Synthesis, enzyme inhibitory kinetics mechanism and computational study ofN-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides as novel therapeutic agents for Alzheimer’s disease

Abstract

The present study comprises the synthesis of a new series of sulfonamides derived from 4-methoxyphenethylamine (1). The synthesis was initiated by the reaction of1with 4-methylbenzenesulfonyl chloride (2) in aqueous sodium carbonate solution at pH 9 to yieldN-(4-methoxyphenethyl)-4-methylbenzensulfonamide(3).This parent molecule3was subsequently treated with various alkyl/aralkyl halides, (4a–j), usingN,N-dimethylformamide (DMF) as solvent and LiH as activator to produce a series of newN-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides(5a–j). The structural characterization of these derivatives was carried out by spectroscopic techniques like IR,1H-NMR, and13C-NMR. The elemental analysis data was also coherent with spectral data of these molecules. The inhibitory effects on acetylcholinesterase and DPPH were evaluated and it was observed that N-(4-Methoxyphenethyl)-4-methyl-N-(2-propyl)benzensulfonamide(5c)showed acetylcholinesterase inhibitory activity 0.075 ± 0.001 (IC500.075 ± 0.001 µM) comparable to Neostigmine methylsulfate (IC502.038 ± 0.039 µM).The docking studies of synthesized ligands5a–jwere also carried out against acetylcholinesterase (PDBID 4PQE) to compare the binding affinities with IC50values. The kinetic mechanism analyzed by Lineweaver-Burk plots demonstrated that compound (5c) inhibits the acetylcholinesterase competitively to form an enzyme inhibitor complex. The inhibition constants Kicalculated from Dixon plots for compound(5c)is 2.5 µM. It was also found from kinetic analysis that derivative 5c irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound5cmay serve as lead structure for the design of more potent acetylcholinesterase inhibitors.