Design, synthesis and evaluation of biphenyl imidazole analogues as potent antifungal agents.

• 22 new compounds with biphenyl imidazole scaffolds were designed and synthesized. • Compound 12m showed better antifungal activity than fluconazole. • The structure-activity relationships of compounds were discussed. • Compound 12m exhibited low inhibition profiles for human cytochrome P450 isoforms. To further explore the structure activity relationships (SARs) of our previously discovered antifungal lead compound (1), a series of biphenyl imidazole analogues were designed, synthesized and evaluated for their in vitro antifungal activity. Many of the synthesized compounds showed excellent activity against Candida albicans and Candida tropicalis. Among these compounds, 2-F substituted analogue 12m displayed the most remarkable in vitro activity against C. albicans , C. neoformans , A. fumigatus and fluconazole-resistant C. alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and itraconazole. Notably, the compound 12m exhibited low inhibition profiles for various human cytochrome P450 isoforms and showed low toxicity to mammalian A549 cells and U87 cells. The SARs and binding mode established in this study will be useful for further lead optimization. [ABSTRACT FROM AUTHOR]