Synthesis, and biological evaluation of novel 4-thiazolidinone derivatives as promising antidiabetic agents: In silico and in vivo investigations.

A novel series of thiazolidinone derivatives (3a-3h) were synthesized through the condensation of 2-(arylamino)-thiazol-4-one and pyrrole-3-carbaldehyde utilizing glacial acetic acid as a medium and physical characterization was done by IR, 1H NMR and MS techniques. The compounds were subjected to In-silico analysis to gain insights into their potential biological activities, followed by molecular docking against the human PPAR-γ receptor (PDB ID: 4EMA). Remarkably, compound 3d (-8.67 kcal/mol) exhibited favorable binding interactions with the PPAR-γ receptor, surpassing the standard Rosiglitazone (-8.39 kcal/mol). The stability of the binding complex between compound 3d and the 4EMA structure was ascertained through RMSD, RMSF, and protein-ligand interactions. Additionally, the reliability of the docking results was corroborated by the MM-GBSA assay. The compounds cytotoxicity was evaluated in C2C12 myoblasts using the MTT assay, followed by glucose uptake assay. Additionally, the compounds were tested to confirm their PPAR-γ transcription activity. The investigation of in vivo antidiabetic activity was carried out utilizing a Streptozotocin-induced diabetic rat model, in parallel with the standard compound. Notably, compounds 3d and 3f demonstrated promising antidiabetic activity, consistent with the computational predictions. Administration of the thiazolidinone derivatives to diabetic rats led to significant reductions in SGOT and SGPT levels, indicative of the derivative's preventive potential against kidney and liver damage under diabetic conditions. Furthermore, the compounds exhibited the ability to markedly decrease levels of HDL, LDL, VLDL, cholesterol, triglycerides, and protein, suggesting their promising antidiabetic efficacy. The synthetic strategy adopted in this study not only facilitated the creation of a novel set of thiazolidinone derivatives but also showed some good insights for the development of future agents with enhanced therapeutic potential and reduced side effects, based on the foundational thiazolidinone scaffold.