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

The present study comprises the synthesis of a new series of sulfonamides derived from 4-methoxyphenethylamine (). The synthesis was initiated by the reaction of with 4-methylbenzenesulfonyl chloride () in aqueous sodium carbonate solution at pH 9 to yield -(4-methoxyphenethyl)-4-methylbenzensulfonamide .This parent molecule was subsequently treated with various alkyl/aralkyl halides, (, using -dimethylformamide (DMF) as solvent and LiH as activator to produce a series of new -(4-methoxyphenethyl)--(substituted)-4-methylbenzenesulfonamides . The structural characterization of these derivatives was carried out by spectroscopic techniques like IR, H-NMR, and C-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 showed acetylcholinesterase inhibitory activity 0.075 ± 0.001 (IC 0.075 ± 0.001 µM) comparable to Neostigmine methylsulfate (IC 2.038 ± 0.039 µM).The docking studies of synthesized ligands were also carried out against acetylcholinesterase (PDBID 4PQE) to compare the binding affinities with IC values. 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 K calculated from Dixon plots for compound 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 compound may serve as lead structure for the design of more potent acetylcholinesterase inhibitors.