Oxadiazolylthiazoles as novel and selective antifungal agents

Studying the structure-activity relationships (SAR) of oxadiazolylthiazole antibiotics unexpectedly led us to identify ethylenediamine- and propylenediamine-analogs as potential antimycotic novel lead structures. Replacement of the ethylenediamine moiety for the lead compound 7 with cis-diaminocyclohexyl group (compound 18) significantly enhanced the antifungal activity. In addition to the high safety margin of 18 against mammalian cells, it showed highly selective broad-spectrum activity against fungal cells without inhibiting the human normal microbiota. The antifungal activity of 18 was investigated against 20 drug-resistant clinically important fungi, including Candida species, Cryptococcus, and Aspergillus fumigatus strains. In addition to the low MIC values that mostly ranged between 0.125 and 2.0 μg/mL, compound 18 outperformed fluconazole in disrupting mature Candida biofilm. [Display omitted] •Replacement ethylenediamine motif with cis-diaminocyclohexane remarkably enhanced the antimycotic effect.•Stereochemistry of the two amines is critical as the trans-isomer is 64-times less active.•Compound 18 is effective vs. fluconazole-resistant albicans and non-albicans candida.•Compound 18 is more efficient in clearing cryptococcal infections than fluconazole.•Compound 18 is selective to fungal cells with antibiofilm activity.