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

Abstract

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.

Drug Discovery and Development on Pma1, Where Are We Now? A Critical Review from 1995 to 2022

“…For over 25 years, only 17 notable studies of chemical agents targeting Pma1 for antifungal purposes were reported. Thioether: possible oxidation in the cell [34]…”

“…In 2018, our group has reported an alternative drug design method based on the LEGO concept called: HFSA-SDOS (from hypothesis-based fragment selection and assembly (HFSA), specific biological relevant scaffold-based diversity-oriented synthesis (SDOS) to rational design) (Figure 17). [34] In this research, the combination of privileged-scaffolds selection and diversity-oriented synthesis has led to the identification of the series of benzo[d]thiazoles containing a 3,4dihydroxyphenyl moiety as potent Pma1 inhibitors. 16 compounds (68-83) were synthesized with IC 50 values ranging from 8 μM to 36 μM (Table 5).…”

“…In 2018, our group has reported an alternative drug design method based on the LEGO concept called: HFSA‐SDOS (from hypothesis‐based fragment selection and assembly (HFSA), specific biological relevant scaffold‐based diversity‐oriented synthesis (SDOS) to rational design) (Figure 17). [34] …”

“…IC 50 values for compounds 68-83 determined from Pma1 ATPase activity measurements. Reproduced from ref [34]. with permission.…”

2-Mercaptoimidazolium halides: structural diversity, stability and spontaneous racemisation

“…Azolium heterocycles are not only present in natural products, but also in countless substances of technical and medicinal importance. [16][17][18][19][20][21][22] The 2-thionated derivatives show valuable biological, e.g. anti-thyroid, properties.…”