title: Design, synthesis and biological evaluation of organophosphorous-homodimers as dual binding site acetylcholinesterase inhibitors.
abstract: The cluster effect is an effective strategy to explore new lead compounds, and has been successfully applied in rational drug design and screening. A series of novel organophosphorous-homodimers were designed and synthesized based on the dual-site structure characteristics of acetylcholinesterase (AChE). The compounds were evaluated in vitro for their inhibitory activity to AChE extracted from Drosophila melanogaster and Musca domestic. Compound 4H showed an excellent inhibitor activity to both Drosophila melanogaster and Musca domestic with the corresponding IC(50) values of 23 and 168 nM, respectively. Meanwhile, its activities against Drosophila melanogaster and Musca domestic AChE were more than 10,00,000 and 100,000-fold higher compared with the parent compound (MH), and was up to 245 and 107-fold higher than those of the positive control omethoate. The molecular docking study revealed that 4H possessed an optimal spacer length and can perfectly fit into the central pocket, active gorge, and peripheral site of DmAChE, and consequently exhibited highly improved inhibitor potency to DmAChE. The bioassay tests showed that 4 series compounds showed prominent insecticidal activities against both Lipaphser erysimi and Tetranychus cinnbarinus at a concentration of 200mg/L. The insecticide activity of compound 4H was particularly significant that can cause 96% mortality to Tetranychus cinnbarinus after 24h of treatment.
authors.affiliation: State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
authors.forename: Ruliang
authors.initials: R
authors.lastname: Xie
authors.forename: Qianfei
authors.initials: Q
authors.lastname: Zhao
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Mei
authors.forename: Jun
authors.initials: J
authors.lastname: Ning
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D004331:Drosophila melanogaster / Q000201:enzymology*; D006793:Houseflies / Q000201:enzymology*; D007313:Insecta / Q000201:enzymology; D007306:Insecticides / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009943:Organophosphorus Compounds; D000110:Acetylcholinesterase