Design, Synthesis, and Evaluation of Multitarget-Directed Ligands Against Alzheimer's Disease Based on the Fusion of Donepezil and Curcumin

Bioorg Med Chem. 2017 Jun 15;25(12):2946-2955. doi: 10.1016/j.bmc.2017.02.048. Epub 2017 Apr 18.

Abstract

By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aβ1-42 self-aggregation at 20μM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.

Keywords: AChE inhibition; Alzheimer’s disease; Aβ(1–42) self-aggregation; Curcumin derivatives.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Blood-Brain Barrier / metabolism
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacokinetics
  • Cholinesterase Inhibitors / pharmacology*
  • Curcumin / analogs & derivatives
  • Curcumin / pharmacokinetics
  • Curcumin / pharmacology*
  • Donepezil
  • Drug Design
  • Electrophorus
  • Humans
  • Indans / chemistry
  • Indans / pharmacokinetics
  • Indans / pharmacology*
  • Ligands
  • Molecular Docking Simulation
  • Molecular Targeted Therapy
  • Peptide Fragments / metabolism*
  • Piperidines / chemistry
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Protein Aggregates / drug effects*
  • Swine

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Indans
  • Ligands
  • Peptide Fragments
  • Piperidines
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • Donepezil
  • Acetylcholinesterase
  • Curcumin