Studies on 1,2,4-triazole derivatives as potential anti-inflammatory agents

Article abstract of DOI:10.1002/ardp.200700134

The reaction of acetic or propionic acid hydrazides with various aryl/alkyl isothiocyanates gave thiosemicarbazides which furnished the 1,2,4-triazoles by alkali cyclization. The 4-aryl/alkyl-5-(1-phenoxyethyl)-3-[N-(substituted) acetamido]thio-4H-1,2,4-t

Full text of DOI:10.1002/ardp.200700134

586
Arch. Pharm. Chem. Life Sci. 2007, 340, 586–590
Full Paper
Studies on 1,2,4-Triazole Derivatives as Potential
Anti-Inflammatory Agents
Gꢀlhan Turan-Zitouni1, Zafer Asim Kaplancikli1, Ahmet ꢁzdemir1, Pierre Chevallet2,
Hilmi Burak Kandilci3, and Bꢀlent Gꢀmꢀsel3
1 Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Eskisehir, Turkey
2 Institut des Biomolꢀcules Max Mousseron UMR 5247, CNRS-Universitꢀ Montpellier 1 et 2, Facultꢀ de
Pharmacie, Montpellier, France
3 Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey
The reaction of acetic or propionic acid hydrazides with various aryl/alkyl isothiocyanates gave
thiosemicarbazides which furnished the 1,2,4-triazoles by alkali cyclization. The 4-aryl/alkyl-5-(1-
phenoxyethyl)-3-[N-(substituted)acetamido]thio-4H-1,2,4-triazole derivatives were synthesized by
reacting the triazoles with 2-chloro-N-(substituted)acetamide. The chemical structures of the
compounds were elucidated by IR, 1H-NMR, FAB+-MS spectral data and elemental analysis. In the
pharmacological studies, anti-inflammatory activities of these compounds have been screened
and significant activities were observed.
Keywords: Anti-inflammatory activity / Carrageenan induced oedema / Triazole /
Received: June 28, 2007; accepted: August 21, 2007
DOI 10.1002/ardp.200700134
show greater selectivity for COX-1 than COX-2 [9]. Conse-
Introduction
quently, long-term therapy with non-selective NSAIDs
may cause appreciable GI irritation, bleeding, and ulcer-
ation. These clinical shortcomings comprise a major
challenge confronting medicinal chemists to develop
safer agents that spare COX-1 and subsequently its gastric
cytoprotective role [10]. For the last many years, there has
been a great interest to develop new NSAIDs which could
specifically inhibit COX-2, the enzyme responsible for
the production of prostaglandins and other mediators
which are directly associated with inflammation proc-
esses. Some selective inhibitors for COX-2 have already
been found and the research in this direction continues
with a view to discover new drugs for inhibiting this
enzyme [11–13].
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
among the most widely used agents in the treatment of
pain, fever, and inflammation, particularly arthritis [1].
The pharmacological activity of NSAIDs arises from their
inhibition of the prostaglandin biosynthesis from arachi-
donic acid by inhibiting the cyclooxygenase enzymes
(COXs) [2]. It was discovered that COX exists in two iso-
forms, COX-1 and COX-2, which are regulated differently
[3–6]. COX-1 is constitutively expressed and provides
cytoprotection in the gastrointestinal tract (GIT) while
COX-2 is inducible and mediates inflammation [7–8]. The
traditional NSAIDs currently in use facilitate non-selec-
tive inhibition of COX-1 and COX-2. In fact, most NSAIDs
Understanding the relationship between chemical
structure and enzyme activity is crucial for the design of
new COX-2-selective inhibitors. Although the active sites
of COX-1 and COX-2 are similar, there are differences
which have been utilized by medicinal chemists to syn-
thesize molecules which have a selective action on COX-
2. Of crucial significance is position 523, which in COX-2
is valine and in COX-1 isoleucine. This difference of a sin-
gle methyl group is sufficient to allow access of a poten-
Correspondence: Gꢁlhan Turan-Zitouni, Anadolu University, Faculty of
Pharmacy, 26470 Eskisehir, Turkey.
