Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors. Academic Article uri icon

Overview

abstract

  • Multi-target-directed ligands (MTDLs) centered on β-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC50 value of 4.11 nM) and BACE-1 inhibition (IC50 value of 18.3 nM) in comparison to donepezil (IC50 values of 6.21 and 194 nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.

publication date

  • June 25, 2018

Research

keywords

  • Acetylcholinesterase
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Cholinesterase Inhibitors
  • Donepezil
  • Drug Design

Identity

Scopus Document Identifier

  • 85049101849

Digital Object Identifier (DOI)

  • 10.1016/j.bioorg.2018.06.031

PubMed ID

  • 29966870

Additional Document Info

volume

  • 80