Synthesis of SGLT2 inhibitor <i>O</i>-glucoside derivatives for enhancing anti-heart failure activity

SGLT2 inhibitors were derived from the natural product phlorizin and were used clinically to treat heart failure with preserved ejection fraction (HFpEF). In this study, based on phlorizin as the lead compound, tyramine moiety was introduced while retaining the pharmacophoric glucoside, thereby enhancing SGLT2 protein inhibitory activity and improving gastrointestinal absorption properties. We synthesized 11 new <i>O</i>-glucoside derivatives and evaluated their anti-heart failure activities. Results showed that compound D4 significantly increased the inhibition rate of the SGLT2 protein and anti-heart failure activity compared with empagliflozin and phlorizin and increased the ATP content in the impaired cardiomyocytes, which exhibited the best inhibition effect on SOD enzymes. According to the docking scores, it was speculated that compound D4 could treat heart failure by inhibiting cellular oxidative stress and reducing ROS and lipid peroxidation. The pharmacokinetic prediction results showed that compound D4 had good plasma protein binding force and hydrophilicity.