Nature-Derived Ferulic Acid Hybrids with Enhanced Antifungal and Antivirulence Activity Against Candida albicans

The high incidence of <i>Candida albicans</i> infections and the limited efficacy of current antifungal therapies highlight the need for new antifungal agents. In this study, we present a bio-based hybridization strategy aimed at enhancing the antifungal activity of natural product scaffolds, with a particular focus on <i>trans</i>-ferulic acid. A library of twenty-nine hybrid molecules was rationally generated by grafting naturally occurring lipophilic moieties onto either the phenolic or carboxylic acid functions of ferulic acid. The antifungal activity of these molecules was then assessed against <i>C. albicans</i>. While the parent natural compounds exhibited weak activity (MIC > 500 µM), several hybrid derivatives (ATF19, ATF20, and MB22) demonstrated enhanced potency, with MIC values of <50 µM. Esters of the carboxylic acid or phenol group were essential for activity, with the most potent effects observed for short linear or mildly branched lipophilic chains. These active compounds exerted a multifaceted anti-virulence effect, including mitochondrial membrane depolarization, inhibition of hyphal morphogenesis, alterations in cell wall composition, and strong suppression of biofilm formation. Additionally, lead compounds showed no detectable cytotoxicity in human macrophages and intestinal epithelial cells and significantly improved host survival in a <i>Caenorhabditis elegans</i> model of <i>C. albicans</i> infection. Overall, the ferulic acid, citronellol, and sinapic hybrid molecules emerged as promising lead compounds for the development of antifungals against <i>C. albicans</i>.