Design, synthesis and biological evaluation of tacrine-sulphonamide hybrids as a potent acetylcholinesterase inhibitor

Abstract

Novel tacrine-based sulphonamide derivatives were designed and evaluated for their ability to inhibit acetylcholinesterase (AChE) using molecular docking and in vitro assays. Docking studies revealed strong interactions with key active-site residues, including Trp86, Trp286, Tyr337, and Phe338, mediated through π–π stacking, π-cation interactions, hydrogen bonding, and hydrophobic contacts. Among the synthesized compounds, 6g, 6i, 6j, and 6k exhibited superior binding affinities, with compound 6j demonstrating the highest docking score of −9.18 kcal mol⁻¹ and a binding energy of −97.92 kcal mol⁻¹. In vitro screening using Ellman's method confirmed potent AChE inhibition, with IC₅₀ values in the nanomolar range. Structure–activity relationship analysis indicated that methyl-substituted piperidine derivatives significantly enhanced inhibitory potency, with compounds 6j and 6k achieving IC₅₀ values of 7.40 nM and 11.33 nM, respectively.