title: Structure-Based Discovery of Potential Fungicides as Succinate Ubiquinone Oxidoreductase Inhibitors.
abstract: 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 Kivalue of 0.081 μM, about 4-fold more potent than penthiopyrad (Ki= 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.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.
authors.forename: Jing-Ming
authors.initials: JM
authors.lastname: Ge
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.
authors.forename: Xiao Lei
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.|Collaborative Innovation Center of Chemical Science and Engineering , Tianjin 300071, People's Republic of China.
authors.forename: Guang-Fu
authors.identifier: http://orcid.org/0000-0003-4384-2593
authors.initials: GF
authors.lastname: Yang
mesh_terms: D001203:Ascomycota / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005659:Fungicides, Industrial / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D012232:Rhizoctonia / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D005659:Fungicides, Industrial; D011720:Pyrazoles; D042963:Electron Transport Complex II
keywords: complex II; diphenyl ether; molecular docking; structure−activity relationship; succinate ubiquinone oxidoreductase