Design, synthesis and biological evaluation of organophosphorous-homodimers as dual binding site acetylcholinesterase inhibitors

文献类型： 外文期刊

第一作者： Xie, Ruliang

作者： Xie, Ruliang;Zhao, Qianfei;Zhang, Tao;Mei, Xiangdong;Ning, Jun;Fang, Jing;Tang, Yun

作者机构：

关键词： Acetylcholinesterase;Dual binding site;Insecticidal activity;Molecular docking;Organophosphorous-homodimers

期刊名称：BIOORGANIC & MEDICINAL CHEMISTRY （ 影响因子：3.641； 五年影响因子：3.319 ）

ISSN：

年卷期：

页码：

收录情况： SCI

摘要： 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 IC50 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 200 mg/L. The insecticide activity of compound 4H was particularly significant that can cause 96% mortality to Tetranychus cinnbarinus after 24 h of treatment.

分类号： R9

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