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

The optimization of our previous lead compound 1 (AChE IC50 = 3.31 mu M) 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 (IC50 = 2.57 mu M), 6b (IC50 = 0.70 mu M) and 6i (IC50 = 2.56 mu M) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC50= 1.11 mu M). 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. (C) 2012 Elsevier Ltd. All rights reserved.