Novel thiazolidin-4-one benzenesulfonamide hybrids as PPAR agonists: Design, synthesis and in vivo anti-diabetic evaluation

In the current study, two series of novel thiazolidin-4-one benzenesulfonamide arylidene hybrids 9a -l and 10a -f were designed, synthesized and tested in vitro for their PPARy agonistic activity. The phenethyl thiazolidin-4-one sulphonamide 9l showed the highest PPARy activation % by 41.7%. Whereas, the 3-methoxyand 4methyl-4-benzyloxy thiazolidin-4-one sulphonamides 9i, and 9k revealed moderate PPARy activation % of 31.7, and 32.8%, respectively, in addition, the 3-methoxy3-benzyloxy thiazolidin-4-one sulphonamide 10d showed PPARy activation % of 33.7% compared to pioglitazone. Compounds 9b, 9i, 9k, 9l, and 10d revealed higher selectivity to PPARy over the PPAR delta, and PPAR alpha isoforms. An immunohistochemical study was performed in HepG-2 cells to confirm the PPARy protein expression for the most active compounds. Compounds 9i, 9k, and 10d showed higher PPARy expression than that of pioglitazone. Pharmacological studies were also performed to determine the anti-diabetic activity in rats at a dose of 36 mg/kg, and it was revealed that compounds 9i and 10d improved insulin secretion as well as anti-diabetic effects. The 3-methoxy-4-benzyloxy thiazolidin-4-one sulphonamide 9i showed a better anti-diabetic activity than pioglitazone. Moreover, it showed a rise in blood insulin by 4-folds and C -peptide levels by 48.8%, as well as improved insulin sensitivity. Moreover, compound 9i improved diabetic complications as evidenced by decreasing liver serum enzymes, restoration of total protein and kidney functions. Besides, it combated oxidative stress status and exerted anti- hyperlipidemic effect. Compound 9i showed a superior activity by normalizing some parameters and amelioration of pancreatic, hepatic, and renal histopathological alterations caused by STZ-induction of diabetes. Molecular docking studies, molecular dynamic simulations, and protein ligand interaction analysis were also performed for the newly synthesized compounds to investigate their predicted binding pattern and energies in PPARy binding site.