Abstract：
Complications of the worldwide use of non-steroidal anti-inflammatory drugs (NSAIDs) sparked scientists to design novel harmless alternatives as an urgent need. So, a unique hybridization tactic of quinoline/pyrazole/thioamide (4a-c) has been rationalized and synthesized as potential COX-2/15-LOX dual inhibitors, utilizing relevant reported studies on these pharmacophores. Moreover, we extended these preceding hybrids into more varied functionality, bearing crucial thiazole scaffolds(5a-l). All the synthesized hybrids were evaluatedin vitroas COX-2/15-LOX dual inhibitors. Initially, series4a-cexhibited significant potency towards 15-LOX inhibition (IC50 = 5.454-4.509 μM) compared to meclofenamate sodium (IC50 = 3.837 μM). Moreover, they revealed reasonable inhibitory activities against the COX-2 enzyme in comparison to celecoxib.Otherwise, conjugates 5a-ldisclosed marked inhibitory activity against 15-LOX and strong inhibitory to COX-2. In particular, hybrids5d(IC50 = 0.239 μM, SI = 8.95), 5h(IC50 = 0.234 μM, SI = 20.35) and 5l (IC50 = 0.201 μM, SI = 14.42) revealed more potency and selectivity outperforming celecoxib (IC50 = 0.512 μM, SI = 4.28). In addition, the most potentcompounds, 4a, 5d, 5h, and 5l have been elected for further in vivoevaluation and displayed potent inhibition of edema in the carrageenan-induced rat paw edema test that surpassed indomethacin. Further, compounds5d, 5h, and 5l decreased serum inflammatory markers including oxidative biomarkersiNO, and pro-inflammatory mediators cytokines like TNF-α, IL-6, and PGE. Ulcerogenic liability for tested compounds demonstrated obvious gastric mucosal safety. Furthermore, a histopathological study for compound 5l suggested a confirmatory comprehensive safety profile for stomach, kidney, and heart tissues. Docking and drug-likeness studies offered a good convention with the obtained biological investigation.
摘要：
全球范围内使用非甾体类抗炎药（NSAIDs）的并发症促使科学家迫切需要设计新型无害替代品。所以,喹啉/吡唑/硫代酰胺（4a-c）的独特杂交策略已被合理化和合成为潜在的COX-2/15-LOX双重抑制剂，利用对这些药效团的相关报道研究。此外，我们将这些先前的混合动力扩展到更多不同的功能，承载至关重要的噻唑支架（5a-l）。所有合成的杂种在体外COX-2/15-LOX双重抑制剂中进行评估。最初，与甲氯芬酸钠（IC50=3.837μM）相比，系列4a-c表现出对15-LOX抑制的显着效力（IC50=5.454-4.509μM）。此外，与塞来昔布相比，它们显示出对COX-2酶的合理抑制活性。否则,缀合物5a-l公开了对15-LOX的显著抑制活性和对COX-2的强抑制。特别是,杂交5d(IC50=0.239μM，SI=8.95)，5h(IC50=0.234μM,SI=20.35)和5l(IC50=0.201μM，SI=14.42）显示出比塞来昔布更高的效力和选择性（IC50=0.512μM，SI=4.28）。此外,最有潜力的化合物，4a,5d,5h,和5l已被选择用于进一步的体内评估，并在角叉菜胶诱导的大鼠爪水肿测试中显示出有效的抑制水肿，超过吲哚美辛。Further,化合物5d，5h,和5l降低血清炎症标志物，包括氧化生物标志物，和促炎介质细胞因子，如TNF-α，IL-6和PGE。受试化合物的溃疡倾向证明了明显的胃粘膜安全性。此外，对化合物5l的组织病理学研究表明，对胃具有确证的综合安全性，肾,和心脏组织。对接和药物相似性研究与获得的生物学研究提供了良好的约定。
