Structure-Guided Discovery of Silicon-Containing Subnanomolar Inhibitor of Hydroxyphenylpyruvate Dioxygenase as a Potential Herbicide,Journal of Agricultural and Food Chemistry

当前位置： X-MOL 学术 › J. Agric. Food Chem. › 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.)

Structure-Guided Discovery of Silicon-Containing Subnanomolar Inhibitor of Hydroxyphenylpyruvate Dioxygenase as a Potential Herbicide
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2021-01-04 , DOI: 10.1021/acs.jafc.0c03844
Ren-Yu Qu ₁ , Jia-Xu Nan ₁ , Yao-Chao Yan ₁ , Qiong Chen ₁ , Ferdinand Ndikuryayo ₁ , Xue-Fang Wei ₁ , Wen-Chao Yang ₁ , Hong-Yan Lin ₁ , Guang-Fu Yang ₁

Affiliation

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been recognized as one of the most promising targets in the field of herbicide innovation considering the severity of weed resistance currently. In a persistent effort to develop effective HPPD-inhibiting herbicides, a structure-guided strategy was carried out to perform the structural optimization for triketone-quinazoline-2,4-diones, a novel HPPD inhibitor scaffold first discovered in our lab. Herein, starting from the crystal structure of Arabidopsis thaliana (At)HPPD complexed with 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(o-tolyl)quinazoline-2,4(1H,3H)-dione (MBQ), three subseries of quinazoline-2,4-dione derivatives were designed and prepared by optimizing the hydrophobic interactions between the side chain of the core structure at the R¹ position and the hydrophobic pocket at the active site entrance of AtHPPD. 6-(2-Hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(3-(trimethylsilyl)prop-2-yn-1-yl)quinazoline-2,4(1H,3H)-dione (60) with the best inhibitory activity against AtHPPD was identified to be the first subnanomolar-range AtHPPD inhibitor (K_i = 0.86 nM), which significantly outperformed that of the lead compound MBQ (K_i = 8.2 nM). Further determination of the crystal structure of AtHPPD in complex with compound 60 (1.85 Å) and the binding energy calculation provided a molecular basis for the understanding of its high efficiency. Additionally, the greenhouse assay indicated that 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-propylquinazoline-2,4(1H,3H)-dione (28) and compound 60 showed acceptable crop safety against peanut and good herbicidal activity with a broad spectrum. Moreover, compound 28 also showed superior selectivity for wheat at the dosage of 120 g ai/ha and favorable herbicidal efficacy toward the gramineous weeds at the dosage of as low as 30 g ai/ha. We believe that compounds 28 and 60 have promising prospects as new herbicide candidates for wheat and peanut fields.

中文翻译：

含羟基的丙酮酸丙酮酸双加氧酶的含硅亚纳摩尔抑制剂作为潜在除草剂的结构指导发现。

考虑到目前对杂草的抗性的严重性，4-羟基苯基丙酮酸双加氧酶（HPPD，EC 1.13.11.27）被公认为是除草剂创新领域最有希望的目标之一。为了开发有效的抑制HPPD的除草剂，我们进行了结构导向的策略，以对三酮喹唑啉-2,4-二酮（我们在实验室中首次发现的新型HPPD抑制剂支架）进行结构优化。在此，从与6-（2-羟基-6-氧代环己基-1-烯-1-羰基）-1,5-二甲基-3-（邻甲苯基）喹唑啉络合的拟南芥（At）HPPD的晶体结构开始-2,4（1 H，3 H）-二酮（MBQ），通过优化R ¹位置核心结构侧链与At HPPD活性位点入口处的疏水口袋之间的疏水相互作用，设计和制备了quinazoline-2,4-dione衍生物的三个亚系列。6-（2-羟基-6-氧代环己-1-烯-1-羰基）-1,5-二甲基-3-（3-（三甲基甲硅烷基）丙-2-炔-1-基）喹唑啉-2,4（对At HPPD具有最佳抑制活性的1 H，3 H）-二酮（60）被确定为第一个亚纳摩尔范围的At HPPD抑制剂（K _i = 0.86 nM），明显优于铅化合物MBQ（K_i = 8.2 nM）。进一步确定At HPPD与化合物60（1.85Å）的配合物的晶体结构以及结合能的计算为理解其高效率提供了分子基础。此外，温室分析表明，6-（2-羟基-6-氧代环己基-1-烯-1-羰基）-1,5-二甲基-3-丙基喹唑啉-2,4（1 H，3 H）-二酮（28）和化合物60显示出对花生的可接受的农作物安全性和广谱的良好除草活性。此外，化合物28还显示了在120 g ai / ha的剂量下对小麦具有优越的选择性，并且在低至30 g ai / ha的剂量下对禾本科杂草具有良好的除草效果。我们认为，化合物28和60作为小麦和花生田的新型除草剂候选物具有广阔的前景。

更新日期：2021-01-13

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南