ABSTRACT
Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1ß. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Cyclooxygenase 2 Inhibitors , Cyclooxygenase 2 , Molecular Docking Simulation , Pyridazines , Pyridazines/pharmacology , Pyridazines/chemistry , Pyridazines/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Animals , Cyclooxygenase 2/metabolism , Structure-Activity Relationship , Molecular Structure , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Humans , Dose-Response Relationship, Drug , Edema/drug therapy , Edema/chemically induced , Rats , Male , Cyclooxygenase 1/metabolism , MiceABSTRACT
Selective cyclooxygenase (COX)-2 inhibitors have several advantages over nonselective COX inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]), including the absence of adverse effects (renal and hepatic disorders) associated with the long-term use of standard NSAIDs, as well as an improved gastrointestinal profile. The pyridazine nucleus is regarded as a promising scaffold for the development of powerful COX-2 inhibitors, particularly when selectively functionalized. This article summarizes some methods for the synthesis of pyridazine derivatives. Furthermore, it covers all of the pyridazine derivatives that have appeared as selective COX-2 inhibitors, making it useful as a reference for the rational design of novel selective COX-2 inhibitors.
