Abstract: OBJECTIVE To disclose the structure-activity relationships of polydatin and its derivatives by inhibiting SGLT2. METHODS Five compounds were synthesized through S_N2 substitution reaction and catalytic hydrogenation in the presence of Pd (OH)₂/C. The compounds were characterized by ¹H-NMR and HR-ESI-MS. The antihyperglycemic activity of the compounds were performed in vitro test taking 1-NBDG as the substrate in the uptake assay to evaluate the Na⁺-dependent glucose transport activities of SGLT2 and operated oral glucose tolerance test and urinary glucose excretion in vivo test. RESULTS Obtained 5 polydatin derivatives, characterized by ¹H-NMR and HR-ESI-MS. Polydatin and derivatives exhibited reasonable inhibition for SGLT2 in vitro test, especially 1b showed the best inhibitory activities in this series derivatives (the inhibition was 98.6% at the dose of 10^-5 mol·L^-1 against SGLT2). However, 1b played a rather weak activity of oral glucose tolerance test (OGTT) with only 11% at 120 mg·kg^-1 dose and urinary glucose excretion (UGE) with 122 mg per 200 g in diabetic SD rats, which was much lower than that in dapagliflozin. CONCLUSION Polydatin and its derivatives as O-aryl glycoside compounds have weaker inhibition of SGLT2 hypoglycemic activity, and its molecular structure has certain guiding significance for the subsequent design of new C-aryl glycoside SGLT2 inhibitors.