Design, Synthesis, andIn VitroandIn VivoEvaluation of Novel Fluconazole-Based Compounds with Promising Antifungal Activities

Abstract

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, compounds8band8cdisplayed broad-spectrum activity and superiorin vitroantifungal capabilities compared to the standard drug FLC against sensitive and resistantCandida albicans(C. albicans). The highly active compounds8band8chad potent antibiofilm properties against FLC-resistantC. albicansspecies. 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,in vivoresults represented a significant reduction in the tissue fungal burden and improvements in the survival rate in a mice model of systemic candidiasis along within vitroandin silicostudies, demonstrating the therapeutic efficiency of compounds8band8cas novel leads for candidiasis drug discovery.