Structural Optimization of Berberine as a Synergist to Restore Antifungal Activity of Fluconazole against Drug-Resistant Candida albicans

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 MIC80 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. 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.