LEGO-inspired drug design: unveiling a class of Benzo[d]thiazoles containing a 3,4-Dihydroxyphenyl moiety as plasma membrane H+-ATPase inhibitors

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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.
Original languageEnglish
Issue number1
Number of pages11
Publication statusPublished - 2018

ID: 188125452