New synthetic 1,2,4-triazole derivatives: Cholinesterase inhibition and molecular docking studies

Abstract

Two series of new N-aryl derivatives (9a-j; 10a-j) of 2-(4-ethyl-5-(3-chlorophenyl)-4H-1,2,4-triazol-3-ylthio)acetamide and 2-(4-phenyl-5-(3-chlorophenyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized by the successive conversions of 3-chlorobenzoic acid (a) into its respective ester (1) hydrazide (2), and into N-substituted 1,2,4-triazole (5, 6) via 3 and 4, respectively. The target compounds (9a-j; 10a-j) were obtained by the reaction of N-substituted 1,2,4-triazole (5, 6) with various electrophiles (8a-j), in N,N-dimethyl formamide (DMF) and sodium hydride (NaH). The synthesized analogues were characterized by using FTIR, 1H, 13C NMR spectroscopy, EIMS and HREIMS spectrometry. All the synthesized compounds, 9a-j and 10a-j, were evaluated for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE), where these compounds showed moderate to good activities against the tested enzymes. Compounds 9j and 10f displayed potent inhibitory potential (IC50 5.41 ± 0.24 & 13.57 ± 0.31 μM, respectively) against AChE while compound 9j exhibited potent inhibitory activity (IC50 7.52 ± 0.18 μM) against BChE. Other compounds showed good to moderate inhibitory activities against the said enzymes in the range of IC50 14.29–43.94 μM for AChE and IC50 21.59–41.54 μM for BChE. To rationalize the binding site interactions, docking studies were carried out. All docked compounds were found to bind in the active site with similar binding orientation and favorable binding interactions with the surrounding amino acids.