Structure-based molecular design of fungicidal β-ketonitrile derivatives with biphenyl moiety as novel succinate dehydrogenase inhibitors

Abstract

Succinate dehydrogenase inhibitor (SDHI) remains one of the most important subclasses of chemical fungicides for the effective control of plant diseases. β-Ketonitrile has been identified as a novel pharmacophoric scaffold in SDHI fungicide research. In this study, a series of innovative biphenyl moiety containing β-ketonitrile compounds were rationally designed and synthetized based on the binding mode with SDH, aiming to strengthen the aromatic interactions and improve the fungicidal activities. The optimal target compounds B24 and B29 exhibited significant in vitro fungicidal activities against Rhizoctonia solani and Sclerotiorum sclerotiorum, with EC₅₀ values of 0.096 μg/mL and 0.072 μg/mL, respectively. Furthermore, the promising in vivo protective fungicidal activities were further validated, with B24 showed certain activity against rice sheath blight and B29 effectively controlled oilseed rape sclerotinia disease. In addition, both compounds demonstrated potent SDH inhibitory activities, with IC₅₀ values of 0.042 μM for B24 and 0.030 μM for B29, respectively. Molecular docking studies further demonstrated that the incorporation of biphenyl moieties enhanced ligand-target aromatic interactions through forming T-shaped π interaction or π-π stacking interaction, thereby contributing to the improved binding affinity and fungicidal activity. Compounds B24 and B29 also exhibited lower toxicities to non-target aquatic organisms, Danio rerio and Daphnia magna, compared to fluxapyroxad. The present work identified potential innovative β-ketonitrile fungicidal lead compounds for following optimization, giving valuable clues to the research and development of agricultural SDHI fungicides.