title: Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors.
abstract: A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9 nM and high AChE/BuChE selectivity (SI>230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Chaolei
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: cpu-jill@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Jieyun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Hequan
authors.initials: H
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: jinyixu@china.com.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xu
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000609114:(Z)-4-((7,8-dimethoxy-4-oxoisochroman-3-ylidene)methyl)-1-(4-fluorobenzyl)pyridin-1-ium bromide; D001578:Benzopyrans; D002800:Cholinesterase Inhibitors; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: 4-Isochromanone; Acetylcholinesterase; Alzheimer’s disease; Dual binding site; Hybrids