LEGO‐Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4‐Dihydroxyphenyl Moiety as Plasma Membrane H+‐ATPase Inhibitors

• Published in: ChemMedChem 2018-01, Vol.13 (1), p.37-47
• Main Authors: Tung, Truong‐Thanh, Dao, Trong T., Junyent, Marta G., Palmgren, Michael, Günther‐Pomorski, Thomas, Fuglsang, Anja T., Christensen, Søren B., Nielsen, John
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - metabolism; Antifungal Agents - pharmacology; antifungal compounds; benzo[d]thiazoles; Candida albicans - drug effects; Candida albicans - enzymology; Cell Membrane - metabolism; Drug Design; Drug development; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; fungal plasma membrane H+-ATPase (Pma1p); Fungal Proteins - antagonists & inhibitors; Fungal Proteins - metabolism; Fungi; Fungicides; H+-transporting ATPase; Hydrogen; Inhibitors; Inhibitory Concentration 50; Kinetics; Liposomes; Molecular structure; Proton-Translocating ATPases - antagonists & inhibitors; Proton-Translocating ATPases - metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology; Structure-Activity Relationship; Thiazoles; Thiazoles - chemistry
• ISSN: 1860-7179; 1860-7187
• 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 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. Toy story: A LEGO‐inspired fragment assembly strategy for drug design, synthesis, and discovery is described. With this method, a series of benzo[d]thiazoles containing a 3,4‐dihydroxyphenyl moiety was found to inhibit fungal plasma membrane H+‐ATPase (Pma1p), with the most potent IC50 value of 8 μm (Ki=6 μm) in an in vitro assay. Structure–activity relationships were established. This LEGO design method will open new ways for the discovery of novel inhibitors for less studied targets.