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

文献类型： 外文期刊

第一作者： He, Bo

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

作者机构：

期刊名称：NATURE COMMUNICATIONS （ 影响因子：15.7； 五年影响因子：17.2 ）

ISSN：

年卷期： 2025 年 16 卷 1 期

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收录情况： SCI

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 alpha-hydroxycarboxylic acid moieties as potential inhibitors and develop an eco-friendly alpha-C(sp(3))-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 (K-d = 1 mu M) than that of the natural substrate (K-d = 5.39 mu M). The 2.19 & Aring; cocrystal structure of the AtDHAD-I-6e complex reveals a unique binding mechanism, confirming the critical role of the alpha-hydroxycarboxylic acid scaffold. This study provides a blueprint for rational DHAD inhibitor design.

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