Synthesis, antifungal activity, and mechanism of action of nicotinohydrazides bearing a biphenyl fragment as potential broad‐spectrum fungicides

BACKGROUND With increasing resistance to traditional fungicides and growing environmental concerns, it is crucial to develop novel succinate dehydrogenase inhibitors to enhance disease management and support sustainable agriculture. RESULTS This study systematically designed and synthesized a series of nicotinohydrazides bearing a biphenyl fragment, evaluating their antifungal activity against six plant pathogenic fungi. The results demonstrated that their fungicidal spectrum significantly surpasses boscalid and carbendazim. Utilizing a palladium‐catalyzed cross‐coupling strategy, combined with diazotization‐reduction and dehydration condensation reactions, we successfully synthesized 35 target compounds ( F1 – F18 , G1 – G17 ). Antifungal assays revealed that most compounds exhibited more than 80% inhibition against the tested fungi at a concentration of 20 mg/L, particularly compound F17 , which showed a half‐maximal effective concentrations value ranging from 0.33 to 2.77 mg/L and achieved an efficacy of 89.94% against Sclerotinia sclerotiorum on canola leaves at a concentration of 200 mg/L. Mechanistic investigations indicated that F17 exerts its antifungal effects through multiple mechanisms, including the inhibition of succinate dehydrogenase, disruption of cell membranes and induction of oxidative damage. Toxicity predictions and cytotoxicity assays assessed the safety of this series of compounds. Density functional theory and molecular electrostatic potential analyses elucidated the reasons for the high activity of F17 . CONCLUSION Nicotinohydrazide derivatives exhibit a broader spectrum of antifungal activity than traditional inhibitors, and their multiple mechanisms of action provide a theoretical basis for further structural optimization and the design of novel agrochemicals.