Design, Synthesis, and and Evaluation of Novel Fluconazole-Based Compounds with Promising Antifungal Activities.

Demand has arisen for developing new azole antifungal agents with the growth of the resistant rate of infective fungal species to current azole antifungals in recent years. Accordingly, the present study reports the synthesis of novel fluconazole (FLC) analogues bearing urea functionality that led to discovering new azole agents with promising antifungal activities. In particular, compounds and displayed broad-spectrum activity and superior antifungal capabilities compared to the standard drug FLC against sensitive and resistant (). The highly active compounds and had potent antibiofilm properties against FLC-resistant species. Additionally, these compounds exhibited very low toxicity for three mammalian cell lines and human red blood cells. Time-kill studies revealed that our synthesized compounds displayed a fungicidal mechanism toward fungal growth. Furthermore, a density functional theory (DFT) calculation, additional docking, and independent gradient model (IGM) studies were performed to analyze their structure-activity relationship (SAR) and to assess the molecular interactions in the related target protein. Finally, results represented a significant reduction in the tissue fungal burden and improvements in the survival rate in a mice model of systemic candidiasis along with and studies, demonstrating the therapeutic efficiency of compounds and as novel leads for candidiasis drug discovery.