Design, Synthesis, and Antifungal Activity of N'-Phenylpicolinohydrazide Derivatives as Potential Antifungal Agents

Discovery and development of novel antifungal agents featuring distinctive chemical scaffolds are of paramount importance for sustainable plant protection. In this study, a series of twenty-one N'-phenylpicolinohydrazide derivatives was designed and synthesized based on our previous work, characterized by spectroscopic analysis. Their antifungal activity was evaluated against nine plant pathogenic fungi, structure-activity relationships (SARs) were elucidated, and the action mechanism was investigated. The results showed that most of the compounds exhibited excellent antifungal activity, especially compounds B2-1 and B5-5, among which the EC₅₀ values for Fusarium graminearum were 1.107 and 0.974 µg/mL, respectively. SAR studies indicated that the carbohydrazide or ─C(Cl) ═ NNH─ fragment in this class of derivatives is the key pharmacophore for antifungal activity. SEM analyses revealed that compound B5-5 can significantly destroy mycelial morphology. Furthermore, molecular docking indicated that B5-5 can bind well with the ubiquinone-binding region of SDH. Thus, N'-Phenylpicolinohydrazide derivatives, especially B2-1 and B5-5, can be considered promising fungicide alternatives for plant protection. SUMMARY: A series of twenty-one N'-phenylpicolinohydrazide derivatives were synthesized. Compounds exhibiting potent and broad-spectrum antifungal activity were discovered. The antifungal mechanism of the compound B5-5 was elucidated. Some compounds, especially B2-1 and B5-5, as promising fungicide alternatives were found.