Structure−Activity Relationship Profiling of Substituted N -Phthalimidopiperidine Analogs as Broad-Spectrum Antifungal Agents

Invasive fungal infections are a major and escalating global health concern, frequently resulting in life-threatening systemic infection. The combination of limited therapeutic options, increasing mortality, and the rapid emergence of multidrug-resistant fungal pathogens highlights the critical need for novel antifungal agents. With this goal in mind, a high-throughput screening assay identified SLB1122168, and a subsequent structure-activity relationship study led to more potent analogs, including SSD2032594, which demonstrated fungicidal activity with a minimum inhibitory concentration of 1-4 μg/mL against Candida auris, Cryptococcus neoformans, Aspergillus fumigatus, and Mucormycosis-causing species. Additionally, SSD2032594 showed potent activity against mature biofilms of C. auris and exhibited a negligible resistance tendency in vitro. Furthermore, SSD2032594 showed a survival benefit in the Caenorhabditis elegans nematode model of C. auris infection, resulting in a ∼30% higher survival rate. Taken together, these results highlight SSD2032594 as a candidate for antifungal drug development, targeting infections caused by different fungal pathogens.