Design, synthesis, and fungicidal evaluation of novel oxysterol binding protein inhibitors for combatting resistance associated with oxathiapiprolin,Pesticide Biochemistry and Physiology

当前位置： X-MOL 学术 › Pestic. Biochem. Phys. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Design, synthesis, and fungicidal evaluation of novel oxysterol binding protein inhibitors for combatting resistance associated with oxathiapiprolin
Pesticide Biochemistry and Physiology ( IF 4.2 ) Pub Date : 2020-10-01 , DOI: 10.1016/j.pestbp.2020.104673
Jian-Long Li ₁ , Li-Ming Zhou ₁ , Meng-Qi Gao ₁ , Zhong-Qiao Huang ₂ , Xi-Li Liu ₂ , Xiao-Lei Zhu ₁ , Guang-Fu Yang ₃

Affiliation

Oxathiapiprolin, the first successful oxysterol binding protein (OSBP) inhibitor for oomycete control, is regarded as an important milestone in the history of fungicide discovery. However, its interaction with OSBP remain unclear. Moreover, some plant pathogenic oomycetes have developed medium to high resistance to oxathiapiprolin. In this paper, the three-dimensional (3D) structure of OSBP from Phytophthora capsici (pcOSBP) was built, and its interaction with oxathiapiprolin was systematically investigated by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. The computational results showed that oxathiapiprolin bound to pcOSBP forms H-bonds with Leu73, Lys74, Ser69, and water molecules. Then, based on its interaction with pcOSBP, oxathiapiprolin was structurally modified to discover new analogs with high fungicidal activity and a low risk of resistance. Fortunately, compound 1e was successfully designed and synthesized as the most potent candidate, and it showed a much lower resistance risk (RF < 1) against LP3-M and LP3-H in P. capsici. The present work indicated that the piperidinyl-thiazole-isoxazoline moiety is useful for further optimization. Furthermore, compound 1e could be used as a lead compound for the discovery of new OSBP inhibitors.

中文翻译：

新型氧甾醇结合蛋白抑制剂的设计、合成和杀真菌评价，用于对抗与氧硫唑嘌呤相关的耐药性

Oxathiapiprolin 是第一个成功控制卵菌的氧甾醇结合蛋白 (OSBP) 抑制剂，被认为是杀菌剂发现史上的一个重要里程碑。然而，它与 OSBP 的相互作用仍不清楚。此外，一些植物病原性卵菌已对氧硫唑嘌呤产生中等至高度抗性。本文构建了辣椒疫霉 OSBP (pcOSBP) 的三维 (3D) 结构，并通过整合分子对接、分子动力学模拟和分子力学泊松-玻尔兹曼表面积 (MM /PBSA) 计算。计算结果表明，与 pcOSBP 结合的 oxathiapiprolin 与 Leu73、Lys74、Ser69 和水分子形成 H 键。然后，基于它与 pcOSBP 的交互，oxathiapiprolin 进行了结构修饰，以发现具有高杀菌活性和低耐药风险的新类似物。幸运的是，化合物 1e 被成功设计和合成为最有效的候选物，它对辣椒中的 LP3-M 和 LP3-H 显示出低得多的耐药风险（RF < 1）。目前的工作表明哌啶基-噻唑-异恶唑啉部分可用于进一步优化。此外，化合物 1e 可用作发现新 OSBP 抑制剂的先导化合物。目前的工作表明哌啶基-噻唑-异恶唑啉部分可用于进一步优化。此外，化合物 1e 可用作发现新 OSBP 抑制剂的先导化合物。目前的工作表明哌啶基-噻唑-异恶唑啉部分可用于进一步优化。此外，化合物 1e 可用作发现新 OSBP 抑制剂的先导化合物。

更新日期：2020-10-01

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11