Graphical Build it better: Structural optimization of berberine led to the identification of the novel scaffold of N -(2-(benzo[ d ][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acetamides 7 a – l , which exhibited remarkable in vitro synergistic antifungal activity against fluconazole-resistant Candida albicans in combination with fluconazole. Compound 7 d exhibited much lower cytotoxicity than berberine toward human umbilical vein endothelial cells. We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole-resistant Candida albicans. A structure–activity relationship study of 95 analogues led us to identify the novel scaffold of N -(2-(benzo[ d ][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acetamides 7 a – l , which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d ( N -(2-(benzo[ d ][1,3]dioxol-5-yl)ethyl)-2-(2-fluorophenyl)acetamide) significantly decreased the MIC 80 values of fluconazole from 128.0 μg mL −1 to 0.5 μg mL −1 against fluconazole-resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells.
Over the past several decades, invasive fungal infections, especially candidiasis, have caused dramatic morbidity and mortality due to ineffective antifungal drugs and severe drug resistance. Herein, new BRD4–histone deacetylase (HDAC) inhibitors were designed to restore the susceptibility of Candida albicans (C. albicans) to fluconazole (FLC). Interestingly, several compounds showed excellent selectivity against fungal HDACs. In particular, compound B2 showed excellent synergistic effect with FLC against resistant C. albicans (FICI = 0.063) with high selectivity against fungal HDACs (SI = 1653) and low cytotoxicity. Compound B2 effectively synergized with FLC and prevented biofilm formation and morphological transition in resistant C. albicans, potentiating the antifungal activity of FLC in vivo and significantly reducing kidney fungal loads. Thus, this drug combination is promising in the treatment of resistant C. albicans infections.
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