Latest advances in dual inhibitors of acetylcholinesterase and monoamine oxidase B against Alzheimer's disease

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2270781. doi: 10.1080/14756366.2023.2270781. Epub 2023 Nov 13.

Abstract

Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided.

Keywords: AChE inhibitors; Alzheimer’s disease; MAO-B inhibitors; dual inhibitors.

Publication types

  • Review

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease* / drug therapy
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology
  • Monoamine Oxidase* / metabolism
  • Structure-Activity Relationship

Substances

  • Monoamine Oxidase
  • Acetylcholinesterase
  • Monoamine Oxidase Inhibitors
  • Cholinesterase Inhibitors

Grants and funding

This project was supported by the Zhejiang Key R&D Program (No. 2021C03085); National Key R&D Program of China (2021YFC2100800); National Natural Science Foundation of China, NSFC (Grant No. 21978273 and 22378360); China Postdoctoral Science Foundation, CPSF (No. 2021M702897).