Synthesis and anti-inflammatory properties of novel 1,2,4-triazole derivatives

Article abstract of DOI:10.1007/s11164-012-0781-9

This research is based on the pharmacological activity of the triazole ring. In the last decade much work has been conducted on the triazole ring. Scientists have developed many new compounds based on this structure and screened them to obtain molecules with good pharmacological activity. In this research starting from 4-amino-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole- 3-thione, a series of new 1,2,4-triazole derivatives were prepared. Results revealed that two compounds had anti-inflammatory potency after 4 h greater than that of indomethacin whereas another derivative had less potency than indomethacin.

Full text of DOI:10.1007/s11164-012-0781-9

Res Chem Intermed (2013) 39:2543–2554
DOI 10.1007/s11164-012-0781-9
Synthesis and anti-inflammatory properties of novel
1,2,4-triazole derivatives
•
Walaa S. El-Serwy Neama A. Mohamed
•
•
Eman M. Abbas Rehab F. Abdel-Rahman
Received: 10 June 2012 / Accepted: 17 August 2012 / Published online: 6 September 2012
ꢀ Springer Science+Business Media B.V. 2012
Abstract This research is based on the pharmacological activity of the triazole
ring. In the last decade much work has been conducted on the triazole ring. Sci-
entists have developed many new compounds based on this structure and screened
them to obtain molecules with good pharmacological activity. In this research
starting from 4-amino-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione, a
series of new 1,2,4-triazole derivatives were prepared. Results revealed that two
compounds had anti-inflammatory potency after 4 h greater than that of indo-
methacin whereas another derivative had less potency than indomethacin.
Keywords Triazole derivatives ꢀ Anti-inflammatory agents
Introduction
Derivatives of 1,2,4-triazole have been reported to have interesting biological activity;
for example, 5-(2-, 3-, and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives
[1], 5-substituted-3-pyridine-1,2,4-triazoles [2], and others [3–22] have anti-inflam-
matory activity. Triazole, thiadiazole, and triazine derivatives of Indomethacin have
been synthesized and tested for anti-inflammatory activity. The test compounds
inhibited the induction of gastric mucosal lesions and their protective effects may be
W. S. El-Serwy (&) ꢀ N. A. Mohamed
Therapeutical Chemistry Department, National Research Center, Dokki, Cairo, Egypt
e-mail: walaasalah16@yahoo.com
E. M. Abbas
Department of Chemistry of Natural and Microbial Products, National Research Center,
Dokki, Cairo, Egypt
R. F. Abdel-Rahman
Department of Pharmacology, National Research Center, Dokki, Cairo, Egypt
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related to inhibition of lipid peroxidation in gastric mucosa [10]. Moreover, triazoles
fused with other heterocyclic rings have attracted particular attention, because of their
diverse applications, for example antibacterial, antidepressant, antiviral, antitumor,
anti-inflammatory, pesticide, herbicide, and lubricant activity, and as analytical
reagents [23, 24]. 1,2,4-Triazoles have been shown to have multifaceted pharmaco-
logical properties, including antihypertensive, cardiac stimulant, antimalarial, anti-
fungal, anti-HBV, antimicrobial, anti-cancer, and herbicidal activity [25–34].
Prompted by these findings, it seemed of interest to synthesize new derivatives of
triazole and investigate their anti-inflammatory activity to study the effect of
positional substitution on biological activity.
Experimental
Chemistry
All melting points are uncorrected and measured by use of an electrothermal
capillary melting point apparatus. Infrared spectra were acquired with a Jasco FT/
IR-6100 using KBr discs.1H NMR spectra were acquired with Jeol 270 MHz and
Jeol sx 500 MHz spectrometers, using TMS as internal standard. Mass spectra were
acquired with a Jeol JMS-AX 500. All reactions were followed and checked by TLC
(aluminium-backed plates) with chloroform–methanol 9:1 (v/v) as mobile phase.
For detection the plates were sprayed with iodine.
General procedure for preparation of compound 2
Iodomethane (0.25 g, 0.34 ml, 1.728 mmol) was added dropwise and with stirring to
a suspension of 1 [35] (1.728 mmol) in absolute ethanol (40 mL). The reaction
mixture was boiled with stirring for 3 h. The solvent was removed with a rotary
evaporator; the solid product was treated, with stirring, with 10 % KOH (15 mL). The
solid product 2 was isolated by filtration, washed with water, dried, and recrystallized.
