Design, Synthesis, and Antifungal Evaluation of Diverse Heterocyclic Hydrazide Derivatives As Potential Succinate Dehydrogenase Inhibitors

Plant pathogenic fungi pose a significant threat to agricultural production, necessitating the development of new and more effective fungicides. The ring replacement strategy has emerged as a highly successful approach in molecular design. In this study, we employed the ring replacement strategy to successfully design and synthesize 32 novel hydrazide derivatives containing diverse heterocycles, such as thiazole, isoxazole, pyrazole, thiadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, thiophene, pyridine, and pyrazine. Their antifungal activities were evaluated and . Bioassay results revealed that most of the title compounds displayed remarkable antifungal activities against four tested phytopathogenic fungi, including , , , and . Especially, compound displayed a broad spectrum of antifungal activity against , , , and , with the corresponding EC values of 0.12, 4.48, 0.33, and 0.15 μg/mL, respectively. In the antifungal growth assay, compound displayed a protection efficacy of 75.5% against Fusarium head blight (FHB) at a concentration of 200 μg/mL. In another antifungal activity evaluation, compound exhibited a noteworthy protective efficacy of 92.0% against rape Sclerotinia rot (RSR) at a concentration of 100 μg/mL, which was comparable to the positive control tebuconazole (97.5%). The existing results suggest that compound has a broad-spectrum antifungal activity. Electron microscopy observations showed that compound might cause mycelial abnormalities and organelle damage in . Moreover, in the enzyme assay, we found that the target compounds , , and displayed significant inhibitory effects toward succinate dehydrogenase, with the corresponding IC values of 1.62, 1.74, and 1.96 μM, respectively, which were superior to that of boscalid (IC = 2.38 μM). Additionally, molecular docking and molecular dynamics simulation results revealed that compounds , , and have the capacity to bind in the active pocket of succinate dehydrogenase (SDH), establishing hydrogen-bonding interactions with neighboring amino acid residues.