title: Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer's disease.
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.
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR Central Drug Research Institute, Lucknow 226 001, India.
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Roy
authors.forename: Santoshkumar
authors.initials: S
authors.lastname: Tota
authors.forename: Tusha
authors.initials: T
authors.lastname: Tripathi
authors.forename: Subhash
authors.initials: S
authors.lastname: Chander
authors.forename: Chandishwar
authors.initials: C
authors.lastname: Nath
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase