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/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1101568

DOI=10.3389/fcimb.2023.1101568

ISSN=2235-2988

ABSTRACT=<p>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-(<italic>N</italic>,<italic>N</italic>-hexamethylene)amiloride (HMA), an inhibitor of human Na<sup>+</sup>/H<sup>+</sup> 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 <italic>Cryptococcus neoformans</italic> were identified. Hits from these series showed broad-spectrum activity against both basidiomycete and ascomycete fungal pathogens, including multidrug-resistant clinical isolates.</p>