BACKGROUNDSuccinate dehydrogenase inhibitor (SDHI) fungicides play important roles in the control of plant fungal diseases. However, they are facing serious challenges from issues with resistance and cross‐resistance, primarily attributed to their frequent application and structural similarities. There is an urgent need to design and develop SDHI fungicides with novel structures.RESULTSAiming to discover novel potent SDHI fungicides, 31 innovative pyrazole β‐ketonitrile derivatives with diphenyl ether moiety were rationally designed and synthesized, which were guided by a 3D‐QSAR model from our previous study. The optimal target compound A23 exhibited not only outstanding in vitro inhibitory activities against Rhizoctonia solani with a half‐maximal effective concentration (EC50) value of 0.0398 μg mL−1 comparable to that for fluxapyroxad (EC50 = 0.0375 μg mL−1), but also a moderate protective efficacy in vivo against rice sheath blight. Porcine succinate dehydrogenase (SDH) enzymatic inhibitory assay revealed that A23 is a potent inhibitor of SDH, with a half‐maximal inhibitory concentration of 0.0425 μm. Docking study within R. solani SDH indicated that A23 effectively binds into the ubiquinone site mainly through hydrogen‐bonds, and cation–π and π–π interactions.CONCLUSIONThe identified β‐ketonitrile compound A23 containing diphenyl ether moiety is a potent SDH inhibitor, which might be a good lead for novel fungicide research and optimization. © 2024 Society of Chemical Industry.

中文翻译：

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具有二苯醚部分的吡唑β-酮腈衍生物作为新型有效琥珀酸脱氢酶抑制剂的3D-QSAR模型导向优化


背景技术琥珀酸脱氢酶抑制剂（SDHI）杀菌剂在植物真菌病害的防治中发挥着重要作用。然而，它们面临着耐药性和交叉耐药性问题的严峻挑战，这主要归因于它们的频繁应用和结构相似性。迫切需要设计和开发具有新颖结构的SDHI杀菌剂。 结果为了发现新型强效SDHI杀菌剂，在3D-QSAR模型的指导下，合理设计和合成了31种具有二苯醚部分的创新吡唑β-酮腈衍生物。我们之前的研究。最佳目标化合物A23不仅对立枯丝核菌表现出优异的体外抑制活性，其半数最大有效浓度（EC50）值为0.0398 μg mL−1，与fluxapyroxad（EC50 = 0.0375 μg mL−1）相当，而且对水稻纹枯病具有中等的体内保护作用。猪琥珀酸脱氢酶（SDH）酶抑制试验表明，A23 是 SDH 的有效抑制剂，半数最大抑制浓度为 0.0425 μm。 R. solani SDH 内的对接研究表明，A23 主要通过氢键、阳离子-π 和 π-π 相互作用有效地结合到泛醌位点。结论：鉴定出的含有二苯醚部分的 β-酮腈化合物 A23 是一种有效的 SDH 抑制剂，可能是新型杀菌剂研究和优化的良好先导。 © 2024 化学工业协会。