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

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。

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

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.