Novel Isoxazole-Based Antifungal Drug Candidates

Microbiological communities have a significant impact on health and disease. <i>Candida</i> are ubiquitous fungal pathogens that colonize the mucosal surfaces of the genital, urinary, respiratory, and gastrointestinal tracts, as well as the oral cavity. If the immune system is inadequate, then <i>Candida</i> infections may pose a significant threat. Due to the limited number of clinically approved drugs for the treatment of <i>Candida albicans</i>-based infections and the rapid emergence of resistance to the existing antifungals, a novel series of isoxazole-based derivatives was synthesized and evaluated in vitro for their anti-<i>Candida</i> potential. Two compounds, <b>PUB14</b> and <b>PUB17</b>, displayed selective antifungal activity without negatively affecting beneficial microbiota, such as <i>Lactobacillus</i> sp., at the same time. Moreover, these compounds exhibited significantly lower cytotoxicity in comparison to conventionally applied local antimicrobial (octenidine dihydrochloride), indicating their potential for safe and effective clinical application in conditions such as vulvovaginal candidiasis. The selective antifungal activity of <b>PUB14</b> and <b>PUB17</b> against <i>C. albicans</i>, coupled with its absence of antibacterial effects and minimal cytotoxicity towards HeLa cells, suggests a targeted mechanism of action that warrants further investigation. Consideration of the need to search for new antifungal agents and the discovery of an antifungal potential drug that does not inhibit lactobacilli growth could be a potential strategy to prevent and combat vulvovaginal candidiasis. This striking capacity to eradicate biofilm formed by <i>Candida</i> reveals a new approach to eradicating biofilms and sheds light on isoxazole-based derivatives as promising anti-biofilm drugs.