Scaffold hopping approach to the novel hexacyclic pyrazol-3-amide derivatives as potential multi-target insect growth regulators candidates

文献类型： 外文期刊

第一作者： Guo, Bingbo

作者： Guo, Bingbo;Luo, Shihui;Feng, Yanjiao;Cao, Congwang;Zhang, Li;Yang, Xinling;Chen, Lei;Yang, Qing;Chen, Lei;Yang, Qing;Wang, Chunying;Wang, Chunying

作者机构：

关键词： Insect growth regulators; Ecdysone receptor; Chitinases; Scaffold hopping; Multi-target IGRs; Action mechanism

期刊名称：PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY （ 影响因子：4.0； 五年影响因子：4.5 ）

ISSN： 0048-3575

年卷期： 2024 年 205 卷

页码：

收录情况： SCI

摘要： Ecdysone receptor (EcR) and three insect chitinases (OfChtI, OfChtII, and OfChi-h) are considered as attractive targets for the development of novel insect growth regulators (IGRs) since they are closely related to the insect molting. In this study, to develop potent multi-target IGRs, a series of hexacyclic pyrazol-3-amide derivatives were rationally designed by utilizing the scaffold hopping strategy with the previously reported compound 6j (N(4-bromobenzyl)-2-phenyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide) as a lead compound. The bioassay results indicated that most of the target compounds exhibited obvious insecticidal activity. Especially, compounds a5 and a21 displayed excellent insecticidal activities against P. xylostella with LC50 values of 82.29 and 69.45 mg/L, respectively, exceeding that of 6j (263.78 mg/L). Compounds a5 and a21 also dramatically disturbed the growth and development of O. furnacalis larvae, and their LC50 values were 124.71 and 127.54 mg/ L, respectively, superior to the lead 6j (267.33 mg/L). The action mechanism study revealed that the most active compound a21 could act simultaneously on EcR (21.4 % binding activity at 8 mg/L), OfChtI (94.9 % inhibitory at 10 mu M), OfChtII (23.1 % inhibitory at 10 mu M), and OfChi-h (94.3 % inhibitory at 10 mu M), significantly higher than that of the lead compound 6j. The result of molecular docking indicated that transferring the carboxamide group from pyrazole position 5 to 3 enhanced the interactions of a21 with the key amino acid residues of the OfChtI, OfChtII, and OfChi-h, resulting in stronger affinity to the three targets than 6j. The present work offers a useful guidance for the further development of novel multi-target IGRs.

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