Discovery of N-Methoxy-(biphenyl-ethyl)-pyrazole-carboxamides as Novel Succinate Dehydrogenase Inhibitors.
Discovery of N-Methoxy-(biphenyl-ethyl)-pyrazole-carboxamides as Novel Succinate Dehydrogenase Inhibitors.
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DOI：
10.1021/acs.jafc.2c04770
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发表时间：
2022-11
影响因子：
6.1
通讯作者：
Yuan-Hui Huang;Ge Wei;Zheng Liu;Qiang Lu;Jia-jia Jiang;Xiao-Lei Zhu;Guangfu Yang
中科院分区：
文献类型：
--
作者：
Yuan-Hui Huang;Ge Wei;Zheng Liu;Qiang Lu;Jia-jia Jiang;Xiao-Lei Zhu;Guangfu Yang
琥珀酸脱氢酶（SDH）抑制剂是杀菌剂开发的研究热点之一。在此，我们描述了通过采用片段组合策略设计和合成具有增强杀菌活性的N-甲氧基-(联苯-乙基)-吡唑-甲酰胺衍生物。对 24 种标题化合物的 SDH 酶活性进行了评估，确定化合物 7s 是针对猪 SDH 的最高活性，IC50 值为 0.014 μM，是 Fluxapyroxad 的 205 倍。此外，温室实验表明，化合物7u对小麦白粉病具有有效的杀菌活性，EC50值为0.633 mg/L，比fluxapyroxad和苯并维氟吡菌活性更高。计算结果表明，吡唑环上的氟原子取代与C_S42形成额外的偶极-偶极相互作用，进而增强了化合物与SDH之间的范德华相互作用。从目前的工作中获得的结构和机制见解将为开发新型 SDH 抑制剂提供宝贵的线索。
Succinate dehydrogenase (SDH) inhibitor is one of the research hotspots for the development of fungicides. Herein, we describe the design and synthesis of N-methoxy-(biphenyl-ethyl)-pyrazole-carboxamide derivatives with enhanced fungicidal activity by employing fragment combination strategy. The SDH enzymatic activity was evaluated for 24 title compounds, and compound 7s was identified as the highest activity against porcine SDH with an IC50 value of 0.014 μM, 205-fold greater than that of fluxapyroxad. Furthermore, the greenhouse experiments showed that compound 7u exhibited potent fungicidal activity against wheat powdery mildew with an EC50 value of 0.633 mg/L, higher activity than fluxapyroxad and benzovindiflupyr. The computational results showed that the fluorine atom substituted on the pyrazole ring formed an extra dipolar-dipolar interaction with C_S42 and then increased the van der Waals interaction between the compound and SDH. The structural and mechanistic insights obtained from the present work will provide a valuable clue to developing novel SDH inhibitors.