title: Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: pharmacophore-based virtual screening, synthesis, and pharmacology.
abstract: 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 nine 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.
authors.affiliation: Division of Medicinal and Process Chemistry, Central Drug Research Institute, CSIR, Lucknow 226001, India.
authors.forename: Shailendra S
authors.initials: SS
authors.lastname: Chaudhaery
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Roy
authors.forename: Neeraj
authors.initials: N
authors.lastname: Shakya
authors.forename: Gunjan
authors.initials: G
authors.lastname: Saxena
authors.forename: Shreesh Raj
authors.initials: SR
authors.lastname: Sammi
authors.forename: Aamir
authors.initials: A
authors.lastname: Nazir
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*; D000284:Administration, Oral; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000502:physiology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016208:Databases, Factual; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012601:Scopolamine / Q000633:toxicity*
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D012601:Scopolamine; D000110:Acetylcholinesterase