Alpha-glucosidase inhibitory and hypoglycemic effects of imidazole-bearing thioquinoline derivatives with different substituents: In silico, in vitro, and in vivo evaluations

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of alpha-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as alpha-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 +/- 0.2 to 102.1 +/- 4.9 mu M) compared to the standard drug acarbose (IC50 = 750.0 +/- 5.0 mu M). 8g as the most potent analog, indicating a competitive inhibition with K-i = 9.66 mu M. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against alpha-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an alpha-glucosidase inhibitor for improving blood sugar control and metabolic health.