结构导向发现苯并噻嗪酮-三酮杂合体作为新型亚纳摩尔级4-羟苯基丙酮酸双加氧酶抑制剂
Structure-Guided Discovery of Benzothiazinone-Triketone Hybrids as Novel Subnanomolar 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.
摘要(中文译文)
4-羟基苯基丙酮酸双加氧酶（HPPD）在酪氨酸代谢途径中发挥关键作用，被视为重要的除草剂靶标。本文中，我们基于结构导向药物设计（SBDD）策略，设计了一类苯并噻嗪酮-三酮杂合体作为新型HPPD抑制剂。酶抑制实验表明，大多数衍生物对HPPD表现出优异的抑制活性。此外，我们测定了化合物（、、和）与HPPD的三种共晶结构（PDB ID：8XQY、8HXF和8X6A），以指导结构优化过程，从而发现了新型亚纳摩尔级HPPD抑制剂。最终，我们发现了一个皮摩尔级抑制剂，其对HPPD的值为226 pM。其效力比硝磺草酮（= 4.56 nM）高约20倍，被认为是迄今为止最有效的HPPD抑制剂。这些结果表明，三酮-苯并噻嗪酮杂合体是发现新型HPPD抑制剂的潜在骨架。
Abstract
4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a pivotal role in the tyrosine metabolism pathway and is regarded as an important herbicide target. Herein, we present a class of benzothiazinone-triketone hybrids as novel HPPD inhibitors designed by using a structure-based drug design (SBDD) strategy. The enzyme inhibitory assay revealed that most of the derivatives exhibited excellent inhibitory efficacy against HPPD (HPPD). Furthermore, three cocrystal structures of compounds (, , and ) in complex with HPPD (PDB ID: 8XQY, 8HXF, and 8X6A) were determined to guide the structural optimization process, resulting in the discovery of novel subnanomolar HPPD inhibitors. Finally, a picomolar inhibitor with a value of 226 pM against HPPD was discovered. It showed about 20-fold higher potency than mesotrione ( = 4.56 nM) and was regarded as the most potent HPPD inhibitor to date. These results demonstrate that the triketone-benzothiazinone hybrid is a potential scaffold for discovering new HPPD inhibitors.
如何引用
AMA
Bai-Feng Zheng, Rui-Ning Ying, Xian-Quan Wang, Long-Can Mei, Wen-Yi Yang, Bo He, et al. Structure-Guided Discovery of Benzothiazinone-Triketone Hybrids as Novel Subnanomolar 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.. Journal of agricultural and food chemistry. 2026; doi:10.1021/acs.jafc.6c05296.
APA
Bai-Feng Zheng, Rui-Ning Ying, Xian-Quan Wang, Long-Can Mei, Wen-Yi Yang, Bo He, et al (2026). Structure-Guided Discovery of Benzothiazinone-Triketone Hybrids as Novel Subnanomolar 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.. Journal of agricultural and food chemistry. https://doi.org/10.1021/acs.jafc.6c05296
GB/T 7714
Bai-Feng Zheng, Rui-Ning Ying, Xian-Quan Wang, Long-Can Mei, Wen-Yi Yang, Bo He, et al. Structure-Guided Discovery of Benzothiazinone-Triketone Hybrids as Novel Subnanomolar 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.[J]. Journal of agricultural and food chemistry, 2026 doi:10.1021/acs.jafc.6c05296.
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