数字农科院2.0

Substrate-based discovery of α-hydroxycarboxylic acid derivatives as potential herbicides targeting dihydroxyacid dehydratase

文献类型： 外文期刊

作者： Bo He;Yanhao Hu;Dongshan Liu;Xin Zang;Xu He;Wang Chen;Jingfang Yang;Mingfeng Feng;Ping Chen;Lirong Wei;Yu Li;Wei Yan;Jun Li;Zhike Feng;Jiahai Zhou;Yonghao Ye

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期刊名称： Nature Communications

ISSN： 2041-1723

年卷期： 2025 年 16 卷 1 期

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收录情况： SCIE（2025版）

摘要： Dihydroxyacid dehydratase (DHAD), a key enzyme in branched-chain amino acid synthesis in plants, is a promising yet unexploited herbicide target. Inspired by the natural DHAD inhibitor aspterric acid, we design benzoxazinone derivatives with α-hydroxycarboxylic acid moieties as potential inhibitors and develop an eco-friendly α-C(sp³)-H hydroxylation method for accessing carbonyl compounds. Among the derivatives, 7-fluoro-2-hydroxy-3-oxo-4-propyne-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (I-6e) completely inhibits Arabidopsis thaliana germination and suppress six weed species by > 50%, with 100% efficacy against Avena fatua and Setaria viridis at 150 g ai/ha. This broad-spectrum activity and rice crop safety highlight its potential as an herbicide lead compound. Compound I-6e exhibits stronger affinity for DHAD (Kd = 1 µM) than that of the natural substrate (Kd = 5.39 µM). The 2.19 Å cocrystal structure of the AtDHAD–I-6e complex reveals a unique binding mechanism, confirming the critical role of the α-hydroxycarboxylic acid scaffold. This study provides a blueprint for rational DHAD inhibitor design.

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