Pyrimidinetrione‐imidazoles as a Unique Structural Type of Potential Agents towards Candida Albicans: Design, Synthesis and Biological Evaluation

Abstract 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 series of pyrimidinetrione‐imidazole conjugates as potentially antifungal agents were developed. Bioassays manifested that 4‐fluobenzyl pyrimidinetrione imidazole 5 f 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 5 f 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 5 f and CYP51. In addition, hybrid 5 f might form 5 f ‐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 5 f endowed good blood compatibility as well as low cytotoxicity towards HeLa and HEK‐293T cells.