The fungal plasma membrane H+-ATPase(Pma1p)isapotential target for the discovery of new antifungal agents. Surprisingly,nostructure–activity rela tionship studies for small molecules targeting Pma1p have been reported. Herein, we disclose aLEGO-inspired fragmentassembly strategy for the design,
synthesis, and discovery of benzo[d]thiazoles containing a3,4-dihydroxyphenyl moiety as potentialPma1p inhibitors. Aseries 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 mm in an in vitro plasma memb rane H+-ATPase assay.These compounds were also found to strongly inhibit the action of proton pumpingwhen Pma1p was reconstituted into liposomes. 1-(3,4-ihydroxyphenyl)-2-((6-(trifluoromethyl)-benzo[d]thiazol-2-yl)thio)ethan-one(compound 38)showed inhibitory activities on the growth of Candida albicans and Saccharomyces cerevisiae ,which could be correlated andsubstantiated with the ability to inhibitPma1p in vitro.