3-(4-Chlorophenyl)-5-(methylsulfanyl)-4H-1,2,4-triazol-4-amine (2)
Crystallized from acetic acid, yellow crystals, m.p. 201 ꢁC, yield 70 %. Analysis:
for C9H9ClN4S, M.Wt. 240.71, calcd: C, 44.91; H, 3.77; N, 23.28. Found: C, 44.54;
H, 3.40; N, 23.01. IR (KBr, cm-1): 1,033–1,345 (C–N), 1,430–1,614 (C=C) and
1
3,199, 3,389 (Prim NH). H NMR (DMSO-d6, d ppm): 2.57 (3H, s, SCH3), 6.1
(2H, s, NH2, exchangeable with D2O) and 7.4–7.9 (4H, m, aromatic). MS: (m/
z) *240 (40.65 %).
General procedure for preparation of compound 3
A mixture of formaldehyde (40 %, 1.5 mL), p-chloroacetophenone (0.001 mol),
and compound 1 [35] (0.001 mol) in ethanol was stirred at room temperature for
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Synthesis and anti-inflammatory properties of novel 1,2,4-triazole derivatives
2545
6 h. The precipitated solid 3 was isolated by suction filtration, washed with ethanol,
and recrystallized.
3-[4-Amino-3-(4-chlorophenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-1-
(4-chlorophenyl)propan-1-one (3)
Crystallized from dimethylformamide, white crystals, m.p. 263 ꢁC, yield 70 %.
Analysis: for C17H14Cl2N4OS, M.Wt. 393.29, calcd: C, 51.92; H, 3.59; N, 14.25.
Found: C, 51.75; H, 3.39; N, 14.08. IR (KBr, cm-1): 1,123-1,384 (C–N),
1
1,484–1,634 (C=C), 1,670 (C=O) and 2,922, 3,409 (Prim NH). H NMR (DMSO-
d6, d ppm): 3.1 (2H, t, CH2), 3.7 (2H, t, CH2), 5.9 (2H, s, NH2, exchangeable with
D2O) and 7.2–8 (8H, m, aromatic). MS: (m/z) [M ? 1]? m/z *209 (100 %) for
(C8H5ClN3S•) and [M]? m/z *281 (1.12 %) for (C11H10ClN4OS•).
General procedure for preparation of compound 4
Absolute triethylamine (0.35 g, 0.48 mL, 3.5 mmol) was added to a suspension of
compound 1 under reflux [35] (3.5 mmol) in absolute acetonitrile (70 mL). The
clear solution obtained was treated with acetyl chloride (0.273 g, 0.25 mL,
3.5 mmol) and the mixture was heated under reflux for 2.5 h. After cooling, the
precipitated product 4 was isolated by filtration, washed with methanol and ether,
dried, and recrystallized.
1-[4-Amino-3-(4-chlorophenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-
1-yl]ethanone (4)
Crystallized from acetic acid, brown crystals, m.p. 125 ꢁC, yield 75 %. Analysis:
C10H9ClN4OS, M.Wt. 268.72, calcd: C, 44.70; H, 3.38; N, 20.85. Found: C, 44.55;
H, 3.26; N, 20.64. IR (KBr, cm-1): 1,021–1,322 (C–N), 1,445–1,609 (C=C), 1,689
(C=O), and 3,233, 3,455 (Prim NH). 1H NMR (DMSO-d6, d ppm): 2.3 (3H, s, CH3),
6.1 (2H, s, NH2, exchangeable with D2O) and 7.4–7.9 (4H, m, aromatic). MS: (m/
z) *268 (15 %).
General procedure for preparation of compounds 5a, b
To a stirred suspension of compound 1 [35] (2 mmol), and triethylamine (0.28 mL,
2 mmol) in tetrahydrofuran (20 mL), the appropriate acid chloride, i.e. acetyl chloride
or benzoyl chloride (2 mmol), was added. The reaction mixture was stirred at ambient
temperature for 12 h. The product 5a, b was isolated by filtration, washed with diethyl
ether, and dried. Crystallization was performed from an appropriate solvent.
