Abstract
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 3 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 9a (IC50 = 15.50 nM, 114.77%), 9b (IC50 = 17.50 nM, 101.65%), 12 (IC50 = 17.10 nM, 104.03%), 16b (IC50 = 16.90 nM, 105.26%), and 17 (IC50 = 17.70 nM, 100.5%) displayed better COX-2 inhibition than celecoxib (IC50 = 17.79 nM, 100%). These outcomes were harmonious with the molecular docking studies of 9a, 9b, 12, 16b, and 17. 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 9a and 12, whereas 9b, 16b, and 17 showed an insignificant ulcerogenic effect compared to celecoxib. The compounds 9a, 9b, 12, 16b, and 17 displayed a better lipid peroxidation profile than celecoxib and indomethacin. The compounds 9a (%ABS = 84.09), 9b (%ABS = 84.09), 12 (%ABS = 66.87), 16b (%ABS = 75.02), and 17 (%ABS = 81.42) also displayed appreciable calculated absorption compared to celecoxib (%ABS = 82.09). The compounds 9a, 9b, 11, 16b, and 17 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.
Highlights
Inflammation is a self-protective reaction of human body tissues towards injurious stimuli like infection, irritants, poisonous substances, irradiation, and tissue injury [1]
Persistent inflammation for a longer time or chronic inflammation may lead to the development of diseases like gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis [1,3]
The cycloalkylation of the thiocarbamoyl group of 4b with the ethyl α-chloroacetate (5a) and ethyl α-chloropropionate (5b) in glacial acetic acid comprising a catalytic amount of the fused sodium acetate at the reflux temperature afforded the corresponding 4-thiazolidinone derivatives, 6a and
Summary
Inflammation is a self-protective reaction of human body tissues towards injurious stimuli like infection, irritants, poisonous substances, irradiation, and tissue injury [1]. The inflammation can be divided into acute inflammation and chronic inflammation. The symptoms of acute inflammation comprise of swelling, heat, immobility, redness, and pain, which may last for several days [2]. Persistent inflammation for a longer time or chronic inflammation may lead to the development of diseases like gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis [1,3]. It is estimated that about 1/4th of the adults in the USA will be affected by osteoarthritis by 2030 [5]
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