Design, synthesis and biological evaluation of pyrazole-aromatic containing carboxamides as potent SDH inhibitors

To continue our ongoing studies on discovery of new potent antifungal leads, 43 novel pyrazole-aromatic containing carboxamides were rationally designed and synthesized. Bioassays indicated that most target compounds displayed good in vitro antifungal activities against Botrytis cinerea, Rhizoctonia cerealis and Sclerotinia sclerotiorum and in vivo antifungal activity against R. solani. Compound 11ea exhibited the most significant in vitro activity against R. cerealis (EC50 = 0.93 mu g/mL) with about 2-fold more potent than a previously reported lead compound A1 (EC50 = 2.01 mu g/mL), and about 11-fold more potent than the positive control/commercial succinate dehydrogenase inhibitor thifluzamide (EC50 = 23.09 mu g/mL). Structure-activity relationship analysis and molecular docking simulations indicated that the presence of difluoromethyl pyrazole-(m-benzene) carboxamide scaffold obviously increased the antifungal activity. The further enzymatic bioassay showed that both thifluzamide and compound 11ea displayed excellent SDH inhibitory effects, and fluorescence quenching analysis suggested that they may share the same target SDH. (C) 2021 Elsevier Masson SAS. All rights reserved.