N-[3-(4-chlorophenyl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]acetamide (5a)
Crystallized from benzene, dark white crystals, m.p. 231 ꢁC, yield 60 %. Analysis:
for C10H9ClN4OS, M.Wt. 268.72, calcd: C, 44.70; H, 3.38; N, 20.85 Found: C,
44.54; H, 3.16; N, 20.64. IR (KBr, cm-1): 1,017–1,365 (C–N), 1,447–1,601 (C=C),
123

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W. S. El-Serwy et al.
1
1,702 (C=O) and 3,300 (Sec NH). H NMR (DMSO-d6, d ppm): 2.1 (3H, s, CH3),
7.1–7.6 (4H, m, aromatic), 8.5 (1H, s, NH, exchangeable with D2O) and 9 (1H, s,
NH, exchangeable with D2O). MS: (m/z) *268 (23 %).
N-[3-(4-chlorophenyl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]benzamide (5b)
Crystallized from benzene, white crystals, m.p. 175 ꢁC, yield 65 %. Analysis: for
C15H11ClN4OS, M.Wt. 330.79, calcd: C, 54.46; H, 3.35; N, 16.94. Found: C, 54.35;
H, 3.25; N, 16.75. IR (KBr, cm-1): 1,067–1,325 (C–N), 1,455–1,601 (C=C), 1,695
(C=O) and 2,922 (Sec NH). 1H NMR (DMSO-d6, d ppm): 7–8.1 (9H, m, aromatic),
9.2 (1H, s, NH, exchangeable with D2O) and 10.3 (1H, s, NH, exchangeable with
D2O). MS: (m/z) *330 (40 %).
General procedure for preparation of compound 6
A solution of bromine (0.48 g, 0.15 mL, 3 mmol) in absolute methanol (10 mL)
was added dropwise with stirring to a solution of compound 1 [35] (3 mmol) in
absolute methanol (125 mL) under reflux. The mixture was heated under reflux for
2.5 h and cooled. The precipitated product, 6, was isolated by filtration, washed with
ether, dried, and recrystallized.
4-(Bromoamino)-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (6)
Crystallized from dimethylformamide, brown crystals, m.p. 116 ꢁC, yield 65 %.
Analysis: for C8H6BrClN4S, M.Wt. 305.58, calcd: C, 31.44; H, 1.98; N, 18.33.
Found: C, 31.35; H, 1.63; N, 17.98. IR (KBr, cm-1): 1,032–1,344 (C–N),
1
1,436–1,612 (C=C) and 2,865 (Sec NH). H NMR (DMSO-d6, d ppm): 2.3 (1H, s,
NH, exchangeable with D2O), 7.6–8 (4H, m, aromatic) and 9.2 (1H, s, NH,
exchangeable with D2O). MS: [M ? 1]? m/z *306 (1.62 %).
General procedure for preparation of compounds 7a, b
A mixture of 1 [35] (0.01 mol) and the corresponding aromatic aldehyde, i.e.
4-methoxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde (0.01 mol) in
ethanol (25 mL) was treated with concentrated HCl (0.5 mL) and heated under
reflux for 2 h. The reaction mixture was cooled to room temperature and the
separated crystalline compound was filtered and recrystallized to give compounds
7a, b.
5-(4-Chlorophenyl)-4-[(E)-(4-methoxybenzylidene)amino]-4H-1,2,
4-triazole-3-thiol (7a)
Crystallized from acetic acid, white crystals, m.p. 241 ꢁC, yield 60 %. Analysis: for
C16H13ClN4OS, M.Wt. 344.81, calcd: C, 55.73; H, 3.80; N, 16.25. Found: C, 55.65;
H, 3.67; N, 16.04. IR (KBr, cm-1): 1,020–1,410 (C–N) and 1,450–1,600 (C=C).
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Synthesis and anti-inflammatory properties of novel 1,2,4-triazole derivatives
2547
1H NMR (DMSO-d6, d ppm): 3.6 (3H, s, OCH3), 7.2–8.7 (8H, m, aromatic), 10 (1H,
s, CH) and 12.5 (1H, s, SH, exchangeable with D2O). MS: (m/z) *344 (13 %).
