1H-NMR (400 MHz, CDCl3): d ppm
8.18(s, 1H, CH=), 8.13(dd, J = 7.6,1.6 Hz, 1H, H-60), 7.64(d,
J = 8.4 Hz, 2H, H-2000 and H-6000), 7.45–7.03(m, 10H, aro-
matic), 2.35(s, 3H, CH3); 13CNMR(400 MHz, CDCl3):
d ppm 176.89(C-6), 169.00(C=O), 159.52(C-8), 156.01(C-2),
151.39(C-100), 150.63(C-20), 150.39(C-4000), 140.21(C-5),
133.80(C-alken), 133.11(C-1000), 131.03(C-40), 129.01(C-300
and C-500), 128.00(C-60), 126.72(C-2000, C-6000), 124.31(C-50),
121.02(C-400), 120.69(C-3000 and C-5000), 120.03(C-10),
119.18(C-30), 118.49(C-200 and C-600), 20.24(CH3); MS: m/z
(%) 455(M?, 100), 412(27), 384(25), 195(26), 150(20),
77(29), 43(70); Anal. Calcd. for C25H17N3O4S: C, 65.92; H,
3.76; N, 9.23. Found: C, 66.24; H, 3.50; N, 9.55.
(5Z)-2-(2-Phenoxyphenyl)-5-[(2E)-3-phenylprop-2-en-1-
ylidene][1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-one (9l)
Yellow crystals, IR (KBr): t cm-1 3050(CH, aromatic),
1
1737(C=O); H-NMR(400 MHz, CDCl3): d ppm 8.12(dd,
J = 7.60, 2.0 Hz, 1H, H-60), 7.91(d, J = 10.08 Hz, 1H,
CH=), 7.58–6.85(m, 12H, aromatic, 2H, CH=); 13CNMR
(400 MHz, CDCl3): d ppm 176.94(C-6), 160.42(C-8),
156.49(C-2), 151.54(C-100), 150.39(C-20), 140.23(C-5),
136.40(C-1000), 132.19(C-alken), 130.91(C-40), 129.05(C-
300 and C-500), 128.77(C-3000 and C-5000), 128.31(C-4000),
127.40(C-60), 126.91(C-alken), 126.48(C-2000 and C-6000),
126.16(C-alken), 124.39(C-50), 121.39(C-400), 120.23(C-
10), 118.94(C-30), 117.98(C-200 and C-600); MS: m/z (%)
423(M?, 100), 394(23), 267(17), 238(17), 196(23),
128(38), 77(46), 55(23) Anal. Calcd. for C25H17N3O2S:
C, 70.90; H, 4.05; N, 9.92. Found: C, 71.11; H, 4.36; N,
9.48.
(5Z)-5-(4-(Dimethylamino)benzylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9j)
Red crystals, IR (KBr): t cm-1 3064(CH, aromatic),
1
1725(C=O); H-NMR (400 MHz, CDCl3): d ppm 8.13(dd,
123

956
Med Chem Res (2014) 23:948–957
118.41(C-200 and C-600), 112.24(C-7000),111.54(C-3000),
23.9(CH3); MS: m/z (%) 478 (M?, 100), 436(38), 269(24),
195(21), 77(23); Anal. Calcd. for C27H18N4O3S: C, 67.77;
H, 3.79; N, 11.71. Found: C, 67.97; H, 3.69; N, 11.50.
(5Z)-5-(Furan-2-ylmethylidene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9m)
Black–Gray crystals, IR (KBr): t cm-1 3050(CH, aro-
matic), 1741(C=O); 1H-NMR (400 MHz, CDCl3): 8.13(dd,
J = 8.0, 2.0 Hz, 1H, H-60),7.93(s, 1H, CH=), 7.77(dd,
J = 1.6 Hz, 1H, H-5000), 7.72–7.02(m, 8H, aromatic),
6.96(d, J = 3.6 Hz, 1H, H-3000), 6.65(q, 1H, H-4000);
13CNMR(400 MHz, CDCl3): d ppm 176.44(C-6), 160.79
(C-8), 156.44(C-2), 151.54(C-100), 150.49(C-20), 150.12(C-
2000), 140.59(C-5), 140.19(C-5000), 133.74(C-alken), 131.30
(C-40), 129.24(C-300 and C-500), 127.19(C-60), 124.21(C-50),
121.22(C-400), 120.19(C-10), 118.99(C-30), 118.15(C-200
and C-600), 114.70(C-4000), 111.4(C-3000); MS: m/z (%)
387(M?, 100), 267(17), 195(11), 124(17), 77(11), 51(10);
Anal. Calcd. for C21H13N3O3S: C, 68.11; H, 3.38; N,
10.58. Found: C, 67.97; H, 3.74; N, 10.74.
Pharmacology
Male NMRI mice (20–25 g) and male Wistar rats
(100–150 g) were purchased from the animal breeding
laboratories of Pasteur Institute (Karaj, Iran), the animals
were left 3 days for acclimatization to animal room con-
ditions and were maintained on the standard pellet diet and
water. A minimum of six animals was used in each group
and all ethical manners for use of laboratory animals were
considered carefully and the protocol of study was
approved by TUMS ethical committee.
