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

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

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Division of Medicinal and Process Chemistry, CSIR Central Drug Research Institute, Lucknow 226 001, India.


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.

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