AUTHOR=Vu Kiem, Buckley Benjamin J., Bujaroski Richard S., Blumwald Eduardo, Kelso Michael J., Gelli Angie TITLE=Antifungal activity of 6-substituted amiloride and hexamethylene amiloride (HMA) analogs JOURNAL=Frontiers in Cellular and Infection Microbiology VOLUME=13 YEAR=2023 URL=https://www.frontiersin.org/articles/10.3389/fcimb.2023.1101568 DOI=10.3389/fcimb.2023.1101568 ISSN=2235-2988 ABSTRACT=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.