Anti-Candida activity of simplified analogs of curcumin

Infections caused by Candida species have considerably increased in recent decades. However, the antifungal agents for the treatment of candidiasis are restricted to few classes of drugs, which have some therapeutic limitations, including high toxicity, low efficacy and resistance development. This perspective encouraged us to synthesize and evaluate a series of simplified analogs inspired by curcumin, a natural product with recognized antifungal activity. Among tested antifungal compounds, 3-hydroxy-dibenzylideneacetone (17) was the most active one against Candida species, with Minimum Inhibitory Concentration (MIC) values ranging from 7.8 to 31.2 µM. Candida albicans and Candida krusei were more susceptible to 17 than fluconazole. Compound 17 at sub-MIC was able to reduce C. albicans adhesion onto human gingival fibroblasts (HGF-1 cell line) and human epidermal keratinocytes (HaCaT cell line). Our investigations demonstrated the inhibition of 17 on C. albicans biofilm formation and preformed biofilm, when tested at MIC (31.2 µM) and 10 × MIC (312 µM) values. Combinations of 17 and amphotericin B or fluconazole showed synergistic effects against C. albicans, with Fractional Inhibitory Concentration Index (FICI) values of 0.5 and 0.2, respectively. Studies on the fungitoxicity dynamics of 17 indicated a dual mode of action, targeting C. albicans membrane and cell wall. Finally, 17 was more stable than curcumin in phosphate buffer and demonstrated low acute toxicity against Galleria mellonella larvae. These findings opened new avenues for the study of simplified analogs as anti-Candida agents based on the curcumin structure and bioactivity.