Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential use in Alzheimer's disease

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127404. doi: 10.1016/j.bmcl.2020.127404. Epub 2020 Jul 12.

Abstract

A library of twelve quinazoline-triazole hybrid compounds were designed, synthesized and evaluated as a novel class of acetylcholinesterase inhibitors to treat Alzheimer's disease (AD). The biological assay results demonstrated the ability of several hybrid compounds to inhibit AChE enzyme (IC50 range = 0.2-83.9 µM). To understand the high potential activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of quinazoline-triazole hybrid compounds. As expected, compounds 8a and 9a-b bind to both catalytic anionic site (CAS) and peripheral anionic site (PAS) in the active site of AChE enzyme, which implicates that these compounds could act as dual binding site inhibitors. These compounds were not cytotoxic and they also displayed appropriated physicochemical as well as pharmacokinetic profile to be developed as novel anti-AD drug candidates.

Keywords: Acetylcholinesterase inhibitor; Alzheimer’s disease; Click chemistry; Hybridization; Quinazoline; Triazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Amino Acid Sequence
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / pharmacology
  • Click Chemistry
  • Drug Evaluation, Preclinical
  • Humans
  • Molecular Docking Simulation
  • Protein Conformation
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacology
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology

Substances

  • Cholinesterase Inhibitors
  • Quinazolines
  • Triazoles
  • Acetylcholinesterase