Design, Synthesis, and Metabolism Studies of N-1,4-Diketophenyltriazinones as Protoporphyrinogen IX Oxidase Inhibitors,Journal of Agricultural and Food Chemistry

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Design, Synthesis, and Metabolism Studies of N-1,4-Diketophenyltriazinones as Protoporphyrinogen IX Oxidase Inhibitors
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-02-13 , DOI: 10.1021/acs.jafc.2c09082
Hong-Yun Liu ₁ , Liang-Kun Yu ₁ , Sheng-Nan Qin ₁ , Huang-Ze Yang ₁ , Da-Wei Wang ₁ , Zhen Xi ₁

Affiliation

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is an established site for green herbicide discovery. In this work, based on structural analysis, we develop an active fragment exchange and link (AFEL) approach to designing a new class of N-1,4-diketophenyltriazinones I–III as potent Nicotiana tabacum PPO (PPO) inhibitors. After systematic structure–activity relationship optimizations, a series of new compounds with K_i values in the single-digit nanomolar range toward NtPPO and promising herbicidal activity were discovered. Among them, Ii (K_i = 0.11 nM) displays 284- and 90-fold improvement in NtPPO inhibitory activity over trifludimoxazin (K_i = 31 nM) and saflufenacil (K_i = 10 nM), respectively. In addition, Ip (K_i = 2.14 nM) not only exhibited good herbicidal activity at 9.375–37.5 g ai/ha but also showed high crop safety to rice at 75 g ai/ha by the postemergence application, indicating that Ip could be developed as a potential herbicide for weed control in rice fields. Additionally, our molecular dynamic simulation clarified the molecular basis for the interactions of these molecules with NtPPO. The metabolism studies in planta showed that IIIc could be converted to Ic, which displayed higher herbicidal activity than IIIc. The density functional theory analysis showed that due to the effect of two sulfur atoms at the triazinone moiety, IIIc is more reactive than Ic, making it more easily degraded in planta. Our work indicates that the AFEL strategy could be used to design new molecules with improved bioactivity.

中文翻译：

原卟啉原 IX 氧化酶抑制剂 N-1,4-二酮苯基三嗪酮的设计、合成和代谢研究

原卟啉原 IX 氧化酶（PPO，EC 1.3.3.4）是绿色除草剂发现的既定场所。在这项工作中，基于结构分析，我们开发了一种活性片段交换和连接 (AFEL) 方法来设计一类新型N -1,4-二酮苯基三嗪酮I – III作为有效的烟草PPO (PPO) 抑制剂。经过系统的构效关系优化，发现了一系列针对 NtPPO 的K _i值在个位数纳摩尔范围内且具有良好除草活性的新化合物。其中， Ii ( K _i = 0.11 nM) 的 NtPPO 抑制活性分别比三氟咪嗪 ( K _i = 31 nM) 和苯嘧磺草胺 ( K _i = 10 nM) 提高 284 倍和 90 倍。此外， Ip ( K _i = 2.14 nM) 不仅在 9.375–37.5 g ai/ha 下表现出良好的除草活性，而且在芽后施用 75 g ai/ha 时对水稻表现出较高的作物安全性，表明Ip可以得到开发作为一种潜在的除草剂，用于控制稻田杂草。此外，我们的分子动力学模拟阐明了这些分子与 NtPPO 相互作用的分子基础。植物体内代谢研究表明， IIIc可转化为Ic ，其除草活性高于IIIc 。密度泛函理论分析表明，由于三嗪酮部分两个硫原子的作用， IIIc比Ic更具反应性，使其更容易在植物中降解。我们的工作表明 AFEL 策略可用于设计具有改善生物活性的新分子。

更新日期：2023-02-13

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