文献类型：期刊文献

英文题名：3D-QSAR model-oriented optimization of Pyrazole β-Ketonitrile derivatives with diphenyl ether moiety as novel potent succinate dehydrogenase inhibitors

作者：Cheng, Liangliang[1];Zhou, Cong[1];Yuan, Qinglong[1];Zhang, Letian[1];Shao, Xusheng[1];Xu, Xiaoyong[1];Li, Zhong[1];Cheng, Jiagao[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, 130 Meilong Rd,POB 544, Shanghai 200237, Peoples R China

年份：2024

卷号：80

期号：10

起止页码：5299

外文期刊名：PEST MANAGEMENT SCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001258142800001)】；

基金：The authors gratefully acknowledge the Natural Science Foundation of Shanghai (22ZR1415600), National Natural Science Foundation of China (22307039), China Postdoctoral Science Foundation (2023M731089), Postdoctoral Fellowship Program of CPSF (GZC20230806) for financial support.

语种：英文

外文关键词：succinate dehydrogenase inhibitors; beta-Ketonitriles; fungicide; diphenyl ether; pesticide molecular design

摘要：BACKGROUND: Succinate 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. RESULTS: Aiming to discover novel potent SDHI fungicides, 31 innovative pyrazole beta-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 halfmaximal effective concentration (EC50) value of 0.0398 mu g mL(-1) comparable to that for fluxapyroxad (EC50 = 0.0375 mu g 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 mu M. Docking study within R. solani SDH indicated that A23 effectively binds into the ubiquinone site mainly through hydrogen-bonds, and cation-pi and pi-pi interactions. CONCLUSION: The identified beta-ketonitrile compound A23 containing diphenyl ether moiety is a potent SDH inhibitor, which might be a good lead for novel fungicide research and optimization. (c) 2024 Society of Chemical Industry.