Synthesis, Molecular Docking Studies and in vitro and in vivo Hypolipidemic Activity of Thiazolidinedione Derivatives

Abstract

This work aimed to design, synthesize novel thiazolidinedione derivatives, which were tested for their antihyperlipidemic effects. Antihyperlipidemic activity was carried through in silico docking study for the 50 thiazolidinedione derivatives (SMI-IV-1 to 50 derivatives) in comparison with standard pioglitazone against the crystal structure of protein PPARgamma (PDB ID: 6QJ5) proteins. Based on the binding energy further, best three derivatives were selected and characterized with IR, NMR and MASS studies. Then, in vitro evaluation of each derivative's antihyperlipidemic activity was carried out by observing their effects on the reduction ability of mature 3T3-L1 adipocyte cells. These cells are susceptible to cytotoxicity because of their internal accumulation of lipids. The vitality of 3T3-L1 adipocytes was identified using the MTT assay. Finally, animal experiments were conducted in order to verify the antihyperlipidemic action of the substance in Wistar rats that had been genetically modified to develop hyperlipidemia. Initially, acute toxicity study was carried out and then based on further study was investigated. Simvastatin (4 mg/kg) was used as standard drug. All the selected three derivatives showed a reversal of the rise in blood triglycerides, cholesterol and LDL from 6 to 48 h and in VLDL from 24 h. All the derivatives showed satisfactory results but derivatives SMI-IV-23 followed by SMI-IV-4 and SMI-IV-31 were given very significant results in terms of binding energy and also in vitro, in vivo experiments. Overall, the results concluded that all the thiazolidinedione derivatives were potent against hyperlipidemic condition and among the all derivatives few derivatives were showed significant role as non-toxic and in mitigation of hyperlipidemia.