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.

biphenyl; fungicidal activity; molecular docking; succinate dehydrogenase inhibitors; β-ketonitriles.