Selected N-substituted benzisoselenazol-3(2H)-ones possess anti-mycotic activity in vitro and in a mouse model of vulvovaginal candidiasis
Prof Blase Billack
New Advances in Medicinal Chemistry: Bioactive Compounds and Exploitable Targets
Host Anti-Cancer Agents in Medicinal Chemistry, Bentham Science Publishers (United Arab Emirates) |
DateFriday, June 20, 2025 1:00 PM to 1:30 PM (UTC) |
Live eventThe live event and other events in this series can be joined through this page. |
The global rise of virulent and drug-resistant Candida albicans strains has intensified the need for novel antifungal agents, especially as fluconazole (FLU) resistance increases in susceptible populations. Ebselen (EB), an organoselenium compound, has emerged as a promising candidate due to its inhibition of the fungal plasma membrane H⁺-ATPase (Pma1p), a target not addressed by current antifungals. However, EB’s poor solubility and off-target effects in mammalian systems limit its therapeutic potential. To overcome these challenges, our studies pursued two parallel strategies: the development of EB nanoformulations and the synthesis of novel EB analogs.
EB-loaded self-nanoemulsifying preconcentrate (EB-SNEP) demonstrated potent antifungal activity in a murine vulvovaginal candidiasis (VVC) model, significantly reducing fungal burden (~800-fold) without signs of toxicity in host tissues or probiotic flora. Concurrently, libraries of EB analogs, including G- and CHB-series compounds, were screened in vitro for activity against both FLU-sensitive and -resistant C. albicans strains. Compounds such as G20 and CHB6 showed superior efficacy (MIC as low as 3.1 µM) and targeted Pma1p-dependent acidification mechanisms. Although some analogs displayed slightly reduced growth inhibition relative to EB, they may offer better host tolerability by minimizing non-specific interactions.
Taken together, our findings support organoselenium-based inhibitors as a compelling class of antifungal agents. Both EB nanoformulations and selected analogs warrant further development as treatments for FLU-resistant candidiasis, with the dual benefits of novel target specificity and improved delivery profiles.