Synthesis and biological evaluation of 3-arylbenzofuranone derivatives as potential anti-Alzheimer's disease agents

J Enzyme Inhib Med Chem. 2020 Dec;35(1):805-814. doi: 10.1080/14756366.2020.1740694.

Abstract

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer's disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC50 value of anti-acetylcholinesterase inhibition of Compound 20 (0.089 ± 0.01 μM) is similar to the positive drug donepezil (0.059 ± 0.003 μM). According to the experimental results, Compounds 7, 13 show a certain effect in the in vitro evaluation performed and have the potential as drug candidates for the treatment of Alzheimer's disease.

Keywords: 3-Arylbenzofuranone derivatives; Alzheimer’s disease; antioxidant activity; cholinesterase inhibitors; monoamine oxidase inhibitors.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Animals
  • Anti-Anxiety Agents / chemical synthesis
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / pharmacology*
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Biphenyl Compounds / antagonists & inhibitors
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Picrates / antagonists & inhibitors
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Anti-Anxiety Agents
  • Antioxidants
  • Benzofurans
  • Biphenyl Compounds
  • Cholinesterase Inhibitors
  • Monoamine Oxidase Inhibitors
  • Picrates
  • 1,1-diphenyl-2-picrylhydrazyl
  • Monoamine Oxidase
  • Acetylcholinesterase

Grants and funding

The authors are grateful to support from the Science and Shandong Provincial Natural Science Foundation [ZR2018LH021], the Innovation Project of Shandong Academy of Medical Sciences and Academic promotion programme of Shandong First Medical University [No. 2019LJ003].