4-[(E)-{[3-(4-chlorophenyl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]imino}methyl]-
2-methoxyphenol (7b)
Crystallized from benzene, brown crystals, m.p. 270 ꢁC, yield 70 %. Analysis: for
C16H13ClN4O2S, M.Wt. 360.81, calcd: C, 53.26; H, 3.63; N, 15.53. Found: C,
53.11; H, 3.54; N, 15.35. IR (KBr, cm-1): 1,051–1,351 (C–N), 1,480–1,610 (C=C)
1
and 3,435 (OH). H NMR (DMSO-d6, d ppm): 3.8 (3H, s, OCH3), 5.6 (1H, s, OH,
exchangeable with D2O), 7.4–8.3 (7H, m, aromatic), 9.7 (1H, s, CH) and 12.8 (1H,
s, SH, exchangeable with D2O). MS: (m/z) *360 (5 %).
General procedure for preparation of compounds 8a, b
Equimolar proportions of 7a, b and chloroacetic acid were dissolved in ethanol
containing 3–4 drops pyridine and heated under reflux for 2–3 h. The reaction
mixture was poured into cold water and the separated crystalline compound was
isolated by filtration and recrystallized to give compounds 8a, b.
({5-(4-Chlorophenyl)-4-[(E)-(4-methoxybenzylidene)amino]-4H-1,2,4-triazol-3-yl}
sulfanyl)acetic acid (8a)
Crystallized from dimethylformamide, yellow crystal, m.p. 162 ꢁC, yield 90 %.
Analysis: for C18H15ClN4O3S, M.Wt. 402.85, calcd: C, 53.67; H, 3.75; N, 13.91.
Found: C, 53.55; H, 3.60; N, 13.79. IR (KBr, cm-1): 1,020–1,260 (C–N), 1,427–1,563
(C=C), 1,732 (C=O) and 3,416 (OH). 1H NMR (DMSO-d6, d ppm): 3.9 (3H, s, OCH3),
4.3 (2H, s, CH2), 7-8.4 (8H, m, aromatic), 9.2 (1H, s, CH) and 10.5 (1H, s, OH,
exchangeable with D2O). MS: (m/z) *402 (6 %).
({5-(4-Chlorophenyl)-4-[(E)-(4-hydroxy-3-methoxybenzylidene)amino]-4H-1,
2,4-triazol-3-yl}sulfanyl)acetic acid (8b)
Crystallized from dimethylformamide, dark yellow crystals, m.p. 87 ꢁC, yield
70 %. Analysis: for C18H15ClN4O4S, M.Wt. 418.85, calcd: C, 51.62; H, 3.61; N,
13.38. Found: C, 51.53; H, 3.59; N, 13.04. IR (KBr, cm-1): 1,022–1,287 (C–N),
1
1,431–1,586 (C=C), 1,726 (C=O) and 3,409 (OH). H NMR (DMSO-d6, d ppm):
3.8 (3H, s, OCH3), 4 (2H, s, CH2), 6.2 (1H, s, OH, exchangeable with D2O), 6.9–7.8
(7H, m, aromatic), 8.6 (1H, s, CH) and 10.2 (1H, s, OH, exchangeable with D2O).
MS: m/z *418 (0.52 %).
General procedure for preparation of compound 9
Triethylamine (0.15 g, 0.2 mL, 1.443 mmol) was added to a boiling suspension of 1
[35] (1.443 mmol) in absolute ethanol (10 mL). The mixture was boiled for 5 min
and then ethyl bromoacetate (0.24 g, 0.16 mL, 1.443 mmol) was added. The
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W. S. El-Serwy et al.
mixture was boiled with stirring for 2 h. The separated product 9 was isolated by
filtration and recrystallized.
Ethyl{[4-amino-5-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (9)
Crystallized from benzene, dark white crystals m.p. 132 ꢁC, yield 65 %. Analysis:
for C12H13ClN4O2S, M.Wt. 312.77, calcd: C, 46.08; H, 4.19; N, 17.91. Found: C,
45.91; H, 4.06; N, 17.78. IR (KBr, cm-1): 1,026–1,310 (C–N), 1,451–1,600 (C=C),
1,739 (C=O) and 3,255, 3,425 (Prim NH). 1H NMR (DMSO-d6, d ppm): 1.2 (3H, t,
CH3), 4.1 (2H, q, CH2), 4.4 (2H, s, CH2), 5.8 (2H, s, NH2, exchangeable with D2O)
and 7.4-8.1 (4H, m, aromatic). MS: (m/z) *312 (21 %).
