Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt.
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt.
Eur J Med Chem. 2024 Apr 5;269:116279. doi: 10.1016/j.ejmech.2024.116279. Epub 2024 Feb 29.
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 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, 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 PPARɣ binding site.
在目前的研究中，设计、合成了两个系列的新型噻唑烷-4-酮苯磺酰胺芳甲叉杂合 9a-l 和 10a-f，并对其过氧化物酶体增殖物激活受体γ（PPARγ）激动活性进行了体外测试。苯乙基噻唑烷-4-酮磺酰胺 9l 表现出最高的 PPARγ 激活率为 41.7%。而 3-甲氧基-和 4-甲基-4-苄氧基噻唑烷-4-酮磺酰胺 9i 和 9k 则分别表现出 31.7%和 32.8%的适度 PPARγ 激活率。此外，3-甲氧基-3-苄氧基噻唑烷-4-酮磺酰胺 10d 的 PPARγ 激活率为 33.7%，与吡格列酮相比。化合物 9b、9i、9k、9l 和 10d 对 PPARγ 的选择性高于 PPARδ 和 PPARα 同工型。在 HepG-2 细胞中进行了免疫组织化学研究，以确认最活跃化合物的 PPARγ 蛋白表达。化合物 9i、9k 和 10d 的 PPARγ 表达高于吡格列酮。还进行了药理学研究，以确定 36mg/kg 剂量下在大鼠中的抗糖尿病活性，结果表明化合物 9i 和 10d 改善了胰岛素分泌和抗糖尿病作用。3-甲氧基-4-苄氧基噻唑烷-4-酮磺酰胺 9i 显示出比吡格列酮更好的抗糖尿病活性。此外，它使血糖胰岛素增加了 4 倍，C 肽水平增加了 48.8%，并提高了胰岛素敏感性。此外，化合物 9i 通过降低肝血清酶、恢复总蛋白和肾功能，改善了糖尿病并发症。此外，它还对抗氧化应激状态并发挥抗高脂血症作用。化合物 9i 通过使一些参数正常化，并改善 STZ 诱导的糖尿病引起的胰腺、肝脏和肾脏组织病理学改变，表现出更好的活性。还进行了新合成化合物的分子对接研究、分子动力学模拟和蛋白质配体相互作用分析，以研究它们在 PPARγ 结合位点的预测结合模式和能量。
