Cryptococcal meningitis is a fungal infection affecting the coverings of the brain (meninges). It is rare in healthy persons and affects those with poor immunity such as AIDS patients or on immunosuppressive treatments.
Cryptococcal meningitis is a fungal infection affecting the coverings of the brain (meninges). It is rare in healthy persons and affects those with poor immunity such as AIDS patients or on immunosuppressive treatments.
Fungal infections have become an increasing threat as a result of growing numbers of susceptible hosts and diminishing effectiveness of antifungal drugs due to multi-drug resistance. This reality underscores the need to develop novel drugs with unique mechanisms of action. We recently identified 5-(N,N-hexamethylene)amiloride (HMA), an inhibitor of human Na+/H+ exchanger isoform 1, as a promising scaffold for antifungal drug development. In this work, we carried out susceptibility testing of 45 6-substituted HMA and amiloride analogs against a panel of pathogenic fungi. A series of 6-(2-benzofuran)amiloride and HMA analogs that showed up to a 16-fold increase in activity against Cryptococcus neoformans were identified. Hits from these series showed broad-spectrum activity against both basidiomycete and ascomycete fungal pathogens, including multidrug-resistant clinical isolates.