Design, Synthesis, and Bioactivity of Triketone-quinoxalin-2-ones as a Novel HPPD Inhibition Herbicide

作者：Zhuo-Mei Cai, Rui-Ning Ying, Xian-Quan Wang, Ren-yu Bai, Ao Sun, Wishwajith Kandegama, Hong‐Yan Lin, Da-Wei Wang, Guang‐Fu Yang · 发表于：Journal of Agricultural and Food Chemistry · 年份：2025 · DOI：10.1021/acs.jafc.5c08188 · 被引用次数：7 · 研究领域：Synthesis and Biological Evaluation、Synthesis and biological activity、Bioactive Compounds and Antitumor Agents

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is recognized as one of the most promising herbicide targets for sustainable weed control in modern agricultural practices. To address agricultural demands, we designed and synthesized a novel series of triketone-quinoxalin-2-ones as potent HPPD inhibitors. In vitro evaluation revealed that the newly synthesized compounds demonstrated remarkable Arabidopsis thaliana HPPD ( At HPPD) inhibitory activity. Significantly, compound 23, 3-(4-chloro-2-fluorophenyl)-6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethylquinoxalin-2(1 H )-one, showed the strongest At HPPD inhibition with an IC 50 value of 0.034 μM, 10-fold more potent than mesotrione (IC 50 = 0.350 μM). Furthermore, the postemergence herbicidal activity evaluation showed that compound 35 exhibited 100% inhibition of Digitaria sanguinalis, Amaranthus retroflexus, Chenopodium serotinum, and Abutilon theophrasti at 150 g ai/ha, and 90% inhibition of Setaria viridis, showing enhanced activity compared to mesotrione. The crystal structure of the At HPPD –35 complex demonstrated that compound 35 engaged in a key bidentate chelating interaction with the metal ion in the catalytic active site and a π–π interaction with Phe381 and Phe424. Moreover, 35 established hydrophobic interactions with Leu427, Leu368, and Met335. These results indicate that the triketone-quinoxalin-2-one hybrid is a promising scaffold and 35 can be considered a viable lead compound for the development of HPPD...