Design, synthesis, and biological evaluation of new 2-(4-(methylsulfonyl)phenyl)-N-phenylimidazo[1,2-a]pyridin-3-amine as selective COX-2 inhibitors

Abstract

Abstract Cyclooxygenase (COX), which plays a role in converting arachidonic acid to inflammatory mediators, could be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Although potent NSAIDs are available for the treatment of pain, fever, and inflammation, some side effects such as gastrointestinal ulcers limit the use of these medications. During recent years, selective COX-2 inhibitors with a lower incidence of adverse effects attained an important position in medicinal chemistry. In order to introduce some new potent COX-2 inhibitors, a new series of 2-(4-(methylsulfonyl)phenyl)-N-phenylimidazo[1,2-a]pyridin-3-amines was designed, synthesized, and evaluated. The designed compounds were synthesized through multistep reactions. Enzyme inhibition assay and formalin test were performed to evaluate the activity of these compounds. The docking studies demonstrated SO2Me pharmacophore was inserted into the secondary pocket of COX-2, and other parts of docked molecules were positioned as well as a crystallographic ligand in the COX-2 active site. Among these compounds, 8-methyl-2-(4-(methylsulfonyl)phenyl)-N-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (5n) exhibited the most potency and selectivity against COX-2 (IC50= 0.07 µM, SI= 508.6). The antinociceptive activity assessment via the formalin test showed that nine derivatives (5a, 5d, 5h, 5i, 5k, 5q, 5r, 5s, and 5t) possessed significant activity compared with the control group with a p-value less than 0.05.