Lead Optimization and Target Identification of Carboline Antifungal Agents

Cryptococcal meningitis is a severe invasive fungal infection that poses a significant global health burden due to the lack of effective treatment options. To address this, there is an urgent need to develop novel antifungal drugs and identify new antifungal targets to provide more effective therapeutic strategies. On the basis of our previously identified anticryptococcal lead compound <b>JYJ-19</b>, herein, four series of new derivatives were designed by scaffold hopping. Notably, hexahydroazepino[3,4-<i>b</i>]indole derivative <b>D2</b> exhibited favorable oral bioavailability (<i>F</i> = 47.13%) and potent antifungal activity both <i>in vitro</i> and <i>in vivo</i>, making it a promising oral antifungal candidate for the treatment of cryptococcal meningitis. Furthermore, we employed affinity-based protein profiling to identify the potential targets of the carboline derivatives. Proteomic analysis of a photoaffinity probe revealed that the SET domain-containing protein was the potential target. Taken together, this study provides a promising lead compound and potential drug target for future antifungal drug development.