Abstract
Multiple drug resistant fungi pose a serious threat to human health, therefore the development of completely new antimycotics is of paramount importance. The in vitro antifungal activity of the original, 1-amino-5-isocyanonaphthalenes (ICANs) was evaluated against reference strains of clinically important Candida species. Structure-activity studies revealed that the naphthalene core and the isocyano- together with the amino moieties are all necessary to exert antifungal activity. 1,1-N-dimethylamino-5-isocyanonaphthalene (DIMICAN), the most promising candidate, was tested further in vitro against clinical isolates of Candida species, yielding a minimum inhibitory concentration (MIC) of 0.04–1.25 µg/mL. DIMICAN was found to be effective against intrinsically fluconazole resistant Candida krusei isolates, too. In vivo experiments were performed in a severly neutropenic murine model inoculated with a clinical strain of Candida albicans. Daily administration of 5 mg/kg DIMICAN intraperitoneally resulted in 80% survival even at day 13, whereas 100% of the control group died within six days. Based on these results, ICANs may become an effective clinical lead compound family against fungal pathogens.
Highlights
Invasive fungal infections cause 1.5 million deaths annually and may show a further increase in the following decades
Repeated experiments led to the same conclusion; the applied dye concentration was well below the LD50 determined for human cells. We assumed that these compounds may have antifungal effect, Candida albicans, one of the most common human pathogenic fungi was selected for further tests
HaCat cell cultures were infected with C. albicans and were treated with different concentrations of MICAN dissolved in DMSO
Summary
Invasive fungal infections cause 1.5 million deaths annually and may show a further increase in the following decades. Most of these infections are caused by Candida species, followed by Aspergillus and Cryptococcus neoformans [1,2,3]. The most recent antifungal compounds, the echinocandins were introduced almost twenty years ago and there are few new drugs in the pipeline in the following years [11]. The emergence of new, drug resistant pathogenic fungi, such as Candida auris pose a serious therapeutic challenge and highlights the need for new compounds with different mechanisms of action [12,13]
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