Discovery of Novel Pyridazine-Based Cyclooxygenase-2 Inhibitors with a Promising Gastric Safety Profile.

Cyclooxygenase-2 (COX-2) is implicated in the development of chronic inflammatory diseases. Recently, pyridazine derivatives have emerged as a novel prototype to develop COX-2 inhibitors. Accordingly, some pyridazine-based COX-2 inhibitors are reported herein. The reaction of aldehyde and different hydrazines yielded the corresponding hydrazones. The hydrazones were further derivatized to the title compounds, which were assessed for COX-1 and COX-2 inhibitory action, gastric ulcerogenic effects, and lipid peroxidation properties. Molecular docking studies and determination of the physicochemical parameters were also carried out. The allocated structures of the reported compounds were coherent with their spectroscopic data. The compounds (IC = 15.50 nM, 114.77%), (IC = 17.50 nM, 101.65%), (IC = 17.10 nM, 104.03%), (IC = 16.90 nM, 105.26%), and (IC = 17.70 nM, 100.5%) displayed better COX-2 inhibition than celecoxib (IC = 17.79 nM, 100%). These outcomes were harmonious with the molecular docking studies of , , , , and . These compounds also displayed comparable onset and the duration of action concerning celecoxib and indomethacin in the in vivo studies. No ulcerogenic effects were observed for and , whereas , , and showed an insignificant ulcerogenic effect compared to celecoxib. The compounds , , , , and displayed a better lipid peroxidation profile than celecoxib and indomethacin. The compounds (%ABS = 84.09), (%ABS = 84.09), (%ABS = 66.87), (%ABS = 75.02), and (%ABS = 81.42) also displayed appreciable calculated absorption compared to celecoxib (%ABS = 82.09). The compounds , , , , and have been recognized and postulated as non-ulcerogenic COX-2 inhibitors with promising physicochemical parameters and gastric safety profile. These compounds may be useful candidates to combat diseases caused by higher levels of COX-2.