title: Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities.
abstract: A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64μM for AChE and 0.42μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease.
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China. Electronic address: luowen83@henu.edu.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Luo
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hong
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Chang
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
authors.forename: Cong-Cong
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China.
authors.forename: Ya-Cheng
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Institute of Chemical Biology, Henan University, Kaifeng 475004, People's Republic of China.
authors.forename: Song-Qiang
authors.initials: SQ
authors.lastname: Xie
authors.affiliation: Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People's Republic of China. Electronic address: wcjsxq@163.com.
authors.forename: Chao-Jie
authors.initials: CJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D002470:Cell Survival; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D016716:PC12 Cells; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D005419:Flavonoids; D002091:Butyrylcholinesterase; D002802:Cholinesterases
keywords: Anti-Alzheimer agent; Cholinesterase; Cytotoxicity; Flavonoid derivatives; Molecular modeling