title: Indolinone-based acetylcholinesterase inhibitors: synthesis, biological activity and molecular modeling.
abstract: A series of indolinone-based compounds bearing benzylpyridinium moiety was designed as dual-binding inhibitors of acetylcholinesterase (AChE). The target compounds 3a-u were synthesized by condensation of oxindole and pyridin-4-carbalehyde, and subsequent N-benzylation. The anti-cholinesterase activity evaluation of synthesized compounds revealed that most of them had very potent inhibitory activity against AChE, superior to standard drug donepezil. Particularly, 2-chlorobenzyl derivative 3c was the most potent compound against AChE with IC50 value of 0.44 nM, being 32-fold more potent than donepezil. Also, most of compounds were more potent than standard drug donepezil against butyrylcholinesterase (BuChE). Docking study revealed that the hydrophobic aromatic part (indoline) of representative compound 3c binds to the PAS and the N-benzylpyridinium residue binds to the CAS of AChE.
authors.affiliation: Department of Chemistry, College of Science, Yazd University, Yazd, P.O. Box 8915813149, Iran.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Akrami
authors.affiliation: Department of Chemistry, College of Science, Yazd University, Yazd, P.O. Box 8915813149, Iran.
authors.forename: Bibi Fatemeh
authors.initials: BF
authors.lastname: Mirjalili
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khoobi
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Nadri
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Moradi
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Amirhossein
authors.initials: A
authors.lastname: Sakhteman
authors.affiliation: Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran. Electronic address: ashafiee@ams.ac.ir.
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D007211:Indoles; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Alzheimer's disease; Docking study; Indolinone; Oxindole