Discovery of Novel Acethydrazide-Containing Flavonol Derivatives as Potential Antifungal Agents.

In this study, a series of novel hydrazide-containing flavonol derivatives was designed, synthesized, and evaluated for antifungal activity. In the antifungal assay, most of the target compounds exhibited potent antifungal activity against seven tested phytopathogenic fungi. In particular, compound showed the best antifungal activity against (EC = 0.170 μg/mL), outperforming carbendazim (EC = 0.360 μg/mL) and boscalid (EC = 1.36 μg/mL). Compound exhibited excellent antifungal activity against , , and with EC values of 0.590, 0.870, and 1.71 μg/mL, respectively. The experiments revealed that compounds and were potential novel agricultural antifungals. 3D quantitative structure-activity relationship (3D-QSAR) models were used to analyze the structure-activity relationships of these compounds. The analysis results indicated that introducing appropriate electronegative groups at position 4 of a benzene ring could effectively improve the anti- activity. In the antifungal mechanism study, scanning electron microscopy and transmission electron microscopy analyses revealed that disrupted the normal growth of hyphae by affecting the structural integrity of the cell membrane and cellular respiration. Furthermore, compound exhibited potent succinate dehydrogenase (SDH) inhibitory activity (IC = 8.42 μM), surpassing that of the SDH fungicide boscalid (IC = 15.6 μM). The molecular dynamics simulations and docking experiments suggested that compound can occupy the active site and form strong interactions with the key residues of SDH. Our findings have great potential for aiding future research on plant disease control in agriculture.