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.
Keywords: 5-LOX; COX-2 inhibitors; PGE2; anti-inflammatory; pyrazolone.
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