Discovery of Novel Thiazolidinedione-Derivatives with Multi-Modal Antidiabetic Activities In Vitro and In Silico

Diabetes mellitus (DM) and related complications continue to exert a significant burden on health care systems globally. Although conventional pharmacological therapies are beneficial in the management of this metabolic condition, it is still necessary to seek novel potential molecules for its management. On this basis, we have synthesised and evaluated the anti-diabetic properties of four novel thiazolidinedione (TZD)-derivatives. The TZD derivatives were synthesised through the pharmacophore hybridisation strategy based on N-arylpyrrole and TZD. The resultant derivatives at different concentrations were screened against key enzymes of glucose metabolism and glucose utilisation in the liver (HEP-G2) cell line. Additionally, peroxisome proliferator-activated receptor-gamma activation was performed through docking studies. Docking of these molecules against PPAR-gamma predicted strong binding, similar to that of rosiglitazone. Hence, TZDD2 was able to increase glucose uptake in the liver cells as compared to the control. The enzymatic inhibition assays showed a relative inhibition activity; with all four derivatives exhibiting >= 50% inhibition activity in the alpha-amylase inhibition assay and a concentration dependent activity in the alpha-glucosidase inhibition assay. All four derivatives exhibited >= 30% inhibition in the aldose reductase inhibition assay, except TZDD1 at 10 mu g/mL. Interestingly, TZDD3 showed a decreasing inhibition activity. In the dipeptidyl peptidase-4 inhibition assay, TZDD2 and TZDD4 exhibited >= 20% inhibition activity.

Automated summary

Diabetes mellitus (DM) and its complications have a significant impact on healthcare systems worldwide. In this study, four novel thiazolidinedione (TZD)-derivatives were synthesized and evaluated for their anti-diabetic properties. The derivatives showed strong binding to peroxisome proliferator-activated receptor-gamma (PPAR-gamma), similar to rosiglitazone. TZDD2 increased glucose uptake in liver cells compared to control. The derivatives exhibited inhibition activity in various enzymatic assays, including alpha-amylase, alpha-glucosidase, aldose reductase, and dipeptidyl peptidase-4.