Preclinical evaluation of acylhydrazone SB-AF-1002 as a novel broad-spectrum antifungal agent

The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, narrow spectrum of activity, and more importantly for the consistent rise of fungal species that are intrinsically resistant or develop resistance due to the prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, BHBM and D13, we performed a SAR study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified as the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N'-(5-bromo-2-hydroxybenzylidene) benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis and aspergillosis. Specifically, animals treated with SB-AF-1002 survive the infection, but also show a clearing of key organs from fungal cells. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to the parent compound D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents, which warrants further development for the treatment of invasive fungal infections.