title: In vitro evaluation and in silico screening of synthetic acetylcholinesterase inhibitors bearing functionalized piperidine pharmacophores.
abstract: A series of densely functionalized piperidine (FP) scaffolds was synthesized following a diastereoselective one-pot multicomponent protocol under eco-friendly conditions. The FPs were evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activity, and in silico studies for all the target compounds were carried out using pharmacophore mapping, molecular docking and quantitative structure-activity relationship (QSAR) analysis in order to understand the structural features required for interaction with the AChE enzyme and the key active site residues involved in the intermolecular interactions. Halogenation, nitration or 3,4-methylenedixoxy-substitution at the phenyl ring attached to the 2- and 6-positions of 1,2,5,6-tetrahydropyridine nucleus in compounds 14-17, 19, 20, 24 and 26 greatly enhanced the AChE inhibitory activity. The docking analysis demonstrated that the inhibitors are well-fitted in the active sites. The in silico studies enlighten the future course of studies in modifying the scaffolds for better therapeutic efficacy against the deadly Alzheimer's disease.
authors.affiliation: Laboratory of Natural Products and Organic Synthesis, Department of Chemistry, Visva-Bharati (a Central University), Santiniketan 731235, West Bengal, India. Electronic address: brahmg2001@yahoo.co.in.
authors.forename: Goutam
authors.initials: G
authors.lastname: Brahmachari
authors.affiliation: MedChem Herbal Research Group, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Puncak Alam, Selangor, Malaysia; PLS Core, UiTM, 40450 Shah Alam, Malaysia.
authors.forename: CheeYan
authors.initials: C
authors.lastname: Choo
authors.affiliation: Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
authors.forename: Pravin
authors.initials: P
authors.lastname: Ambure
authors.affiliation: Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India; Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom.
authors.forename: Kunal
authors.initials: K
authors.lastname: Roy
mesh_terms: D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D066298:In Vitro Techniques; D010880:Piperidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010880:Piperidines
keywords: Acetylcholinesterase (AChE) inhibition; Docking; Functionalized piperidines; Green synthesis; In silico; Pharmacophore