Anti-inflammatory and antinociceptive evaluation of newly synthesized 4-(substituted ethanoyl) amino-3-mercapto-5-(4-methoxy) phenyl-1,2,4-triazoles

Abstract

Introduction:1,2,4-triazoles and its derivatives have been reported to possess anti-inflammatory, analgesic, antimicrobial, anticancer, antitumor, antitubercular, anticonvulsant, openers of Ca-activated potassium (Maxi-K) channels, antiviral properties, hypoglycemic, anxiolytic and antidepressant activity. Therefore, 1,2,4-triazole seems to be an important pharmacophore.Materials and Methods:The synthesis of 4-(substituted ethanoyl) amino-3-mercapto-5-(4-methoxy) phenyl-1,2,4-triazoles (6a-o) were prepared following six step starting 4-methoxy benzoic acid and using different secondary amines and were characterized with the help of FT-IR,1H,13C NMR, FAB Mass and nitrogen analysis. These synthesized compounds (6a-o) were then evaluated for anti-inflammatory activity by carrageenan induced paw edema method.Out of these synthesized compounds, some (6f, i and k) were evaluated for antinociceptive activity by Hot plate method and Tail immersion method.Results and Discussion:The synthesis of 4-(substituted amino)-3-mercapto-5-(4-methoxy) phenyl-1,2,4-triazoles (6a-o) was accomplished. The IR spectra exhibited characteristic bands for C-N, C=N, SH and C=O at 1350-1360, 1511-1548, 2520-2594.3 and 1650-1719 cm-1. The C-O-C asymmetric and symmetric str. was at 1250-1254 and 1027-1079.3 cm-1 respectively. In1H-NMR spectra, a singlet of CONH was found in the range of δ 9.92-10.18 ppm and another singlet of thiol group was observed in the range of δ 8.63-9.92 ppm. A singlet of Ar-OCH3 was also found between δ 3.57-3.91 ppm. In13 C- NMR spectra, C-3 and C-5 of the 1,2,4 - triazole nucleus were observed in the range of δ 147-166.9 ppm. Carbonyl carbon and methylene carbon of –NHCOCH2 N< were found between δ 166.5-177.5 and δ 47.1-62 ppm respectively. Acute toxicity study was donr following OECD-423 and cut-off dose was found to be between 1000-1500 mg/kg body weight. At the dose level of 100 mg/kg, 6f, 6i and 6k exhibited appreciable inhibition of oedema especially 6k exhibiting a percentage of oedema inhibition of 40.28%, which was comparable to that of the standard drug indomethacin (62.50% at 10mg/kg dose). Among the compounds tested, compound 6k exhibited good anti-nociceptive activity in both methods used. Pethidine (20mg/kg body weight s.c) is used as the standard drug.Conclusion:SAR of these synthesized compounds shows that substitution with heterocyclic moiety at C-2 of the acetamido group at position 4 of the 1,2,4-triazole produces appreciable activity as compared to substitution with aliphatic moieties since among all the synthesized compounds, the most active ones are 6f, 6i and 6k that have piperdine, 1-benzyl piperazine and morpholine group, respectively at C-2 of the acetamido group at position 4 of the 1,2,4-triazole.