New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5‐lipoxygenase (5‐LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX‐2 selectivity index. Moreover, they showed potent 5‐LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti‐inflammatory activity using the carrageenan‐induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX‐2 and 5‐LOX active sites was performed to rationalize their anti‐inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual‐acting COX‐2/5‐LOX inhibitors to be used as potent and safe anti‐inflammatory agents.

中文翻译：

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吡唑啉酮类似物作为靶向环氧化酶和 5-脂肪氧化酶的潜在抗炎剂的合成和生物学评价

合成了与塞来昔布和 FPL 62064 结构相关的新型吡唑啉酮衍生物，并对其对环氧合酶 (COX) 和 5-脂加氧酶 (5-LOX) 的抑制活性进行了生物学评估，并计算了它们的选择性指数。结果表明，化合物 3f、3h、3l 和 3p 具有优异的 COX-2 选择性指数。此外，相对于作为阳性对照的塞来昔布和齐留通，它们显示出有效的 5-LOX 抑制活性。使用角叉菜胶诱导的大鼠爪水肿方法和溃疡形成倾向进一步研究了这些有希望的候选物的抗炎活性。结果显示没有溃疡，这意味着它们的胃安全性。此外，还评估了这些化合物在大鼠血清中的前列腺素 (PGE2) 产量。在 COX-2 和 5-LOX 活性位点进行分子对接以使其抗炎活性合理化。确定了强结合相互作用和有效对接分数。结果表明，这些衍生物是双作用 COX-2/5-LOX 抑制剂的良好先导，可用作有效且安全的抗炎剂。