Design, Synthesis, and Antifungal Structure‐Activity Relationship of Hydrazide Derivatives Containing a Cyclopropyl Group Against Phytopathogenic Fungi

ABSTRACT

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 EC ₅₀ 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.