Reddy_2026_RSC.Adv_16_18061

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 Pi-Pi stacking, Pi-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 IC(50) 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 IC(50) values of 7.40 nM and 11.33 nM, respectively.