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 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. All the synthesized hybrids were evaluatedas COX-2/15-LOX dual inhibitors. Initially, seriesexhibited significant potency towards 15-LOX inhibition (IC = 5.454–4.509 μM) compared to meclofenamate sodium (IC = 3.837 μM). Moreover, they revealed reasonable inhibitory activities against the COX-2 enzyme in comparison to celecoxib.Otherwise, conjugates disclosed marked inhibitory activity against 15-LOX and strong inhibitory to COX-2. In particular, hybrids(IC = 0.239 μM, SI = 8.95), (IC = 0.234 μM, SI = 20.35) and (IC = 0.201 μM, SI = 14.42) revealed more potency and selectivity outperforming celecoxib (IC = 0.512 μM, SI = 4.28). In addition, the most potentcompounds, , , , and have been elected for further evaluation and displayed potent inhibition of edema in the carrageenan-induced rat paw edema test that surpassed indomethacin. Further, compounds, , and decreased serum inflammatory markers including oxidative biomarkersNO, 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 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.

中文翻译：

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定制的喹啉杂合体作为有前景的 COX-2/15-LOX 双重抑制剂，具有多种安全性：设计、合成、SAR 和组织病理学研究

全球范围内使用非甾体类抗炎药 (NSAID) 所带来的并发症促使科学家们迫切需要设计新型无害替代品。因此，利用有关这些药效团的相关报道研究，喹啉/吡唑/硫代酰胺的独特杂交策略已被合理化并合成为潜在的COX-2/15-LOX双重抑制剂。此外，我们将这些先前的杂化物扩展到更多不同的功能，并带有关键的噻唑支架。所有合成的杂化物均被评估为COX-2/15-LOX双重抑制剂。最初，与甲氯芬那酸钠 (IC = 3.837 μM) 相比，该系列对 15-LOX 抑制表现出显着的效力 (IC = 5.454–4.509 μM)。此外，与塞来考昔相比，它们显示出对 COX-2 酶的合理抑制活性。此外，缀合物显示出对 15-LOX 的显着抑制活性和对 COX-2 的强抑制活性。特别是，杂化物（IC = 0.239 μM，SI = 8.95）、（IC = 0.234 μM，SI = 20.35）和（IC = 0.201 μM，SI = 14.42）显示出优于塞来昔布（IC = 0.512 μM，SI）的效力和选择性。 = 4.28）。此外，最有效的化合物 、 、 、 和 已被选为进一步评估，并在角叉菜胶诱导的大鼠爪水肿试验中显示出优于吲哚美辛的有效抑制水肿作用。此外，化合物，并减少血清炎症标志物，包括氧化生物标志物NO和促炎介质细胞因子，如TNF-α、IL-6和PGE。受试化合物的致溃疡倾向显示出明显的胃粘膜安全性。此外，化合物的组织病理学研究表明，对胃、肾和心脏组织具有确认性的综合安全性。对接和药物相似性研究为所获得的生物学研究提供了良好的惯例。