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

Abstract

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, 0.220 μM for eeAChE; 1.23 μM for eqBuChE; 0.454 μM for hAChE) and an acceptable inhibitory activity against monoamine oxidases (IC₅₀, 3.14 μM for MAO-B; 13.4 μM 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.

Keywords:

• Alzheimer’s disease
• donepezil
• cholinesterase
• monoamine oxidase
• molecular modeling

Declaration of interest

The authors declare no conflicts of interest.

We gratefully acknowledge the financial support by the National Natural Science Foundation of China (81573313), the program for Changjiang Scholars and Innovative Research Team in University (IRT_15R63), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Supplementary material available online