E-mail: gturan@anadolu.edu.tr
Fax: +90 222 335-0750
Abbreviations: Nonsteroidal anti-inflammatory drugs (NSAIDs); cyclo-
oxygenase enzymes (COXs); gastrointestinal tract (GIT); structure-activ-
ity-relationship (SAR)
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2007, 340, 586–590
,2,4-Triazole Derivatives as Anti-Inflammatory Agents
587
tial inhibitor to a side pocket in COX-2. In addition, prox-
imity to an arginine residue at position 513 (histidine in
COX-1) is important, which provides hydrogen bonding
for an inhibitor of a structure that enables it to extend
into the side pocket. Another significant difference
between COX-2 and COX-1 is at position 503, which is the
aromatic amino acid phenylalanine in COX-1 but the rel-
atively small, non-aromatic leucine in COX-2; this allows
leucine at position 384 to re-orient its methyl side chain
away from the enzymatic site of the COX-2 enzyme
[14, 15]. The final result of these differences is an approx-
imate 20% increase in the active site of COX-2 compared
to COX-1. In the light of these findings, it could be specu-
lated that acetic or propionic acids act non-selectively,
probably because of their relatively small size tolerated
by both COX-1 and COX-2. It appears that bulkier struc-
tures are more likely to confer selectivity to COX-2 due to
its wider active site [16, 17].
It has been reported that modification of the carboxyl
function of representative NSAIDs results in retained
anti-inflammatory activity with minimized ulcerogenic
potential along with reduced lipid peroxidation [18–22].
In addition, several examples of NSAIDs having a tria-
zole structure have been noted in the medicinal chemis-
try literature. Among them, 1,2,4-triazol-3-thiol deriv-
atives are of particular interest and have been studied
and patented in recent years [23–25]. In this study, we
were interested in replacing the carboxyl function of ace-
tic and propionic acids by selected bulkier moieties with
the goal of improving the safety profile of these agents
while retaining anti-inflammatory activity.
Scheme 1. The general synthesis route of presented com-
pounds.
Table 1. Some characteristics of the compounds.
Results and discussion
Com-
pound
R1
R2
H
R3
Mp.
(8C)
Yield Mol. Formula
(%)
Chemistry
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
C6H5
C6H5 Cl
CH3
CH3
C6H5
C6H5 156–158 80
C6H5 145–147 76
C6H5
C31H28N4O2S
C31H27ClN4O2S
C26H25ClN4O2S
C27H28N4O2S
C31H34N4O2S
C32H36N4O2S
C26H32N4O2S
C26H31ClN4O2S
C27H34N4O2S
In the present work, nine new compounds (Va–i) which
are thioether derivatives of 1,2,4-triazol-3-thiol, were syn-
thesized (Table 1, Scheme 1). The structures of the
obtained compounds were elucidated by spectral analy-
ses. According to the spectroscopic data of the final com-
pounds the IR showed characteristic C=O (amide) stretch-
ing bands in the 1699–1665 cm– 1 region.
Cl
48–50 81
82–84 78
CH3 C6H5
H
C6H11 148–150 75
C6H5 CH3 C6H11 160–162 80
CH3
CH3
CH3
H
Cl
C6H11
C6H11
54–56 72
20–21 77
CH3 C6H11 110–112 81
1
In the H-NMR spectra of the compounds, the signal
due to the S-CH2 methylene protons present in all com-
pounds appeared at 3.95–4.15 ppm, as singlets. NH pro- Pharmacology
ton was observed at 8.65–9.20 ppm as a doublet band. All In the acute inflammation model, compounds Va, Vc, Vg,
the other aromatic and aliphatic protons were observed and Vh showed maximum inhibition of carrageenan-
at the expected regions. Mass spectra (MS (FAB)) of the induced rat paw oedema. Carrageenan-induced hind paw
compounds showed a [M+1] peak, in agreement with oedema is the standard experimental model of acute
their molecular formula.
inflammation. Carrageenan is the phlogistic agent of
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588
G. Turnan-Zitouni et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 586–590
choice for testing anti-inflammatory drugs as it is not 2-Phenoxypropionic acid hydrazides II
These compounds were prepared according to the reported
method, by reacting ethyl 2-phenoxypropionates with hydra-
zine hydrate [28, 29].
known to be antigenic and is devoid of apparent systemic
effects. Moreover, the experimental model exhibits a
high degree of reproducibility. Carrageenan-induced
oedema is a biphasic response. The first phase is medi-
ated through the release of histamine, serotonin, and
kinins, whereas the second phase is related to the release
of prostaglandin and other slow-reacting substances [26].
The compounds Va, Vc, Vg, and Vh exhibited maximum
inhibition values of 70.5%, 73.1%, 73.8%, 72.1%, respec-
tively, while the standard drug indomethacin showed an
inhibition of 67.3% in the carrageenan-induced rat paw
oedema (acute) model. Thus, we may conclude that the
tested compounds Va, Vc, Vg, and Vh showed higher anti-
inflammatory activity than the standard drug indome-
thacin. Compounds Vb and Vd showed notable activity
(57.2% and 57.6%, respectively) compared with the stand-
ard drug. Ve, Vf, and Vi also showed interesting activity
(43.2%, 20.2%, and 37.6%).
1-(2-Phenoxypropionyl)-4-phenyl/cyclohexyl-3-
thiosemicarbazides III
Equimolar quantities of acid hydrazide (30 mmol) and phenyl/
cyclohexyl isothiocyanate in 25 mL of absolute ethanol were
refluxed for 3–5 h. The resulting solid was filtered and recrystal-
lized from ethanol [30, 31].
4-Phenyl/cyclohexy-5-(1-phenoxyethyl)-2,4-dihydro-3H-
1,2,4-triazol-3-thione IV
Suitable substituted thiosemicarbazides III (20 mmol) were dis-
solved in 2 N sodium hydroxide and the resulting solution was
heated under reflux for 3 h. The solution was cooled and acidi-
fied to pH 2–3 with hydrochloric acid solution and recrystal-
lized from ethanol [30, 31].
4-Phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-
The SAR (structure-activity-relationship) observations
show that the substitution on the phenoxy moiety has an
interesting role on the activity. The unsubstituted phe-
noxy and p-Cl-substituted phenoxy derivatives are the
more active than the p-methyl derivatives. The modifica-
tions on R1 and R3 do not play a remarkable role on the
activity.
(substituted)acetamido]thio-4H-1,2,4-triazole Va–i
A mixture of the acetamide I (10 mmol), appropriate triazoles IV
and anhydrous potassium carbonate in acetone was mixed at
room temperature for 6 h. The mixture was filtered; the filtrate
was evaporated until dryness. The residue was washed with
water and recrystallized from ethanol.
Va: IR (KBr, cm– 1): 3115 (NH), 1675 (C=O), 1590–1415 (C=C and
1
C=N), 1265–1051 (C–O). H-NMR (250 MHz) (DMSO-d6) d (ppm):
1.60 (3H, d [J = 6.47 Hz], CH–CH3), 4.15 (2H, s, S–CH2), 5.55 (1H, q,
CH –CH3), 6.10 (1H, d [J = 8.38 Hz], N-CH), 6.75–7.55 (20H, m, aro-
matic protons), 9.20 (1H, d [J = 8.48 Hz], NH). MS (FAB) [M+1]: m/z
521, Anal. Calc. for C31H28N4O2S: C, 71.51; H, 5.42; N, 10.76.
Found: C, 71.55; H, 5.40; N, 10.77.
The authors have declared no conflict of interest.
Vb: IR (KBr, cm– 1): 3105 (NH), 1695 (C=O), 1560–1403 (C=C and
1
C=N), 1275–1025 (C–O). H-NMR (250 MHz) (DMSO-d6) d (ppm):
1.55 (3H, d, J = 6.45 Hz, CH–CH3), 4.05 (2H, s, S–CH2), 5.45 (1H, q,
CH –CH3), 6.05 (1H, d, J = 8.45 Hz, N-CH), 6.70–7.50 (19H, m, aro-
matic protons), 9.15 (1H, d, J = 8.53 Hz, NH). MS (FAB) [M+1]: m/z
555; Anal. Calc. for C31H27ClN4O2S: C, 67.08; H, 4.90; N, 10.09.
Found: C, 67.10; H, 4.94; N, 10.10.
Experimental
Chemistry
All reagents were used as purchased from commercial suppliers
without further purification. Melting points were determined
by using an Electrothermal 9100 digital melting point appara-
tus and were uncorrected (Electrothermal, Essex, UK). The com-
pounds were checked for purity by TLC on silica gel 60 F254. Spec-
troscopic data were recorded on the following instruments: IR,
Shimadzu 435 IR spectrophotometer (Shimadzu, Tokyo, Japan);
1H-NMR, Bruker 250 MHz NMR spectrometer (Bruker Bioscience,
Billerica, MA, USA) in DMSO-d6 using TMS as internal standard;
MS-FAB, VG Quattro mass spectrometer (Fisons Instruments Ver-
triebs GmbH, Mainz, Germany); Elemental analyses were per-
formed on a Perkin Elmer EAL 240 elemental analyser (Perkin-
Elmer, Norwalk, CT, USA).
