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

作者：Bo He, Yanhao Hu, D. 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 · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-60489-8 · 被引用次数：11 · 研究领域：Biochemical and Molecular Research、Biochemical Acid Research Studies、Chemical Reaction Mechanisms

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. Dihydroxyacid dehydratase (DHAD) is an essential enzyme for the synthesis of branched-chain amino acids in plants. Here, the authors rationally design a range of DHAD inhibitors as herbicides and present the crystal structure of a lead compound in complex with Arabidopsis DHAD.