Cryptococcal infections remain a major cause of mortality worldwide due to the ability of Cryptococci to pass through the blood-brain barrier (BBB) causing lethal meningitis. The limited number of available therapeutics, which exhibit limited availability, severe toxicity and low tolerability, necessitates the development of new therapeutics. Investigating the antifungal activity of a novel series of naphthylthiazoles provided trans-diaminocyclohexyl derivative 18 with many advantageous attributes as a potential therapeutic for cryptococcal meningitis. Briefly, the antimycotic activity of 18 against cryptococcal strains was highly comparable to that of amphotericin-B and fluconazole with MIC values as low as 1 μg mL-1. Moreover, compound 18 possessed additional advantages over fluconazole; it significantly reduced the intracellular burden of Cryptococci and markedly inhibited cryptococcal biofilm formation. Initial PK assessment of 18 indicated its ability to reach the CNS after oral administration with high permeability, and it maintained therapeutic plasma concentrations for 18 h. Its antifungal activity extended to other clinically relevant strains, such as fluconazole-resistant C. auris.
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