Background: Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. Objective: Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. Methods: After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. Results: LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 μM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. Conclusion: These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.

中文翻译：

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新型噻唑烷二酮喹啉衍生物的合成及其体外和计算机抗炎活性


背景：炎症是一系列复杂的防御相关反应。炎症级联反应产生各种促炎介质。这些促炎介质的产生不受控制会导致多种疾病，包括类风湿性关节炎、败血症和炎症性肠病。在文献中，喹啉和噻唑烷二酮核的抗炎作用已得到充分证实，无论是单独的还是与其他核相关的。杂化分子的合成是由于已知与药理活性相关的药效核的结合而获得更有效的分子的策略。目的：基于此，本工作介绍了噻唑烷二酮-喹啉分子杂化物的合成及其在炎症反应级联中细胞因子的调节中的作用。方法：合成和表征后，将化合物进行细胞活力测试 (MTT)、ELISA IFN-γ 和 TNF-α、脂肪形成分化以及与 PPARy 和 COX-2 靶标的分子对接测定。结果：LPSF/ZKD2 和 LPSF/ZKD7 显示 IFN-γ 和 TNF-α 浓度显着降低，且具有剂量依赖性行为。浓度为 50 μM 的 LPSF/ZKD4 显着降低 IL-6 表达。 LPSF/ZKD4 显示脂质积累在未处理组和阴性对照组之间存在显着差异，表明对 PPARγ 受体具有相关的激动作用。分子对接表明，所有合成的化合物均与PPARγe COX-2具有良好的亲和力，结合能接近-10,000 Kcal/mol。结论：这些结果表明，喹啉-噻唑烷二酮杂化物的合成可能是获得有希望的新型抗炎药物候选物的有用策略。