Design, Synthesis, and Antifungal Structure-Activity Relationship of Hydrazide Derivatives Containing a Cyclopropyl...

To discover novel antifungal agents with unique scaffolds for crop protection, a series of 23 hydrazide derivatives containing a cyclopropyl group, including 14 new chemical entities, were designed, synthesized, and evaluated for their antifungal activity against eight phytopathogenic fungi. The in vitro bioassay results at 50 µg/mL revealed that most target compounds exhibited moderate to excellent antifungal activities. Notably, three compounds (4, 6, 7) displayed the most potent broad-spectrum activity with inhibition rates of 95.0%-100.0% against all eight tested fungi. Their EC₅₀ values were below 10 µg/mL against most fungi. SEM analysis revealed that the parent compound 1 caused pronounced morphological alterations in A. alternata mycelia, including shrinkage, collapse, and irregular distortion, providing a preliminary indication of the cellular effect of the series. Molecular docking of compound 1 with succinate dehydrogenase (SDH) generated a plausible binding model, suggesting SDH as a potential target candidate for this series, pending direct enzymatic validation. SAR analysis demonstrated that the phenyl ring was consistently associated with high activity, and para-substitution with halogen atoms is favorable for enhancing antifungal activity. These findings suggest that cyclopropyl-containing hydrazide derivatives, particularly compounds 4, 6, and 7, represent promising lead candidates for the development of novel antifungal agents.