The antihyperglycemic potential of pyraozolobenzothiazine 1,1-dioxide novel derivative in mice using integrated molecular pharmacological approach

Abstract

Diabetes Mellitus (DM) is a extensively studied metabolic disease characterized by elevated blood sugar levels caused by inadequate insulin production, which subsequently leads to hyperglycemia. This study was intended to investigate the in silico, in vitro, and in vivo antidiabetic potential of pyrazolobenzothiazine derivatives. Molecular docking of pyrazolobenzothiazine derivatives was performed against α-glucosidase and α-amylase and compounds were selected based on docking score, bonding interactions and low root mean square deviation (RMSD). In vitro enzyme inhibition assay against α-glucosidase and α-amylase was performed using p-nitrophenyl- α -D-glucopyranoside (PNPG) and starch substrate. Synthetic compound S1 exhibits little conformational changes during MD simulation run at 100ns. S1 also revealed effective IC50 values for α-glucosidase (3.91 µM) and α-amylase (8.89 µM) and an enzyme kinetic study showed low ki (-0.186, -1.267) and ki’ (-0.691, -1.78) values with the competitive type of inhibition for both enzymes α-glucosidase and α-amylase, respectively. Moreover, studies were conducted to check the effect of the synthetic compound in a mouse model. A low necrosis rate was observed in the liver, kidney, and pancreas through histology analysis performed on mice. Compound S1 also exhibited good biochemical profile with lower sugar level (110–115 mg/dL), increased insulin level (25–30 µM/L), and low level of cholesterol (85mg/dL) and creatinine (0.6 mg/dL) in blood. The treated mice group also exhibited a low % of glycated hemoglobin (3%). This study concludes that S1 is a new antidiabetic agent that helps lower blood glucose levels and minimizes the complications associated with type II diabetes.