靶向蜕皮激素受体的新型4,5,6,7-四氢-2H-吲唑酰肼类衍生物的设计、合成及杀虫活性  

Design,synthesis and insecticidal activity of novel 4,5,6,7-tetrahydro-2Hindazole hydrazide derivatives targeting ecdysone receptor

作　　者：郭兵博 蒋标标 董雅雯 金小宇 崔丽[2] 张莉[1] 杨新玲[1] GUO Bingbo;JIANG Biaobiao;DONG Yawen;JIN Xiaoyu;CUI Li;ZHANG Li;YANG Xinling(Innovation Center of Pesticide Research,Department of Applied Chemistry,College of Science,China Agricultural University,Beijing 100193,China;Institute of Plant Protection,Chinese Academy of Agricultural Sciences,Beijing 100193,China)

机构地区：[1]中国农业大学理学院应用化学系农药创新研究中心,北京100193 [2]中国农业科学院植物保护研究所,北京100193

出　　处：《农药学学报》2022年第1期39-48,共10页Chinese Journal of Pesticide Science

基　　金：国家自然科学基金(21977114);国家重点研发计划项目(2017YFD0200504).

摘　　要：为了发现结构新颖的昆虫生长调节剂,以蜕皮激素受体(EcR)为靶标,以课题组发现的高活性化合物C(N-(4-(叔丁基)苯基)-2-苯基-2,4,5,6,7,8-六氢环庚基[C]吡唑-3-甲酰胺)为先导化合物,利用活性亚结构拼接的方法,设计合成了25个未见文献报道的新型4,5,6,7-四氢-2H-吲唑酰肼类衍生物,其结构经过核磁共振氢谱、碳谱和高分辨质谱确证。分子对接结果表明,所有目标化合物与EcR具有较好的结合力,其中化合物I-15可以很好地结合到EcR的活性位点,其结合模式和虫酰肼相似;靶标蛋白结合实验证明,I-15在40 mg/L下与EcR具有较好的结合活性(75.8%±7.2%)。初步杀虫活性测定结果表明,部分目标化合物在500 mg/L下对鳞翅目害虫小菜蛾表现出一定的杀虫活性,但总体活性均不如虫酰肼和先导化合物C;进一步分析发现,目标化合物的脂水分配系数(ClogP)普遍低于先导化合物和对照药剂虫酰肼,推测是由于目标化合物的亲脂性较差,从而影响其穿透昆虫表皮的能力,导致杀虫活性较弱。该研究对后续化合物的结构优化具有重要参考价值。In order to discover insect growth regulators with new structures,25 novel 4,5,6,7-tetrahydro-2H-indazole hydrazide derivatives were designed and synthesized by the method of linking active substructures with the lead compound C based on the ecdysone receptor(EcR).The structures of these target compounds were confirmed by 1H NMR,13C NMR and HRMS.Moreover,molecular docking study revealed that all target compounds had a good binding force with the EcR,wherein the compound I-15 had the similar binding mode with EcR as tebufenozide,which can bind well with the active site of EcR.And the protein binding experiments showed that the binding activity of I-15 to EcR was 75.8%±7.2%at a concentration of 40 mg/L.In addition,preliminary bioassay results showed that some target compounds had certain insecticidal activity against the Plutella xylostella at 500 mg/L,but their activities were not as good as tebufenozide and C.The ClogP values of target compounds were lower than the lead compound,which indicated that their liposolubility was not good enough to penetrate the insect cuticle,resulting in poor insecticidal activity.This work provides important clues for the further structure optimization.

关 键 词：蜕皮激素受体 昆虫生长调节剂 4 5 6 7-四氢-2H-吲唑酰肼衍生物 合成 杀虫活性 蛋白结合活性 

分 类 号：O623.626[理学—有机化学] TQ450.1[理学—化学]