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

Eur J Med Chem. 2024 Feb 29;269:116279. doi: 10.1016/j.ejmech.2024.116279. Online ahead of print.ABSTRACTIn 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 PPARɣ agonistic activity. The phenethyl thiazolidin-4-one sulphonamide 9l showed the highest PPARɣ activation % by 41.7%. Whereas, the 3-methoxy- and 4-methyl-4-benzyloxy thiazolidin-4-one sulphonamides 9i, and 9k revealed moderate PPARɣ activation % of 31.7, and 32.8%, respectively, in addition, the 3-methoxy-3-benzyloxy thiazolidin-4-one sulphonamide 10d showed PPARɣ activation % of 33.7% compared to pioglitazone. Compounds 9b, 9i, 9k, 9l, and 10d revealed higher selectivity to PPARɣ over the PPARδ, and PPARα isoforms. An immunohistochemical study was performed in HepG-2 cells to confirm the PPARɣ protein expression for the most active compounds. Compounds 9i, 9k, and 10d showed higher PPARɣ 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,...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research