Structural Optimization of Antifungal Peptoids targeting <i>Candida albicans</i>

Fungal infections pose a significant global health threat, with rising antifungal resistance, high mortality rates, and limited treatment options. Peptoids offer a promising alternative to traditional antifungal agents due to their enhanced stability and bioavailability. This study sought to optimize the antifungal peptoid RMG9-11 through an iterative structure–activity relationship (SAR) approach, focusing on improving antifungal potency while minimizing cytotoxicity. A total of 50 derivatives were synthesized across four rounds of modification, incorporating diverse structural alterations. Several derivatives demonstrated enhanced antifungal activity, with five top-performing compounds exhibiting improved selectivity ratios and good efficacy against <i>Candida albicans</i>. Among them, 911-M12 emerged as the most promising candidate, displaying potent activity against multidrug resistant <i>C</i>. <i>albicans</i> (MIC = 3.13–6.25 μg/mL), <i>C</i>. <i>auris</i> (MIC = 3.13 μg/mL), and <i>C</i>. <i>neoformans</i> (MIC = 3.13 μg/mL) while maintaining low cytotoxicity (TD₅₀ = 145 μg/mL). These findings underscore the importance of SAR studies in antifungal peptoid development.