Analgesic activity
(5Z)-2-(2-Phenoxyphenyl)-5-(thiophen-2-
ylmethylidene)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9n)
Acetic acid writhing test was performed on mice and me-
fenamic acid was used as the standard drug (Moradi et al.,
2010). Test compounds were injected ip to the animals at
the dose of 30 mg/kg as suspension in saline and Tween 80
(4 % w/v) 30 min after the animals were injected ip with
acetic acid (0.6 %, 0.1 ml/10 g). The mean number of
Writhes for each experimental group and percentage
decrease compared with that of the control group were
calculated during 30 min.
Yellowish green crystals, IR (KBr): t cm-1 3050(CH,
aromatic), 1737(C=O); 1H-NMR (400 MHz, CDCl3):
d ppm 8.36(s, 1H, CH=), 8.13(dd, J = 7.6, 1.6 Hz, 1H,
H-60), 7.77(d, J = 5.2 Hz, 1H, H-3000), 7.54(d, J = 3.6 Hz,
1H, H-5000), 7.55–7.03(m, 8H, aromatic, 1H, thiophen);
13CNMR(400 MHz, CDCl3): d ppm 176.31(C-6), 160.53
(C-8), 156.30(C-2), 151.77(C-100), 150.39(C-20), 140.81(C-
5), 138.50(C-2000), 133.68(C-alken), 131.24(C-40), 131.08
(C-5000), 129.28(C-300 and C-500), 127.99(C-4000), 127.32(C-
3000), 127.10(C-60), 124.30(C-50), 121.08(C-400), 120.22(C-
10), 118.91(C-30), 118.15(C-200 and C-600); MS: m/z (%)
403(M?, 100), 267(24), 195(20), 140(26), 77(20), 51(13);
Anal. Calcd. for C21H13N3O2S2: C, 62.57; H, 3.25; N,
10.41. Found: C, 62.76; H, 3.04; N, 10.76.
Anti-inflammatory activity in carrageenan-induced rat
paw edema
Anti-inflammatory activity was determined by carra-
geenan-induced rat paw edema test (Rineh et al., 2007).
Wistar male rats were used. The standard groups received
ip Indomethacin or mefenamic acid 30 mg/kg body weight
suspended in 4 % Tween in saline and the control animals
received 4 % Tween in saline. Acute inflammation was
induced by injecting freshly prepared 0.1 % w/v aqueous
solution of carrageenan (Sigma-Aldrich, Dorset, UK) in the
sub-plantar region of right hind paw. The difference in
footpad thickness between the right and left foot was
measured with a pair of dial thickness gauge calipers.
Mean values of treated groups were compared with mean
values of the control group and analyzed using statistical
methods.
(5Z)((1-acetyl-1H-indole-2-yl)methylene)-2-(2-
phenoxyphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (9o)
Brown crystals, IR (KBr): t cm-1 3050(CH, aromatic),
1739, 1714(C=O); 1H-NMR (400 MHz, CDCl3): d ppm
8.45(d, J = 8.0 Hz, 1H, H-4000), 8.41(s, 1H, CH=), 8.13(d,
J = 7.2 Hz, 1H, H-60), 7.84–7.80(m, 2H, H-40 and H-7000),
7.49–7.03(m, 10H, aromatic), 2.78 (s, 3H, CH3); 13CNMR
(400 MHz, CDCl3): d ppm 176.27(C-6), 169.80(C=O),
160.54(C-8), 156.30(C-2), 152.01(C-100), 150.44(C-20),
140.81(C-5), 137.91(C-9000), 133.70(C-alken), 131.36(C-
40), 129.33(C-300 and C-500), 127.11(C-60), 126.19(C-8000),
124.44(C-50), 123.41(C-2000), 123.03(C-5000), 121.49(C-6000),
121.11(C-400), 120.91(C-10), 120.74(C-4000), 118.84(C-30),
Ulcerogenic activity
Ulcerogenic activity of the newly synthesized compounds
were checked and scored by method of Cioli (Cioli et al.,
1967). Wistar rats were fasted for 24 h prior to drug
administration. All animals were sacrificed under deep
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957
and anticancer activities of new pyrazole-3(5)-carboxylic acid
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spot ulcers.
˘
Dogdas¸ E, Tozkoparan B, Kaynak FB, Eriksson L, Ku¨peli E,
Compounds and Indomethacin as the reference drug
were given orally to test animals at the dose of 90 mg/kg
after suspending in 0.5 % aqueous sodium carboxymethyl
cellulose (CMC) and distilled water. The control group
animals received the same experimental handling as for
those of test groups and the drug treatment was replaced
with appropriate volumes of dosing vehicle. For each
stomach, the mucosal damage was evaluated according to
the following scoring system: 0.5:redness; 1.0:spot ulcers;
1.5:hemorrhagic streaks; 2.0:ulcers [3 but B5; and
3.0:ulcers[5. The mean score of each treated group minus
the mean score of control group was regarded as gastric
mucosal ulceration score.
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Statistics
Statistics were performed with one-way analysis of vari-
ance (ANOVA), which was followed by Tukey multi-
comparison test. All data are presented as mean SEM,
p \ 0.05 was considered to be significant.
Acknowledgments This work was supported by a Grant from Iran
National Science Foundation (INSF).
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