New lead discovery of insect growth regulators based on the scaffold hopping strategy
New lead discovery of insect growth regulators based on the scaffold hopping strategy
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基于支架跳跃策略的昆虫生长调节剂新发现
DOI：
10.1016/j.bmcl.2020.127500
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发表时间：
2020-11-01
影响因子：
2.7
通讯作者：
Yang, Xinling
中科院分区：
文献类型：
--
作者：
Jiang, Biaobiao;Guo, Bingbo;Yang, Xinling
昆虫生长调节剂（IGRs）是一种被广泛应用于害虫综合治理的低毒农药，具有阻断或抑制害虫生命周期的作用。蜕皮激素类似物和几丁质酶抑制剂是常见的igr，由于其独特的作用方式和对非靶生物的低毒性而引起了相当大的关注。为了寻找具有新机制的新型高效候选igr，以D-08 （N-（4-（叔丁基）苯基）-2-苯基-2,4,5,6,7,8-六氢环庚[c]吡唑-5-羧酰胺）为先导化合物，采用支架跳跃策略设计合成了一系列新型七环吡唑酰胺衍生物。生物测定结果表明，111-27 （N-（2-甲基苯基）-1-苯基-1,4,5,6,7,8-六氢环庚[c]吡唑-5-羧酰胺）对小菜蛾具有良好的抑菌活性。蛋白验证和分子对接表明，III-27可同时作用于ecdysone受体（EcR）和Ostrinia furnacalis几丁质酶（ChtI），是一种有前景的新型先导IGRs。通过分子对接研究了111-27与EcR和of ChtI的相互作用机理。这些结果对新型双靶点igr的研究具有重要的指导意义。
Insect growth regulators (IGRs), which can interrupt or inhibit pest life cycles, are low-toxicity pesticides widely used in integrated pest management (IPM). Ecdysone analogues and chitinase inhibitors are familiar IGRs that have attracted considerable attention because of their unique modes of action and low toxicity to non-target organisms. To find new and highly effective candidate IGRs with novel mechanisms, D-08 (N-(4-(tert-butyl) phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) was chosen as a lead compound, and a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized using the scaffold hopping strategy. The bioassay showed that 111-27 (N-(2-methylphenethyl)-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) had excellent activity against Plutella xylostella. Protein verification and molecular docking indicated that III-27 could act on both the ecdysone receptor (EcR) and Ostrinia furnacalis chitinase (Of ChtI) and is a promising new lead IGRs. The interaction mechanism of 111-27 with EcR and Of ChtI was then studied by molecular docking. These results provide important guidance for the study of new dual-target IGRs.