Elgohary Mohamed K, Elkotamy Mahmoud S, Alkabbani Mahmoud Abdelrahman, El Hassab Mahmoud A, Al-Rashood Sara T, Binjubair Faizah A, Alsulaimany Marwa, Ghabbour Hazem A, Eldehna Wagdy M, Abdel-Aziz Hatem A
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt.
Int J Biol Macromol. 2025 Mar;293:139170. doi: 10.1016/j.ijbiomac.2024.139170. Epub 2024 Dec 28.
The current research focuses on the design and synthesis of celecoxib analogues incorporating sulphonamide and pyrazole moieties (4, 5, 6a-e, and 7a-f) with the aim of achieving a broad range of COX-2 selectivity in vitro. Among these, compounds 6b-d, 7a, 7e, and 7d exhibited potent inhibition, with IC values ranging between 0.05 and 0.08 μM, and were selected for in vivo evaluation using the formalin-induced paw edema model. To further assess the safety profile of compound 6d, a histopathological examination of paw tissue was conducted alongside routine blood analyses evaluating key liver and kidney function parameters, including creatinine, urea, AST, and ALT levels. The results indicated normal profiles, comparable to reference drugs celecoxib and indomethacin. Additionally, compound 6d was evaluated for its effect on inflammatory biomarkers using ELISA assays. Markedly, 6d elicited a remarkable reduction in TNF-α (71.43 %) and PGE (77.11 %) levels, surpassing the effects of both celecoxib and indomethacin, confirming its potent anti-inflammatory properties. In terms of analgesic activity, Importantly, cardiac toxicity assessment revealed no adverse effects associated with compound 6d. Finally, compound 6d underwent in silico analysis, including molecular docking and molecular dynamics simulations, which confirmed its selective interaction with the COX-2 active site and favorable free insertion into the selectivity side pocket.
当前的研究聚焦于含有磺酰胺和吡唑部分（4、5、6a - e以及7a - f）的塞来昔布类似物的设计与合成，目的是在体外实现广泛的COX - 2选择性。其中，化合物6b - d、7a、7e和7d表现出强效抑制作用，IC值在0.05至0.08 μM之间，并被选用福尔马林诱导的爪肿胀模型进行体内评估。为进一步评估化合物6d的安全性，在评估包括肌酐、尿素、谷草转氨酶和谷丙转氨酶水平等关键肝肾功能参数的常规血液分析的同时，对爪组织进行了组织病理学检查。结果表明其各项指标正常，与对照药物塞来昔布和吲哚美辛相当。此外，使用酶联免疫吸附测定法评估了化合物6d对炎症生物标志物的影响。值得注意的是，6d使肿瘤坏死因子 - α（TNF - α）（71.43%）和前列腺素E（PGE）（77.11%）水平显著降低，超过了塞来昔布和吲哚美辛的效果，证实了其强大的抗炎特性。在镇痛活性方面，重要的是，心脏毒性评估显示化合物6d没有相关不良反应。最后，化合物6d进行了计算机模拟分析，包括分子对接和分子动力学模拟，证实了其与COX - 2活性位点的选择性相互作用以及顺利插入选择性侧袋的有利情况。
