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

摘要

We have conducted systematic structural modification, decon-struction, 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-re-sistant 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)acet- amides 7a-l, which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7d (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 μgmL~(-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.