Investigation of thiazolidinedione derivatives for anti-diabetic screening: synthesis, in silico analysis, and in vivo evaluation

Background: Diabetics possess inadequate amounts of insulin to control high glucose levels. Current WHO research estimates that 382 million people have diabetes mellitus, and by 2035, 592 million will. Thiazolidinedione, a physiologically active heterocyclic molecule, including thiazolidine-2,4-dione, is being studied for its anti-diabetic action. Thiazolidinediones, a class of hypoglycaemic drugs used to treat noninsulin-dependent diabetes, were first discovered as insulin-sensitive tissue stimulators. Methodology: In-silico applications like Lipinski's rule of five and Molinspiration evaluate physicochemical characteristics, and Molegro Virtual Docker docks molecules. Additionally, compounds are screened in vivo using alloxan as a diabetes inducer and pioglitazone as a comparator medication. Result and Discussion: Docking results determine the interactions of derivatives with 5U5L's active site (H2, H3, H5, H7, H9, and H14). Compound H3 interacts with Cys285, Tyr327, Ser289, His323, and Ala278, whereas compound H14 involves Ser289, Leu353, Phe360, Cys285, and Tyr473 with the PPAR-γ receptor, yielding docking scores of -128.341 and -129.766, respectively, and an RMSD value of 2.55 Å. Docking results showed anti-diabetic effects for H3 and H14. In animal screening, both compounds demonstrated efficacy against alloxan-induced diabetes models, supporting their computational findings. Conclusion: Pioglitazone interacts with hydrogen bonds involving Ser342, Tyr473, Ser289, Glu291, and Leu228 with a docking score of -118.485, while its co-crystal ligand interacts with Tyr327 and Tyr473 with -121.439. This work demonstrates that the thiazolidinedione pharmacophore is crucial for the discovery of anti-diabetic drugs. Both compounds showed significant anti-diabetic effectiveness in computational and in vivo screening. Thus, more research could prove the compound's anti-diabetic properties.