General procedure for preparation of compound 10
A solution of compound 9 (10 mmol) in n-butanol was heated under reflux with
hydrazine hydrate (25 mmol) for 4 h. After cooling it to room temperature, a white
solid appeared. The solid was recrystallized from dimethyl sulfoxide–water (1:1) to
afford the desired product 10.
2-{[4-Amino-5-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetohydrazide (10)
Crystallized from dimethyl sulfoxide–water (1:1), white crystals, m.p. 195 ꢁC, yield
60 %. Analysis: for C10H11ClN6OS, M.Wt. 298.75, calcd: C, 40.20; H, 3.71; N, 28.13.
Found: C, 40.10; H, 3.66; N, 28.01. IR (KBr, cm-1): 1,006–1,368 (C–N), 1,463–1,619
(C=C), 1,717 (C=O), 3,295 (Sec NH) and 3,330, 3,400 (Prim NH) .1H NMR (DMSO-
d6, d ppm): 2.43 (2H, s, NH2, exchangeable with D2O), 3.7 (2H, s, CH2), 5.7 (2H, s,
NH2, exchangeable with D2O), 7.5–8 (4H, m, aromatic) and 13 (1H, s, NH,
exchangeable with D2O). MS: (m/z) *298 (0.19 %).
General procedure for preparation of compound 11
A mixture of compound 9 (1.25 mmol) and sodium methoxide (from 0.03 g,
1.25 mmol, sodium) in methanol (20 mL) was boiled with stirring for 5 h. The
reaction mixture was neutralized with dilute HCl (1:1). The precipitate of product
11 was isolated by filtration, washed with ether, dried, and recrystallized.
3-(4-Chlorophenyl)-5H-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazin-6(7H)-one (11)
Crystallized from acetic acid, white crystals, m.p. [300 ꢁC, yield 90 %. Analysis:
for C10H7ClN4OS, M.Wt. 266.70, calcd: C, 45.03; H, 2.65; N, 21.01. Found: C,
44.95; H, 2.54; N, 20.89. IR (KBr, cm-1): 1,092–1,315 (C–N), 1,465–1,542 (C=C),
1
1,632 (C=O) and 3,456 (Sec NH). H NMR (DMSO-d6, d ppm): 3.8 (2H, s, CH2),
7.1–7.9 (4H, m, aromatic) and 8.9 (1H, s, NH, exchangeable with D2O). MS:
(m/z) *266 (32 %).
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Synthesis and anti-inflammatory properties of novel 1,2,4-triazole derivatives
2549
General procedure for preparation of compound 12
A mixture of 1 [35] (0.01 mol), phenacyl bromide, and fused sodium acetate
(0.02 mol) in ethanol (40 mL) was heated under reflux for 2 h. The product
obtained was collected by filtration, washed with water, and recrystallized from the
appropriate solvent to give 12.
3-(4-Chlorophenyl)-6-phenyl-5H-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazine (12)
Crystallized from dimethylformamide, brown crystals, m.p. 280 ꢁC, yield 75 %.
Analysis: for C16H11ClN4S, M.Wt. 326.80, calcd: C, 58.80; H, 3.39; N, 17.14.
Found: C, 58.73; H, 3.25; N, 17.03. IR (KBr, cm-1): 1,016–1,294 (C–N),
1
1,455–1,600 (C=C) and 3,456 (Sec NH). H NMR (DMSO-d6, d ppm): 5.2 (1H, s,
CH), 7.1–8.3 (9H, m, aromatic) and 9 (1H, s, NH, exchangeable with D2O). MS:
(m/z) *326 (12 %).
General procedure for preparation of compound 13
A mixture of 1 [35] (0.01 mol), chloroacetone (0.01 mol), and fused sodium acetate
(0.02 mol) in ethanol (40 mL) was heated under reflux for 2 h. The product
obtained was collected by filtration, washed with water, and recrystallized from the
appropriate solvent to give 13.
