Karović Marko, Nikolić Miloš, Nedeljković Nikola, Vesović Marina, Nikolić Marina, Anđić Marijana, Lazarević Nevena, Jakovljević Vladimir, Nedeljković Jelena, Đaković Sanja, Bošković Jelena, Dobričić Vladimir
Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
Antioxidants (Basel). 2025 Jun 27;14(7):796. doi: 10.3390/antiox14070796.
In the present study, five novel dexketoprofen amide derivatives with a free carboxyl group in their side chains were synthesized. The in vivo anti-inflammatory potential of dexketoprofen derivatives was evaluated using a carrageenan-induced paw edema model of acute inflammation. Additionally, the local and systemic redox status in rats following acute administration of the compounds was assessed by measuring levels of pro-oxidative markers and the activity of antioxidant enzymes. Among the analyzed molecules, derivatives and exhibited the most potent in vivo anti-inflammatory activity, showing effects comparable to those of the parent compound dexketoprofen. In vitro results revealed that all newly synthesized compounds exhibited low inhibitory activity toward COX-1, whereas only compound showed significant COX-2 inhibition. The stronger binding affinity of derivative for COX-2 in comparison to other tested compounds is likely attributed to its ability to form multiple electrostatic interactions within the enzyme's active site. Furthermore, compounds and demonstrated efficacy comparable to the parent drug in restoring redox balance, indicating their potential antioxidant properties under acute inflammatory conditions. The findings of this study underscore the therapeutic potential of the novel dexketoprofen amide derivatives as dual-function agents with the capacity to modulate both inflammatory responses and oxidative stress.
在本研究中，合成了五种侧链带有游离羧基的新型右酮洛芬酰胺衍生物。使用角叉菜胶诱导的急性炎症爪肿胀模型评估了右酮洛芬衍生物的体内抗炎潜力。此外，通过测量促氧化标志物水平和抗氧化酶活性，评估了化合物急性给药后大鼠的局部和全身氧化还原状态。在所分析的分子中，衍生物 和 表现出最有效的体内抗炎活性，其效果与母体化合物右酮洛芬相当。体外结果表明，所有新合成的化合物对COX-1均表现出低抑制活性，而只有化合物 表现出显著的COX-2抑制作用。与其他测试化合物相比，衍生物 对COX-2具有更强的结合亲和力，这可能归因于其在酶活性位点内形成多个静电相互作用的能力。此外，化合物 和 在恢复氧化还原平衡方面表现出与母体药物相当的疗效，表明它们在急性炎症条件下具有潜在的抗氧化特性。本研究结果强调了新型右酮洛芬酰胺衍生物作为具有调节炎症反应和氧化应激能力的双功能药物的治疗潜力。
