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Novel Carbamates as Orally Active Acetylcholinesterase Inhibitors Found to Improve Scopolamine-Induced Cognition Impairment: Pharmacophore-Based Virtual Screening, Synthesis and Pharmacology

IR@CDRI: CSIR-Central Drug Research Institute, Lucknow


Field	Value

Creator	Chaudhaery, S S Roy, K K Shakya, Neeraj Saxena, Gunjan Sammi, Shreesh Raj Nazir, Aamir Nath, Chandishwar Saxena, A K

Date	2011-03-23T11:35:09Z 2011-03-23T11:35:09Z 2010

Identifier	Journal of Medicinal Chemistry, 53(17), 6490-6505 http://hdl.handle.net/123456789/660

Description	A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of 9 carbamates against three diverse assay systems, namely (i) in-vitro Ellman method, (ii) in-vivo passive avoidance test and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved Scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization.

Format	1123916 bytes application/pdf

Language	en

Relation	CDRI Communication No 7948

Subject	Alzheimer’s disease Acetylcholinesterase inhibitor Carbamates Pharmacophore Virtual screening Memory

Title	Novel Carbamates as Orally Active Acetylcholinesterase Inhibitors Found to Improve Scopolamine-Induced Cognition Impairment: Pharmacophore-Based Virtual Screening, Synthesis and Pharmacology

Type	Article