Vc: IR (KBr, cm– 1): 3095 (NH), 1672 (C=O), 1520–1425 (C=C and
C=N), 1225–1015 (C–O). 1H-NMR (250 MHz) (DMSO-d6) d (ppm):
1.30 (3H, d, J = 6.99 Hz, N-CH–CH3), 1.55 (3H, d, J = 6.45 Hz, O-
CH–CH3), 3.95 (2H, s, S–CH2), 4.90 (1H, q, CH–CH3), 5.50 (1H, d,
J = 6.30 Hz, N-CH), 6.70–7.40 (14H, m, aromatic protons), 8.70
(1H, d, J = 8.13 Hz, NH). MS (FAB) [M+1]: m/z 493. Anal. Calc. for
C26H25ClN4O2S: C, 63.34; H, 5.11; N, 11.36. Found: C, 63.30; H,
5.11; N, 11.38.
Vd: IR (KBr, cm– 1): 3157 (NH), 1685 (C=O), 1505–1402 (C=C and
1
C=N), 1295–1095 (C–O). H-NMR (250 MHz) (DMSO-d6) d (ppm):
1.35 (3H, d, J = 7.00 Hz, N-CH–CH3), 1.55 (3H, d, J = 6.44 Hz, O-
CH–CH3), 2,30 (3H, s, phenyl-CH3), 4.00 (2H, s, S–CH2), 4.85 (1H, q,
CH –CH3), 5.45 (1H, d, J = 6.43 Hz, N-CH), 6.60 and 7.00 (4H, two d,
J = 8.48 and 8.41 Hz, 1,4-disubstituted phenyl protons), 7.30–
7.60 (10H, m, aromatic protons), 8.75 (1H, d, J = 8,09 Hz, NH). MS
(FAB) [M+1]: m/z 473. Anal. Calc. for C27H28N4O2S: C, 68.62; H, 5.97;
N, 11.85. Found: C, 68.60; H, 6.00; N, 11.83.
General procedure for synthesis of the compounds
2-Chloro-N-(substituted)acetamides I
Chloroacetylchloride (20 mmol) and triethylamine (20 mmol)
were added to a solution of amine (20 mmol) in anhydrous ben-
zene and the mixture was treated as described in the literature
[27].
Ve: IR (KBr, cm– 1): 3162 (NH), 1668 (C=O), 1520–1386 (C=C and
1
C=N), 1233–1042 (C–O). H-NMR (250 MHz) (DMSO-d6) d (ppm):
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Arch. Pharm. Chem. Life Sci. 2007, 340, 586–590
,2,4-Triazole Derivatives as Anti-Inflammatory Agents
589
0.90–1.60 (8H, m, cyclohexyl protons), 1.65 (3H, d, J = 6.39 Hz,
CH–CH3), 1.70–2.05 (3H, m, cyclohexyl protons), 4.10 (2H, s, S–
CH2), 5.85 (1H, q, CH –CH3), 6.05 (1H, d, J = 8.45 Hz, N-CH), 6.90–
7.40 (15H, m, aromatic protons), 9.15 (1H, d, J = 8.45 Hz, NH). MS
(FAB) [M+1]: m/z 527. Anal. Calc. for C31H34N4O2S: C, 70.69; H, 6.51;
N, 10.64. Found: C, 70.72; H, 6.54; N, 10.60.
Table 2. Anti-inflammatory activity.
Compounda)
Anti-inflammatory activity (%)
(n = 6)b)
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
70.5 l 1.1*
57.2 l 14.3
73.1 l 0.8*
57.6 l 14.4
43.2 l 17.6
20.2 l 12.9
73.8 l 1.8*
72.1 l 0.4*
37.6 l 16.2
67.3 l 4.6*
Vf: IR (KBr, cm– 1): 3141 (NH), 1699 (C=O), 1495–1346 (C=C and
1
C=N), 1243–1062 (C–O). H-NMR (250 MHz) (DMSO-d6) d (ppm):
1.00–1.60 (8H, m, cyclohexyl protons), 1.65 (3H, d, J = 6.48 Hz,
CH–CH3), 1.70–2.10 (3H, m, cyclohexyl protons), 2.20 (3H, s, phe-
nyl-CH3), 4.15 (2H, s, S–CH2), 5.80 (1H, q, CH–CH3), 6.10 (1H, d, J =
8.47 Hz, N-CH), 6.90 and 7.10 (4H, two d, J = 8.53 and 8.44 Hz, 1,4-
disubstituted phenyl protons), 7.20–7.40 (10H, m, aromatic pro-
tons), 9.20 (1H, d, J = 8.48 Hz, NH). MS (FAB) [M+1]: m/z 541. Anal.
