Design, synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity

Drug Dev Res. 2020 Apr;81(2):206-214. doi: 10.1002/ddr.21585. Epub 2019 Aug 9.

Abstract

The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer's disease (AD), antioxidants could attenuate the AD syndrome and prevent the disease progression. In this study, BACE1 inhibitors (D1-D18) with free radical-scavenging activities were synthesized by molecular hybridization of 2-aminopyridine with natural antioxidants. The biological activity evaluation showed that D1 had obvious inhibitory activity against BACE1, and strong antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS+• ) assay, which could be used as a lead compound for further study.

Keywords: Alzheimer's disease; BACE1; antioxidant activity; molecular docking; molecular hybridization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemistry*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / chemistry*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / chemistry*
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Oxidants / chemical synthesis*
  • Oxidants / chemistry
  • Oxidants / pharmacology

Substances

  • Aminopyridines
  • Enzyme Inhibitors
  • Oxidants
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • alpha-aminopyridine