Liangliang Cheng, Cong Zhou, Qinglong Yuan, Letian Zhang, Xusheng Shao, Xiaoyong Xu, Zhong Li, Jiagao Cheng
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{"title":"以 3D-QSAR 模型为导向,优化具有二苯醚分子的吡唑 β-Ketonitrile 衍生物,使其成为新型强效琥珀酸脱氢酶抑制剂","authors":"Liangliang Cheng, Cong Zhou, Qinglong Yuan, Letian Zhang, Xusheng Shao, Xiaoyong Xu, Zhong Li, Jiagao Cheng","doi":"10.1002/ps.8269","DOIUrl":null,"url":null,"abstract":"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 <jats:italic>β</jats:italic>‐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 <jats:italic>in vitro</jats:italic> inhibitory activities against <jats:italic>Rhizoctonia solani</jats:italic> with a half‐maximal effective concentration (EC<jats:sub>50</jats:sub>) value of 0.0398 μg mL<jats:sup>−1</jats:sup> comparable to that for fluxapyroxad (EC<jats:sub>50</jats:sub> = 0.0375 μg mL<jats:sup>−1</jats:sup>), but also a moderate protective efficacy <jats:italic>in vivo</jats:italic> 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 μ<jats:sc>m</jats:sc>. Docking study within <jats:italic>R. solani</jats:italic> SDH indicated that A23 effectively binds into the ubiquinone site mainly through hydrogen‐bonds, and cation–π and π–π interactions.CONCLUSIONThe identified <jats:italic>β</jats:italic>‐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.","PeriodicalId":218,"journal":{"name":"Pest Management Science","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"3D‐QSAR model‐oriented optimization of Pyrazole β‐Ketonitrile derivatives with diphenyl ether moiety as novel potent succinate dehydrogenase inhibitors\",\"authors\":\"Liangliang Cheng, Cong Zhou, Qinglong Yuan, Letian Zhang, Xusheng Shao, Xiaoyong Xu, Zhong Li, Jiagao Cheng\",\"doi\":\"10.1002/ps.8269\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 <jats:italic>β</jats:italic>‐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 <jats:italic>in vitro</jats:italic> inhibitory activities against <jats:italic>Rhizoctonia solani</jats:italic> with a half‐maximal effective concentration (EC<jats:sub>50</jats:sub>) value of 0.0398 μg mL<jats:sup>−1</jats:sup> comparable to that for fluxapyroxad (EC<jats:sub>50</jats:sub> = 0.0375 μg mL<jats:sup>−1</jats:sup>), but also a moderate protective efficacy <jats:italic>in vivo</jats:italic> 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 μ<jats:sc>m</jats:sc>. Docking study within <jats:italic>R. solani</jats:italic> SDH indicated that A23 effectively binds into the ubiquinone site mainly through hydrogen‐bonds, and cation–π and π–π interactions.CONCLUSIONThe identified <jats:italic>β</jats:italic>‐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.\",\"PeriodicalId\":218,\"journal\":{\"name\":\"Pest Management Science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-06-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pest Management Science\",\"FirstCategoryId\":\"97\",\"ListUrlMain\":\"https://doi.org/10.1002/ps.8269\",\"RegionNum\":1,\"RegionCategory\":\"农林科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"AGRONOMY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pest Management Science","FirstCategoryId":"97","ListUrlMain":"https://doi.org/10.1002/ps.8269","RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"AGRONOMY","Score":null,"Total":0}
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