Discovery of Novel Flexible β-Ketonitrile Derivatives Bearing a Biphenyl Moiety as Potential Succinate Dehydrogenase Inhibitors

Plant pathogenic fungi pose a significant threat to global agriculture, highlighting an urgent need for the development of novel fungicides due to resistance issues. A series of pyrazole-β-ketonitrile compounds incorporating a biphenyl structure were designed and synthesized. Notably, compound A37 demonstrated superior potency against Rhizoctonia solani, with an EC50 value of 0.0144 μg/mL, more potent than the commercial fungicide fluxapyroxad (EC50 = 0.0270 μg/mL). In vivo assays demonstrated that A37 exhibited good protective activity against rice sheath blight. Enzyme inhibition activity assays revealed that A37 was a potent inhibitor of succinate dehydrogenase (SDH), with an IC50 value of 0.0263 μM. Docking studies within R. solani SDH indicated that A37 effectively binds into the ubiquinone site mainly through hydrogen-bond and cation−π and π–π interactions. The identified optimal pyrazole-β-ketonitrile compound A37, containing a biphenyl structural motif, served as a potent lead for further structural optimization as a potential agricultural SDH inhibitor fungicide.