Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer's disease

摘要

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of donepezil-like compounds were designed, synthesized and evaluated. In vitro studies showed that most of the designed compounds displayed potent inhibitory activities toward AChE, BuChE, MAO-B and MAO-A. Among them, w18 was a promising agent with balanced activities, which exhibited a moderate cholinesterase inhibition (IC50, 0.220M for eeAChE; 1.23M for eqBuChE; 0.454M for hAChE) and an acceptable inhibitory activity against monoamine oxidases (IC50, 3.14M for MAO-B; 13.4M for MAO-A). Moreover, w18 could also be a metal-chelator, and able to cross the blood-brain barrier with low cell toxicity on PC12 cells. Taken together, these results suggested that w18 might be a promising multitargeted compound for AD treatment.