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We recently identified 5-(<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>-hexamethylene)amiloride (HMA), an inhibitor of human Na<jats:sup>+<\/jats:sup>\/H<jats:sup>+<\/jats: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 <jats:italic>Cryptococcus neoformans<\/jats:italic> were identified. Hits from these series showed broad-spectrum activity against both basidiomycete and ascomycete fungal pathogens, including multidrug-resistant clinical isolates.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1101568","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T09:20:24Z","timestamp":1676625624000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Antifungal activity of 6-substituted amiloride and hexamethylene amiloride (HMA) analogs"],"prefix":"10.3389","volume":"13","author":[{"given":"Kiem","family":"Vu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin J.","family":"Buckley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard S.","family":"Bujaroski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Blumwald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Kelso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angie","family":"Gelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2832","DOI":"10.12688\/f1000research.10327.2","article-title":"Candida antifungal drug resistance in sub-Saharan African populations: A systematic review","volume":"5","author":"Africa","year":"2016","journal-title":"F1000Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"C131","DOI":"10.1152\/ajpcell.1982.242.3.C131","article-title":"Amiloride: A molecular probe of sodium transport in tissues and cells","volume":"242","author":"Benos","year":"1982","journal-title":"Am. 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