Synthesis, inhibition studies against AChE and BChE, drug-like profiling, kinetic analysis and molecular docking studies of N-(4-phenyl-3-aroyl-2(3H)-ylidene) substituted acetamides

Abstract

Halogenated and non-halogenated N-(4-phenyl-3-aroyl-2(3H)-ylidene) substituted acetamides were prepared by base-catalyzed cyclization of corresponding acetyl thioureas with phenacyl bromide. The synthesized compounds were structurally characterized by 1H NMR and 13C NMR spectroscopy and were screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme inhibition activities. Molecular docking studies, drug-like profiling and kinetic analysis were performed to further investigate the inhibition mechanism of the compounds. This study provided useful insights into the design and development of novel dual inhibitors, in addition to understanding the mechanism by which such drugs interact with targets and exert their biochemical action. All the compounds showed superior inhibition profile compared to the standards possessing sub-micromolar and micromolar IC50 values for AChE and BChE, respectively. Docking simulations revealed that the compound 6g showed strong binding inside the active site gorges of both AChE and BChE. An excellent agreement was obtained as the best docked poses showed important binding features mostly based on interactions due to aromatic moieties and oxygen atoms of the compound. Cation-pi/pi-pi interactions together with hydrogen bond forces were the key players responsible for ligand anchoring in the active sites. The striking results accomplished both in docking computations and experimental findings ascertained that the compound 6g can serve as a scaffold for both AChE and BChE inhibition.