Design, synthesis and evaluation of N-arylmethylamide derivatives as cholinesterase inhibitors

Abstract

Abstract A series of N-arylmethylamide derivatives were designed and synthesized as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer’s disease (AD). Furthermore, the compounds were assayed for their inhibitory activity to cholinesterase in vitro, and the results indicated that most of the compounds had moderate inhibitory activity to cholinesterase. Among them, compound 22j showed the best inhibitory activity against BuChE (IC50 = 0.46 µM) and moderate inhibitory activity against AChE (IC50 = 6.52 µM); remarkably, compound 22c was found to be a dual inhibitor of AChE (IC50 = 1.11 µM) and BuChE (IC50 = 1.14 µM). In addition, the results of molecular docking studies exhibited that 22j could simultaneously bind to both CAS and PAS of BuChE, which was consistent with the mixed mode of inhibition shown by enzyme kinetic studies of 22j. Moreover, the molecular properties of all compounds were predicted by the molinspiration server, and the compounds 22j and 22c matched the most properties of orally administered drugs. All these suggested that 22j and 22c could be considered as a lead compound for the development of AD drugs.