Abstract
ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active against Cryptococcus neoformans in vitro and had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.
Highlights
The incidence of invasive fungal infections has risen dramatically in recent decades
The three selected compounds and BHBM were resynthesized in our laboratory at high purity and used for further studies
D13 was selected to be tested in animal models of cryptococcosis, candidiasis, pulmonary aspergillosis, and pneumocystosis
Summary
The incidence of invasive fungal infections has risen dramatically in recent decades. Current major classes of antifungal drugs include azoles (e.g., fluconazole), polyenes (e.g., amphotericin B), and echinocandins (e.g., caspofungin) [20] These drugs come with their own range of challenges, such as nephrotoxicity, drug-drug interactions, narrow spectrum of activity, and resistance [21,22,23,24]. For these reasons, there is an urgent need for a new class of antifungal drugs targeting a different fungal pathway(s)
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