title: 3D-QSAR studies of azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives as anti-AChE and anti-AD agents by the CoMFA method.
abstract: In the present study, a series of novel azaoxoisoaporphine derivatives were reported and their inhibitory activities toward acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Aβ aggregation were evaluated. The new compounds remained high inhibitory potency on Aβ aggregation, with inhibitory activity from 29.42% to 89.63% at a concentration of 10μM, but had no action on AChE or BuChE, which was very different from our previously reported oxoaporphine and oxoisoaporphine derivatives. By 3D-QSAR studies, we constructed a reliable CoMFA model (q(2)=0.856 and r(2)=0.986) based on the inhibitory activities toward AChE and discovered key information on structure and anti-AChE activities among the azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives. The model was further confirmed by the test-set validation (q(2)=0.873, r(2)=0.937, and slope k=0.902) and Y-randomization examination. The statistically significant and physically meaningful 3D-QSAR/CoMFA model provided better insight into understanding the inhibitory behaviors of those chemicals, which may provide useful information for the rational molecular design of azaoxoisoaporphine derivatives anti-AChE and anti-AD agents.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Weng
authors.forename: Fang-Xian
authors.initials: FX
authors.lastname: Ning
authors.forename: Jie-Bin
authors.initials: JB
authors.lastname: Ou
authors.forename: Jin-Qiang
authors.initials: JQ
authors.lastname: Hou
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Huang
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry; D001060:Aporphines / Q000737:chemistry* / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D001060:Aporphines; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase