Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer's disease

Bioorg Med Chem. 2012 Nov 1;20(21):6313-20. doi: 10.1016/j.bmc.2012.09.005. Epub 2012 Sep 12.

Abstract

The optimization of our previous lead compound 1 (AChE IC(50)=3.31 μM) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC(50)=2.57μM), 6b (IC(50)=0.70 μM) and 6i (IC(50)=2.56 μM) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC(50)=1.11 μM). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE-carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE-carbamate Michaelis complexes have been investigated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / metabolism
  • Animals
  • Carbamates / chemical synthesis
  • Carbamates / chemistry
  • Carbamates / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Mice
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Carbamates
  • Cholinesterase Inhibitors
  • Acetylcholinesterase