Thiazolidine-2, 4-Diones as Non-Hepatotoxic Tri-action Drug Candidates: Design, Synthesis, Characterization, Biological Evaluation and Docking Studies

Abstract

Background: Thiazolidine-2, 4-diones and their derivatives are well-established chemical class of compounds that express their pharmacological actions through insulin sensitization and enhanced glucose utilization in peripheral tissues. In the current research different approaches have been employed to synthesize thiazolidine-2, 4-dione derivatives and these synthesized compounds were chemically characterized for the establishment of their chemical structures. Method: A series of thiazolidine-2, 4-dione (TZD) derivatives, scheme I (3A-3V) 22 compounds were synthesized and characterized by FT-IR, 1H NMR and mass spectral analysis. The title compounds were screened for their in vitro and in vivo anti-diabetic, antioxidant, and cytotoxicity studies. In vivo antihyperglycemic effect was assessed by measuring plasma glucose (PG) levels in alloxan-induced type II diabetic rat models. The synthesized TZD derivatives were evaluated for hepatotoxicity and pancreatic tissue integrity. Antioxidant activity was evaluated by the DPPH method and H2O2 method. Thiazolidinedione derivatives were subjected to predict free energy of binding towards target PPARγ, using rosiglitazone as the reference compound for molecular docking visualization through FlexX docking program. Molecular docking studies are also performed for understanding the binding of ligand to receptor. Results: The compound 3V 4-(5-(naphthalen-1-ylmethylene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better blood glucose lowering activity than that of the standard drug rosiglitazone. Compound 3T and 3U exhibited potent antioxidant activity. Among the tested compounds for cytotoxicity using an MTT assay, compound 3H 5-(4-chlorobenzylidene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better viability and cytotoxicity activity. From selected anti-diabetic targets, the proposed derivatives exhibited better interaction with PPARγ receptor, for example while rosiglitazone showed docking score of -19.891 kJ/mol, compound 3V exhibited highest docking score of -31.6617 kJ/mol. Conclusion: Computational molecular docking study demonstrated the selectivity and provided a binding model for the further refinement of this chemotype. Therefore, this series of thiazolidine-2, 4-diones derivatives (3A–3V) have considerable promise for development as potential antihyperglycemic and hypolipidemic agents.