In vitro dual-target activities and in vivo antidiabetic effect of 3-hydroxy- N -( p -hydroxy-phenethyl) phthalimide in high-fat diet and streptozotocin-induced diabetic golden hamsters

The 3-hydroxy-N-(p-hydroxy-phenethyl) phthalimide (HNHP), which showed in vitro peroxisome proliferator-activated receptor-γ (PPAR-γ) activation and in vivo anti-inflammatory effect in our previous study, was speculated to be a dual-target lead compound because similar structures exhibited α-glucosidase inhibitory activities. To investigate the dual targeting potential, molecular docking of HNHP was performed targeting on PPAR-γ and α-glucosidase, and HNHP was found to bind with dual targets in the known active sites with relatively high affinities. The in vitro α-glucosidase inhibitory evaluation showed that HNHP inhibited the enzyme (IC50 = 0.669 µM) better than acarbose (IC50 = 49.133 µM). For in vivo antidiabetic activity study, type 2 diabetes mellitus was induced by high-fat diet (20%) and streptozotocin (30 mg/kg) in golden hamsters. The diabetic hamsters were administered with different doses (1, 2, 4 mg/kg/day) of HNHP and rosiglitazone (1 mg/kg/day, positive control) for consecutive 14 days, respectively. Compared with rosiglitazone, HNHP significantly increased the insulin sensitivity, while the fasting blood glucose, glycated hemoglobin Alc, urine sugar, body weight, food/water intake, and lipid profile of media-dose (2 mg/kg/day) group golden hamsters were significantly normalized. Furthermore, pathological investigation found that the media-dose of HNHP showed the best protection on pancreatic tissue. These findings indicated that the PPAR-γ activator HNHP possessed in vitro α-glucosidase inhibitory and in vivo antidiabetic activities. Thereby, HNHP would serve as a new dual-target optimization lead.