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T.T. Tung, T.T. Dao, M.G. Junyent, M. Palmgren, T. Günther-Pomorski, A.T. Fuglsang, S.B. Christensen, and J. Nielsen (2018).
LEGO-inspired drug design: unveiling of the novel class of benzo[d]thiazole containing a 3,4-dihydroxyphenyl moiety as plasma membrane H⁺-ATPase inhibitors.
ChemMedChem 13(1): 37–47.
doi: 10.1002/cmdc.201700635

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 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 of 8 µM in an in vitro plasma membrane H⁺-ATPase assay. These compounds also strongly inhibited the action of proton pumping when Pma1p was reconstituted into liposomes. Compound 38 showed inhibitory activities on the growth of Candida albicans and Saccharomyces cerevisiae, which could be correlated and substantiated to the ability to inhibit Pma1p in vitro.