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LEGO‐Inspired Drug Design: Unveiling a Class of Benzo[ d ]thiazoles Containing a 3,4‐Dihydroxyphenyl Moiety as Plasma Membrane H + ‐ATPase Inhibitors
Author(s) -
Tung TruongThanh,
Dao Trong T.,
Junyent Marta G.,
Palmgren Michael,
GüntherPomorski Thomas,
Fuglsang Anja T.,
Christensen Søren B.,
Nielsen John
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700635
Subject(s) - moiety , stereochemistry , chemistry , thio , in vitro , candida albicans , trifluoromethyl , atpase , biochemistry , enzyme , biology , organic chemistry , genetics , alkyl
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 IC 50 value of 8 μ m 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.