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

• Published in: Chemistry, an Asian journal Vol. 16; no. 11; pp. 1417 - 1429
• Main Authors: Sui, Yan‐Fei, Ansari, Mohammad Fawad, Zhou, Cheng‐He
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.06.2021
• Subjects: Antifungal; Biocompatibility; Chemistry; Conjugates; Depolarization; DNA; Fungicides; Imidazole; Membrane; Membranes; Molecular docking; Pyrimidinetrione; Toxicity; Membrane; Antifungal; Pyrimidinetrione; DNA; Imidazole
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.202100146

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. A unique type of potential antifungal pyrimidinetrione‐imidazole conjugates was developed, and their antifungal efficacy and possible action mechanisms were investigated.