A novel method for the synthesis of 1,2,4-triazole-derived heterocyclic compounds: enzyme inhibition and molecular docking studies

Abstract

Two series of new N-aryl/aralkyl derivatives (9a–q) of 2-(4-ethyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide and N-aryl/aralkyl derivatives (10a–q) of 2-(4-phenyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized. The methods included successive conversions of thiophen-2-acetic acid (a) into its respective ester, hydrazide and N-aryl/aralkyl 1,3,4-triazole. The target compounds (9a–q; 10a–q) were obtained by the reaction of N-aryl/aralkyl 1,3,4-triazole (5, 6) with various electrophiles, (8a–q), in N,N-dimethyl formamide (DMF) and sodium hydroxide at room temperature. The characterization of these compounds was done by FTIR, ¹H-, ¹³C-NMR, EI-MS and HR-EI-MS spectral data. All compounds were evaluated for their enzyme inhibitory potentials against electric eel acetylcholinesterase, AChE (10f, 10d; IC₅₀ values 32.26 ± 0.12, 45.72 ± 0.11 µM, respectively), equine butyrylcholinesterase, BChE (9d, 9l, 9b, 10d, 10h; IC₅₀ values 12.52 ± 0.19, 12.52 ± 0.19, 21.72 ± 0.18, 23.62 ± 0.22, 24.52 ± 0.21 µM, respectively), jack bean urease (10i, 10n, 9e; IC₅₀ values 7.27 ± 0.05, 7.35 ± 0.04, 8.79 ± 0.05 µM, respectively) and yeast α-glucosidase enzymes (9o, 10i; IC₅₀ values 62.94 ± 0.19, and 69.46 ± 0.15 µM, respectively). The molecular docking studies supported these findings. This study provides cheaper bioactive triazole amides as promising future lead molecules.