TY - JOUR
T1 - LEGO-inspired drug design
T2 - unveiling a class of Benzo[d]thiazoles containing a 3,4-Dihydroxyphenyl moiety as plasma membrane H+-ATPase inhibitors
AU - Thanh Tung, Truong
AU - Dao, Trong Tuan
AU - Grifell Junyent, Marta
AU - Palmgren, Michael Broberg
AU - Günther-Pomorski, Thomas
AU - Fuglsang, Anja Thoe
AU - Christensen, Søren Brøgger
AU - Nielsen, John
PY - 2018/1/8
Y1 - 2018/1/8
N2 - 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.
AB - 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.
U2 - 10.1002/cmdc.201700635
DO - 10.1002/cmdc.201700635
M3 - Journal article
C2 - 29139202
SN - 1860-7179
VL - 13
JO - Farmaco, Edizione Pratica
JF - Farmaco, Edizione Pratica
IS - 1
ER -