# Discovery of Bacillamide–Acylhydrazone Hybrids as Novel Fungicide Lead Compounds

## TL;DR

Scientists designed and tested new fungicide compounds, finding BAD-15 as a promising lead that disrupts copper balance in fungi.

## Contribution

The study introduces bacillamide–acylhydrazone hybrids as a novel scaffold for fungicides with a unique mode of action.

## Key findings

- Compound BAD-15 showed potent antifungal activity with an EC50 of 6.725 μg/mL against B. cinerea.
- BAD-15 likely disrupts fungal growth by inhibiting copper ion transporters, affecting copper homeostasis.

## Abstract

This study reports the design and synthesis of 33 novel bacillamide–acylhydrazone derivatives based on the structural features of natural products, aiming to identify novel antifungal lead scaffolds. Antifungal activity screening led to the discovery of a promising lead compound, BAD-15, whose mechanism of action was subsequently preliminarily investigated. The results suggest that compound BAD-15 may inhibit copper ion transmembrane transporters, thereby disrupting copper homeostasis and ultimately suppressing fungal growth. This study establishes a theoretical foundation for the development of fungicides with novel modes of action, thereby contributing significant theoretical insights to antifungal agent research.

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.