Discovery of novel isoflavone derivatives as AChE/BuChE dual-targeted inhibitors: synthesis, biological evaluation and molecular modelling

J Enzyme Inhib Med Chem. 2017 Dec;32(1):968-977. doi: 10.1080/14756366.2017.1347163.

Abstract

AChE and BuChE are druggable targets for the discovery of anti-Alzheimer's disease drugs, while dual-inhibition of these two targets seems to be more effective. In this study, we synthesised a series of novel isoflavone derivatives based on our hit compound G from in silico high-throughput screening and then tested their activities by in vitro AChE and BuChE bioassays. Most of the isoflavone derivatives displayed moderate inhibition against both AChE and BuChE. Among them, compound 16 was identified as a potent AChE/BuChE dual-targeted inhibitor (IC50: 4.60 μM for AChE; 5.92 μM for BuChE). Molecular modelling study indicated compound 16 may possess better pharmacokinetic properties, e.g. absorption, blood-brain barrier penetration and CYP2D6 binding. Taken together, our study has identified compound 16 as an excellent lead compound for the treatment of Alzheimer's disease.

Keywords: AChE/BuChE dual-targeted inhibitor; Alzheimer’s disease; isoflavone derivatives; molecular modelling.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Butyrylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Isoflavones / chemical synthesis
  • Isoflavones / chemistry
  • Isoflavones / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Isoflavones
  • Acetylcholinesterase
  • Butyrylcholinesterase

Grants and funding

This work was partly supported by National Major Scientific and Technological Special Project for Significant New Drugs Development [2012ZX09301002-001, 2013ZX09402103 and 2014ZX09507003-002] and National Natural Science Foundation of China [81603027].