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Pyrimidinetrione-imidazoles as a unique structural type of potential agents towards Candida albicans: Design, synthesis and biological evaluation.

Substantial morbidity and mortality of fungal infections have aroused concerns all over the world, and common Candida spp. currently bring about severe systemic infections. A battery of pyrimidinetrione-imidazole conjugates as potentially antifungal agents was developed. Bioassays manifested that 4-fluobenzyl pyrimidinetrione imidazole 5f exerted favorable inhibition towards C. albicans (MIC = 0.002 mM), being 6.5 folds more active than clinical antifungal drug fluconazole (MIC = 0.013 mM). Preliminary mechanism research indicated that compound 5f could not only depolarize membrane potential but also permeabilize the membrane of C. albicans. Molecular docking was operated to simulate the interaction mode between molecule 5f and CYP51. In addition, hybrid 5f might form 5f-DNA supramolecular complex via intercalating into DNA. The interference of membrane and DNA might contribute to its fungicidal capacity with no obvious tendency to induce the resistance against C. albicans. Conjugate 5f endowed good blood compatibility as well as low cytotoxicity towards HeLa and HEK-293T cells.