Design, Synthesis, and Biological Evaluation of Thioglucoside Analogues of Gliflozin as Potent New Gliflozin Drugs.

In this study, we have investigated the potential of two classes of thioglucoside analogues of gliflozins as antidiabetic drugs, one with substitutions of S-atoms in meta-positions (similar to C-glucoside SGLT2 inhibitors, TAGs A, B, and C) and the other with substitutions of S-atoms in ortho-positions (similar to O-glucoside SGLT2 inhibitors, TAGs D, E, F, and G). These TAGs were confirmed to show good stability against β-glucosidase and to have no acute toxicity to cultured cells. Most importantly, TAGs D, E, F, and G all showed high inhibitory activity against SGLT2 (IC50: 2.0-5.9 nM) and thus have great potential to be developed as new gliflozin drugs. Compared with the synthesis of C-glucoside gliflozins, the synthesis of TAGs is simple, efficient, and associated with low costs, high yields, and very mild reaction conditions.