The fungal plasma membrane H+‐ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure–activity relationship studies for small molecules targeting Pma1p have been reported.… Click to show full abstract
The fungal plasma membrane H+‐ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure–activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO‐inspired fragment assembly strategy for the design, synthesis, and discovery of benzo[d]thiazoles containing a 3,4‐dihydroxyphenyl moiety as potential Pma1p inhibitors. A series of 2‐(benzo[d]thiazol‐2‐ylthio)‐1‐(3,4‐dihydroxyphenyl)ethanones was found to inhibit Pma1p, with the most potent IC50 value of 8 μm in an in vitro plasma membrane H+‐ATPase assay. These compounds were also found to strongly inhibit the action of proton pumping when Pma1p was reconstituted into liposomes. 1‐(3,4‐Dihydroxyphenyl)‐2‐((6‐(trifluoromethyl)benzo[d]thiazol‐2‐yl)thio)ethan‐1‐one (compound 38) showed inhibitory activities on the growth of Candida albicans and Saccharomyces cerevisiae, which could be correlated and substantiated with the ability to inhibit Pma1p in vitro.
               
Click one of the above tabs to view related content.