屏蔽三酮-喹啉骨架中的代谢热点获得强效4-羟苯基丙酮酸双加氧酶抑制剂
Shielding Metabolic Hotspots in the Triketone-Quinoline Scaffold Yields Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.
摘要(中文译文)
4-羟基苯基丙酮酸双加氧酶（HPPD；EC 1.13.11.27）是现代除草剂发现的重要靶标。为将HPPD抑制剂转化为有效的除草剂候选物，我们开发了一种以代谢为导向的设计策略，以提高三酮-喹啉类HPPD抑制剂的体内药效。通过屏蔽骨架内的代谢热点，我们发现了一系列新的类似物，其芽后除草活性普遍提高，对拟南芥HPPD（AtHPPD）的抑制作用也显著增强。值得注意的是，化合物9i对AtHPPD的Ki值为0.0012 μM，优于硝磺草酮一个数量级。化合物11b不仅在15.625-250 g ai/ha剂量下表现出优异的杂草防效，而且在250 g ai/ha剂量下对小麦表现出较高的作物安全性。分子模拟表明，喹啉取代可增强与Phe360和Phe403的π-π相互作用，从而提高生物活性。我们的工作建立了一个代谢导向的除草剂发现优化框架，并提供了一个有前景的小麦选择性除草剂候选物。
Abstract
4-Hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) is an important target for modern herbicide discovery. To translate HPPD inhibitors into effective herbicide candidates, we developed a metabolism-oriented design strategy to improve the in vivo efficacy of triketone-quinoline HPPD inhibitors. By shielding the metabolic hotspots within the scaffold, we discovered a series of new analogues with broadly improved postemergence herbicidal activity and substantially enhanced inhibition of Arabidopsis thaliana HPPD (AtHPPD). Notably, 9i showed a Ki value of 0.0012 μM toward AtHPPD, outperforming mesotrione by an order of magnitude. 11b not only exhibited excellent weed control at 15.625-250 g ai/ha, but also showed high crop safety to wheat at 250 g ai/ha. Molecular simulations showed that quinoline substitutions could enhance π-π interactions with Phe360 and Phe403, improving bioactivity. Our work establishes a metabolism-guided optimization framework for herbicide discovery and provides a promising wheat-selective herbicide candidate.
如何引用
AMA
Min Li, Han Xiao, Si-Mei Zhou, Zi-Xuan Li, Li-Jun Chen, Lei Wu, et al. Shielding Metabolic Hotspots in the Triketone-Quinoline Scaffold Yields Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.. Journal of agricultural and food chemistry. 2026; doi:10.1021/acs.jafc.5c15585.
APA
Min Li, Han Xiao, Si-Mei Zhou, Zi-Xuan Li, Li-Jun Chen, Lei Wu, et al (2026). Shielding Metabolic Hotspots in the Triketone-Quinoline Scaffold Yields Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.. Journal of agricultural and food chemistry. https://doi.org/10.1021/acs.jafc.5c15585
GB/T 7714
Min Li, Han Xiao, Si-Mei Zhou, Zi-Xuan Li, Li-Jun Chen, Lei Wu, et al. Shielding Metabolic Hotspots in the Triketone-Quinoline Scaffold Yields Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.[J]. Journal of agricultural and food chemistry, 2026 doi:10.1021/acs.jafc.5c15585.
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