Discovery of Bacillamide–Acylhydrazone Hybrids as Novel Fungicide Lead Compounds

To identify fungicide lead compounds with novel scaffolds and high efficacy, 33 novel bacillamide–acylhydrazone derivatives were successfully designed and synthesized by using a molecular hybridization strategy. The bioassay results showed that most of the target compounds exhibited promising inhibitory activity against B. cinerea. Among them, compound BAD-15 displayed the most potent antifungal activity with an EC50 value of 6.725 μg/mL. Furthermore, preliminary SAR analysis revealed that the R group in hydrazine fragments exerts a significant influence on antifungal potency. Studying the molecular mechanism by morphological observation and transcriptome analyses revealed that BAD-15 may inhibit the activity of copper ion transmembrane transporters, leading to disrupted copper ion homeostasis and subsequent suppression of fungal growth. The present work indicates that bacillamide–acylhydrazone has potential as a novel scaffold for the development of fungicides, and compound BAD-15 may serve as a potential lead compound for the further development of novel fungicides.