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

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 () and Yonghao Ye ()
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Bo He: Nanjing Agricultural University
Yanhao Hu: Nanjing Agricultural University
Dongshan Liu: Chinese Academy of Science
Xin Zang: Chinese Academy of Science
Xu He: Nanjing Agricultural University
Wang Chen: Nanjing Agricultural University
Jingfang Yang: Chinese Academy of Agricultural Sciences
Mingfeng Feng: Nanjing Agricultural University
Ping Chen: Nanjing Agricultural University
Lirong Wei: Nanjing Agricultural University
Yu Li: Nanjing Agricultural University
Wei Yan: Nanjing Agricultural University
Jun Li: Nanjing Agricultural University
Zhike Feng: Nanjing Agricultural University
Jiahai Zhou: Chinese Academy of Science
Yonghao Ye: Nanjing Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60489-8

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