title: Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.
abstract: Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
authors.affiliation: School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Kia
authors.affiliation: School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia. Electronic address: osman.hasnah2012@yahoo.com.
authors.forename: Hasnah
authors.initials: H
authors.lastname: Osman
authors.affiliation: Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh, Saudi Arabia. Electronic address: sraju@ksu.edu.sa.
authors.forename: Raju
authors.initials: R
authors.lastname: Suresh Kumar
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.
authors.forename: Alireza
authors.initials: A
authors.lastname: Basiri
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.
authors.forename: Vikneswaran
authors.initials: V
authors.lastname: Murugaiyah
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014101:Torpedo
chemical_list: D002800:Cholinesterase Inhibitors; D011759:Pyrrolidines; D013141:Spiro Compounds; D002802:Cholinesterases
keywords: 1,3-Dipolar cycloaddition; AChE; Alzheimer’s disease; BChE; Molecular docking; Spiropyrrolidines