Structure-Based Discovery of Potential Fungicides as Succinate Ubiquinone Oxidoreductase Inhibitors

• Published in: Journal of agricultural and food chemistry 2017-02, Vol.65 (5), p.1021-1029
• Main Authors: Xiong, Li, Li, Hua, Jiang, Li-Na, Ge, Jing-Ming, Yang, Wen-Chao, Zhu, Xiao Lei, Yang, Guang-Fu
• Format: Article
• Language: English
• Subjects: Ascomycota - drug effects; Ascomycota - enzymology; Ascomycota - genetics; Electron Transport Complex II - antagonists & inhibitors; Electron Transport Complex II - chemistry; Electron Transport Complex II - genetics; Electron Transport Complex II - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - chemistry; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungicides, Industrial - chemistry; Fungicides, Industrial - pharmacology; Kinetics; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rhizoctonia - drug effects; Rhizoctonia - enzymology; Rhizoctonia - genetics; Structure-Activity Relationship
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.6b05134

A series of diphenyl ether-containing pyrazole-carboxamide derivatives was designed and synthesized as new succinate ubiquinone oxidoreductase (SQR) inhibitors. This highly potent molecular scaffold was developed from a moderately activie hit 3, obtained from our previous pharmacophore-linked fragment virtual screening (PFVS) method. The results of greenhouse tests indicated that some analogues showed good SQR inhibitory activity, with promising fungicidal activity against Rhizoctonia solani and Sphaerotheca fuliginea at a dosage of 200 mg/L. Most surprisingly, compound 62 showed the highest SQR inhibitory activity with a K i value of 0.081 μM, about 4-fold more potent than penthiopyrad (K i = 0.307 μM). In addition, compounds 43 and 62 displayed excellent fungicidal activity even at a dosage as low as 6.25 mg/L, which was superior to thifluzamide. Moreover, compound 62 exhibited excellent protection effect against R. solani and provided about 81.2% protective control efficancy after 21 days with two sprayings. The present work indicated that these two compounds could be used as potential agricultural fungicides targeting SQR.