Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase

Bioorg Med Chem. 2012 Nov 15;20(22):6739-50. doi: 10.1016/j.bmc.2012.09.016. Epub 2012 Sep 17.

Abstract

Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with K(i) of 6.47nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacology
  • Binding Sites
  • Butyrylcholinesterase / chemistry*
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology
  • Drug Design*
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Quinolinium Compounds / chemical synthesis*
  • Quinolinium Compounds / chemistry
  • Quinolinium Compounds / pharmacology

Substances

  • 1-(5-(4-((2-acetylphenyl)carbamoyl)phenoxy)pentyl)quinolin-1-ium
  • Amyloid beta-Peptides
  • Benzamides
  • Cholinesterase Inhibitors
  • Quinolinium Compounds
  • Butyrylcholinesterase
  • Amyloid Precursor Protein Secretases