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 <b>A37</b> demonstrated superior potency against <i>Rhizoctonia solani</i>, with an EC₅₀ value of 0.0144 μg/mL, more potent than the commercial fungicide fluxapyroxad (EC₅₀ = 0.0270 μg/mL). <i>In vivo</i> assays demonstrated that <b>A37</b> exhibited good protective activity against rice sheath blight. Enzyme inhibition activity assays revealed that <b>A37</b> was a potent inhibitor of succinate dehydrogenase (SDH), with an IC₅₀ value of 0.0263 μM. Docking studies within <i>R. solani</i> SDH indicated that <b>A37</b> effectively binds into the ubiquinone site mainly through hydrogen-bond and cation-π and π-π interactions. The identified optimal pyrazole-β-ketonitrile compound <b>A37</b>, containing a biphenyl structural motif, served as a potent lead for further structural optimization as a potential agricultural SDH inhibitor fungicide.