New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation

Bioorg Med Chem Lett. 2020 Oct 15;30(20):127477. doi: 10.1016/j.bmcl.2020.127477. Epub 2020 Aug 8.

Abstract

A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Among the synthesized compounds 13b showed most potent acetylcholinesterase (AChE) inhibition (IC50 = 0.059 μΜ) with mixed type inhibition scenario. Structure-activity relationship revealed that three-carbon alkyl chain connecting coumarin and triazole is well tolerable for inhibitory potential. Hybrids obtained from 4-hydroxycoumarin and 1-benzotriazole were most potent AChE inhibitors. The inhibitory potential of all compounds against butyrylcholinesterase was also evaluated but all showed negligible activity suggesting that the hybrid molecules are selective AChE inhibitors. 13b (most potent AChE inhibitor) also showed copper-induced Aβ1-42 aggregation inhibition (34.26% at 50 μΜ) and chelating properties for metal ions (Cu2+, Fe2+, and Zn2+) involved in AD pathogenesis along with DNA protective potential against degenerative actions of OH radicals. Molecular modelling studies confirm the potential of 13b in blocking both PAS and CAS of AChE. In addition, interactions of 13b with Aβ1-42 monomer are also streamlined. Therefore, hybrid 13b can act as an effective hit lead molecule for further development of selective AChE inhibitors as multifunctional anti-Alzheimer's agents.

Keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; Amyloid aggregation inhibitor; Coumarin-benzotriazole hybrids; Molecular docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Protein Aggregates / drug effects*
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / metabolism
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Coumarins
  • Peptide Fragments
  • Protein Aggregates
  • Triazoles
  • amyloid beta-protein (1-42)
  • benzotriazole
  • coumarin
  • Acetylcholinesterase