Discovery of Bioactive Hydrazide Derivatives and Their Evaluation as Agricultural Fungicide Candidates

With the growing challenge of pathogen resistance and the continuous expansion of the global fungicide market, the discovery of novel fungicidal lead structures has become increasingly imperative. Inspired by the previously identified hydrazide moiety as a promising fungicidal pharmacophore, we designed and synthesized three novel series of hydrazide derivatives to further explore the effects of structural modifications on fungicidal activity and ecological safety. Most compounds exhibited excellent and broad-spectrum fungicidal activity, among which compound B5 achieved 100% inhibition rates at 50 μg/mL against six fungal pathogens, with EC 50 values, fungicidal spectrum, and in vivo preventive efficacy comparable to those of tebuconazole. Mechanistic studies revealed that compound B5 caused hyphal shriveling, lipid droplets disappearance, and reduced total lipid content in Rhizoctonia solani . qRT-PCR analysis indicated the downregulation of key genes in glycolysis/gluconeogenesis and lipid metabolism-related pathways, accompanied by upregulation in the steroid biosynthesis pathway. Ecotoxicological assessment demonstrated compound B5 was highly toxic to zebrafish, with a 100% mortality rate within 2 d at 10 μg/mL. Meanwhile, it degraded rapidly in alkaline environments, decreasing from 70 μg/mL to 5.5 μg/mL in 2 d, highlighting the need for further structural optimization. These findings will provide important theoretical guidance for the development of novel hydrazide-based fungicidal candidates. • Three series of novel hydrazide derivatives were designed and synthesized. • Compound B5 exhibited excellent and broad-spectrum fungicidal efficacy. • Compound B5 exerted its fungicidal effects by regulating lipid metabolism. • Modifications to the hydrazide bridge influence the toxicity and stability.