Calc. for C32H36N4O2S: C, 71.08; H, 6.71; N, 10.36. Found: C, 71.11;
H, 6.70; N, 10.36.
Vi
Indomethacin
a)
100 mg/kg (p.o.).
Vg: IR (KBr, cm– 1): 3108 (NH), 1671 (C=O), 1471–1337 (C=C and
C=N), 1223–1101 (C–O). 1H-NMR (250 MHz) (DMSO-d6) d (ppm):
1.00–1.30 (4H, m, cyclohexyl protons), 1.35 (3H, d, J = 6.93 Hz, N-
CH–CH3), 1.50–1.70 (5H, m, cyclohexyl protons), 1.70 (3H, d, J =
6.36 Hz, O-CH–CH3), 1.80–2.05 (2H, m, cyclohexyl protons), 4.10
(2H, s, S–CH2), 4.80–5.00 (1H, q, CH –CH3), 5.85–6.05 (1H, m, N-
CH), 6.95–7.40 (10H, m, aromatic protons), 8.75 (1H, d, J =
8.07 Hz, NH). MS (FAB) [M+1]: m/z 465. Anal. Calc. for C26H32N4O2S:
C, 67.21; H, 6.94; N, 12.06. Found: C, 67.20; H, 6.98; N, 12.10.
Vh: IR (KBr, cm– 1): 3128 (NH), 1688 (C=O), 1441–1330 (C=C and
C=N), 1238–1162 (C–O). 1H-NMR (250 MHz) (DMSO-d6) d (ppm):
1.00–1.25 (4H, m, cyclohexyl protons), 1.30 (3H, d, J = 7.03 Hz, N-
CH–CH3), 1.40-1.50 (5H, m, cyclohexyl protons), 1.55 (3H, d, J =
6.76 Hz, O-CH–CH3), 1.70–2.00 (2H, m, cyclohexyl protons), 4.15
(2H, s, S–CH2), 4.75-5.00 (1H, q, CH–CH3), 5.80–6.05 (1H, m, N-
CH), 6.95-7.40 (9H, m, aromatic protons), 8.65 (1H, d J = 8.17 Hz,
NH). MS (FAB) [M+1]: m/z 499. Anal. Calc. for C26H31ClN4O2S: C,
62.57; H, 6.26; N, 11.23. Found: C, 62.60; H, 6.28; N, 11.24.
Vi: IR (KBr, cm– 1): 3138 (NH), 1679 (C=O), 1441–1317 (C=C and
b)
Results are expressed as their mean l SEM values.
* activity, n = 6, P a 0.05.
geenan solution into the subplantar tissue of the right hind
paw. With Peacock-thickness gauge, the volume of the paw was
measured immediately and 2 h after the carrageenan injection.
The control group of animals received appropriate volumes of
the dosing vehicle only. Percent inhibition of the effects of the
drugs was calculated according to the following equation:
Anti-inflammatory activity (%) = [(n – n9)/n]6100
n = difference in thickness between first and second measure of
paw in the control group; n9 = difference in thickness between
first and second measure of paw in the control group which had
been administered the test sample. Indomethacin (100 mg/kg)
was used as reference compound.
1
C=N), 1201–1098 (C–O). H-NMR (250 MHz) (DMSO-d6) d (ppm):
0.90-1.20 (4H, m, cyclohexyl protons), 1.35 (3H, d, J = 6.85 Hz, N-
CH–CH3), 1.40–1.55 (5H, m, cyclohexyl protons), 1.65 (3H, d, J =
6.31 Hz, O-CH–CH3), 1.75–2.10 (2H, m, cyclohexyl protons), 2.20
(3H, s, phenyl-CH3), 4.05 (2H, s, S–CH2), 4.85 (1H, q, CH –CH3), 5.80
(1H, m, N-CH), 6.85 and 7.05 (4H, two d, J = 8.48 and 8.20 Hz, 1,4-
disubstituted phenyl protons), 7.15–7.40 (5H, m, aromatic pro-
tons), 8.70 (1H, d, J = 8.12 Hz, NH). MS (FAB) [M+1]: m/z 479. Anal.
Calc. for C27H34N4O2S: C, 67.75; H, 7.16; N, 11.70. Found: C, 67.78;
H, 7.19; N, 11.71.
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