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.