文献类型：期刊文献

英文题名：Rational Exploration of Novel SDHI Fungicide through an Amide-?-ketonitrile Bioisosteric Replacement Strategy

作者：Zhou, Cong[1];Sun, Xujuan[1];Fu, Wen[1];Li, Zhong[1];Cheng, Jiagao[1];Maienfisch, Peter[1]

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

年份：2023

卷号：71

期号：14

起止页码：5483

外文期刊名：JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY

收录：;EI(收录号：20231413846706);WOS:【SCI-EXPANDED(收录号:WOS:000962376300001)】；

基金：? ACKNOWLEDGMENTS The authors gratefully acknowledge the National Natural Science Foundation of China (21977030) , the Natural Science Foundation of Shanghai, and the Innovation Program of Shanghai Municipal Education Commission (22ZR1415600 and 201701070002E00037) for the financial support. Thanks for the kind assistance from Letian Zhang in the in vivo fungicidal activity assay.

语种：英文

外文关键词：?-ketonitriles; succinate dehydrogenase inhibitors; fungicidal activity; bioisosteric replacement; molecular docking; 3D-QSAR

摘要：The identification of succinate dehydrogenase inhibitor (SDHI) fungicides bearing a novel scaffold is of great importance to control pathogenic fungi. Difluoromethyl-pyrazole beta-ketonitrile derivatives were rationally designed through an innovative amide-beta-ketonitrile bioisosteric replacement strategy and evaluated for their antifungal activities. In preliminary fungicidal screening, our new beta-ketonitrile compounds showed outstanding in vitro activity. Compounds A7 and A14 exhibited EC50 values of 0.116 and 0.165 mu g/mL against Sclerotinia sclerotiorum, respectively, and A14 also displayed an EC50 of 0.0774 mu g/mL against Rhizoctonia solani. Furthermore, A14 exhibited moderate in vivo protective activity against rice sheath blight on rice plants. Results from SDH enzymatic assays demonstrated that A14 possesses significant inhibitory effect toward porcine heart SDH, with an IC50 value of 0.183 mu M, which was 20-fold more potent than that of fluxapyroxad (IC50 = 3.76 mu M). A docking study indicated that H-bonds, cation-pi interactions, and edge-to-face pi-pi interactions play key roles in the binding of A14 with R. solani SDH. The CoMSIA model guided the approach to further structural optimizations and indicated that hydrophobic and steric substituents on the benzene ring have decisive effects on the fungicidal activity against R. solani. The present work describes for the first time the successful bioisosteric replacement of the common SDHI amide moiety by a beta-ketonitrile group and highlights the potential of beta- ketonitriles as an innovative novel SDHI subclass.