The incidence of invasive fungal infections has risen dramatically in the past 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 nineteen derivatives were highly active against Cryptococcus neoformans in vitro and had low toxicity on 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.
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