3-(4-Chlorophenyl)-6-methyl-5H-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazine (13)
Crystallized from benzene, dark brown crystals, m.p. 130 ꢁC, yield 85 %. Analysis:
for C11H9ClN4S, M.Wt. 264.73, calcd: C, 49.91; H, 3.43; N, 21.16. Found: C, 49.89;
H, 3.14; N, 20.94. IR (KBr, cm-1): 1,037–1,321 (C–N), 1,464–1,633 (C=C) and
1
3,386 (Sec NH). H NMR (DMSO-d6, d ppm): 2.3 (3H, s, CH3), 5 (1H, s, CH),
7.1-7.6 (4H, m, aromatic) and 8.5 (1H, s, NH, exchangeable with D2O). MS: (m/
z) *264 (3 %).
Anti-inflammatory activity
The anti-inflammatory testing was performed in accordance with the method of
Winter et al. [36]. Paw edema was induced in rats by subcutaneous (s.c.) injection of
0.1 mL 1 % (w/v) carrageenan in distilled water in the sub-plantar region of their left
hind paws. A group of rats was left without any treatment but given the same volume of
the solvent (distilled water) and kept as controls. The selected compounds were
administered at doses of (25 mg/kg, p.o.). Indomethacin (20 mg/kg, p.o.) was used as
reference drug. The paw volumes of the rats were measured, by use of a
plethysmometer, before injection of 1 % carrageenan and after different times (1, 2,
3, and 4 h). Edema and inhibition rates for each group were calculated after the above-
mentioned times as follows:
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W. S. El-Serwy et al.
Edema ð%Þ ¼ ½Vt ꢁ Vo=Voꢂ ꢃ 100
Inhibition ð%Þ ¼ ½Ec ꢁ Et=Ecꢂ ꢃ 100
where, Vo is the volume before carrageenan injection (mL), Vt is the volume t hours
after carrageenan injection (mL), Ec is the incidence of edema in the control group,
and Et is the incidence of edema of the treated group.
Animals
The rats used in this study were procured from the Animal House Colony at the
National Research Centre (NRC), Egypt. Wistar rats of both sexes, 150–200 g b.wt.
were used. All animals were housed under standard conditions of natural 12 h light
and dark cycle with free access to food and water. Animals were allowed to adapt to
the laboratory environment for one week before experimentation. All animal
procedures were performed after approval from the Ethics Committee of The
National Research Centre, Egypt, and in accordance with the recommendations of
the proper care and use of laboratory animals.
Statistical analysis
Statistical analysis of results was performed by use of SPSS statistics software 17.0
(Released Aug. 23, 2008), Chicago, USA.
Results and discussion
Chemistry
A new 3-(4-chlorophenyl)-5-(methylsulfanyl)-4H-1,2,4-triazol-4-amine 2 was syn-
thesized by reaction of 4-amino-5-(4-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-
thione 1 [35] with methyl iodide. Compound 1 [35] was also reacted with
p-chloroacetophenone and formaldehyde to give 3-[4-amino-3-(4-chlorophenyl)-
5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-1-(4-chlorophenyl)propan-1-one 3.
