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

ABSTRACT 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 EC 50 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.