title: Design, synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents.
abstract: A series of 4-dimethylamine flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83-33.20 μM for AChE and 0.82-11.45 μM for BChE). A Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aβ aggregation inhibitory activity at 20 μM with percentage from 25% to 48%. In addition, some compounds (5j-5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent 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.forename: Ya-Bin
authors.initials: YB
authors.lastname: Su
authors.forename: Chen
authors.initials: C
authors.lastname: Hong
authors.forename: Run-Guo
authors.initials: RG
authors.lastname: Tian
authors.forename: Lei-Peng
authors.initials: LP
authors.lastname: Su
authors.forename: Yue-Qiao
authors.initials: YQ
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Yue
authors.forename: Chao-Jie
authors.initials: CJ
authors.lastname: Wang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004123:Dimethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D004123:Dimethylamines; D005419:Flavonoids; C034516:dimethylamine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Anti-Alzheimer agent; Antioxidation; Cholinesterase; Flavonoid derivatives; Self-induced Aβ aggregation