Compound 1 [35] was also reacted with acetyl chloride to give 1-[4-amino-3-(4-
chlorophenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]ethanone 4. Compound 1
[35] was also reacted with appropriate acid chlorides to give N-[3-(4-chlorophenyl)-5-
thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]substituted compounds 5a, b. Compound 1
[35] was also reacted with bromine to give 4-(bromoamino)-5-(4-chlorophenyl)-2,
4-dihydro-3H-1,2,4-triazole-3-thione 6. Compound 1 [35] was also reacted with
various aromatic aldehydes to give 5-(4-chlorophenyl)-4-[(E)-(substituted)amino]-
4H-1,2,4-triazole-3-thiols 7a, b which were then reacted with chloroacetic acid to
give 5-(4-chlorophenyl)-4-[(E)-(substituted) amino]-4H-1,2,4-triazol-3-yl}sulfanyl)
acetic acids 8a, b. Compound 1 [35] was also reacted with ethyl bromoacetate to
give ethyl{[4-amino-5-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl] sulfanyl}acetate 9
which was then reacted with hydrazine hydrate and with sodium methoxide to give
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Synthesis and anti-inflammatory properties of novel 1,2,4-triazole derivatives
2551
O
O
N
NH
Cl
N
N
Cl
CH3
N
Cl
N
S
HN
S
N
N
O
NH2
S
Cl
R
N
4
5 a,b
NH2
3
N
Et3
N
N
N
N
NH
N
Br2
NH
S
MeI
Cl
Cl
Cl
EtOH
N
N
S
S
CH3
MeOH
NH2
NH2
Br
NH
1
2
6
N
N
Cl
N
S
HN
N
13
CH3
N
Cl
N
N
N
SH
Cl
N
N
N
N
S
Cl
HN
N
S
Ar
NH2
O
7 a,b
9
O
H5C2
12
MeOH
abs. EtOH
ClCH2COOH
MeONa
NH2NH2
dry Pyridine
N
N
Cl
N
S
N
HN
N
Cl
N
N
N
O
O
Cl
S
11
N
NH
2
NH
N
S
OH
NH
2
O
Ar
10
8 a,b
CH3
O
CH3
a, Ar=
b, Ar=
a,R =
b,R =
OH
O
CH3
Scheme 1 Preparation of a series of new 1,2,4-triazole derivatives from 4-amino-5-(4-chlorophenyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thione
123

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W. S. El-Serwy et al.
123

Synthesis and anti-inflammatory properties of novel 1,2,4-triazole derivatives
2553
2-{[4-amino-5-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}aceto hydrazide 10
and 3-(4-Chlorophenyl)-5H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazin-6 (7H)-one 11,
respectively. Compound 1 [35] also reacted with phenacyl bromide and with
chloroacetone to give 3-(4-chlorophenyl)-6-phenyl-5H-[1,2,4] triazolo[3,4-b][1,3,4]
thiadiazine 12 and 3-(4-chlorophenyl)-6-methyl-5H-[1,2,4] triazolo[3,4-b][1,3,4]
thiadiazine 13, respectively (Scheme 1).
Biological activity
Some of the synthesized compounds were evaluated for possible anti-inflammatory
effects in a rat model of carrageenan-induced paw edema. Carrageenan-induced
paw edema is a widely used animal model for determining the acute phase of
inflammation. (Table 1) shows the effect of selected compounds (2, 3, 5a, 5b, 6, 8a,
8b, 9, 10, and 13) on carrageenan-induced paw edema in rats in comparison with
indomethacin as reference drug. Intra-plantar injection of carrageenan in rats led to
an increase in paw volume denoting edema in the control non-treated group, as
shown in Table 1. It was noticed that all the synthesized derivatives in oral doses of
25 mg/kg significantly reduced paw edema throughout the 4-h time period in
comparison with the control non-treated group. The anti-inflammatory potency of
compounds 2, 3, 5a, 5b, 6, 8a, 8b, 9, 10, and 13 was calculated by comparing their
inhibition after different times with that for animals receiving indomethacin, as
standard anti-inflammatory drug. The anti-inflammatory potency of the tested
compounds after 4 h, compared with indomethacin, were, in descending order,
188.2, 111.8, 99.1, 97.5, 93.4, 89.7, 89.2, 73.1, 69.6, and 47.6 % for 3, 10, 2, 6, 8b,
9, 5b, 5a, 13, and 8a, respectively. Administration of indomethacin significantly
reduced carrageenan-induced edema starting from the first hour and was persistent
until the end of the experiment. The inhibitory effect of indomethacin on paw edema
was 42.58, 42.23, 41.62, and 43.40 % at the 1st, 2nd, 3rd and 4th hour, respectively.
It is noteworthy to mention that derivatives 3 and 10 had anti-inflammatory potency
after 4 h greater than that of indomethacin. Derivative 8a had the least potency.
Analysis of structure–anti-inflammatory activity relationships for the tested
derivatives revealed that the triazole N-2 and S substituents greatly affect anti-
inflammatory activity. Compound 10 is more active than compound 9, possibly as a
result of replacing the OC2H5 group by NHNH2. Also, compound 5b is more active
than compound 5a, possibly because of presence of the benzene ring in 5b instead
of the methyl group in 5a.
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