S-substituted derivatives of 1,2,4-triazol-3-thiol as new drug candidates for type II diabetes

Abstract

The therapeutic applications of 1,2,4-triazoles motivated us to synthesize some new derivatives. Two series of $S$-substituted derivatives (8a-8j, 12a-12i) of 5-$\{$1-[(4-chlorophenyl)sulfonyl]-3-piperidinyl$\}$-4-phenyl-4$H$-1,2,4-triazol-3-thiol (6) have been synthesized and evaluated for their biological potential. Using 4-chlorobenzene sulfonyl chloride (1) and ethyl piperidine-3-carboxylate (2), ethyl 1-[(4-chlorophenyl)sulfonyl]piperidine-3-carboxylate (3) was synthesized and converted into 3,4,5-trisubstituted 1,2,4-triazole (6) through formation of the corresponding carbohydrazide (4) and hydrazinecarbothioamide (5). Compound 6 was transformed into 8a-8j by alkyl halides (7a-7j) and into 12a-12i by $N$-aralkyl/aryl-2-bromoacetamides (11a-11i) in an aprotic solvent. The electrophiles, 11a-11i, were synthesized by gearing up $N$-substituted aralkyl/aryl amines (10a-10i) with 2-bromoacetyl bromide (9) under dynamic pH control by aqueous sodium carbonate. Structures were elucidated through the spectral techniques of IR, EIMS, $^{1}$H NMR, and $^{13}$C NMR. Most of the synthesized derivatives were found to be potent inhibitors of $\alpha $-glucosidase enzyme and even better than acarbose. Acarbose is a reference standard and is a commercially available $\alpha $-glucosidase inhibitor to treat patients with type II diabetes. The low hemolytic activity also emphasized the potential of the synthesized compounds as new drug candidates.