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

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. In 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 docking studies performed by AutoDock Vina demonstrated that docked molecules were positioned as well as a crystallographic ligand in the COX-2 active site, and SO2Me pharmacophore was inserted into the secondary pocket of COX-2 and formed hydrogen bonds with the active site. The designed compounds were synthesized through two-step reactions. In the first step, different 1-(4-(methylsulfonyl)phenyl)-2-(phenylamino)ethan1-one derivatives were obtained by the reaction of aniline derivatives and alpha-bromo-4-(methylsulfonyl)acetophenone. Then, condensation of intermediates with different 2-aminopyridines gave final compounds. Enzyme inhibition assay and formalin test were performed to evaluate the activity of these compounds. Among these compounds, 8-methyl-2-(4-(methylsulfonyl) phenyl)-N-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (5n) exhibited the highest potency (IC50 = 0.07 mu M) and selectivity (selectivity index = 508.6) against COX-2 enzyme (selectivity index: COX-1 IC50/COX-2 IC50). 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.

Automated summary

Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit Cyclooxygenase (COX), which converts arachidonic acid to inflammatory mediators. Selective COX-2 inhibitors have become important in medicinal chemistry due to their lower incidence of adverse effects. A series of new 2-(4-(methylsulfonyl)phenyl)-N-phenylimidazo[1,2-a]pyridin-3-amines were designed, synthesized, and evaluated as potential COX-2 inhibitors. Among them, 8-methyl-2-(4-(methylsulfonyl) phenyl)-N-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (5n) showed the highest potency and selectivity against the COX-2 enzyme, and nine derivatives exhibited significant antinociceptive activity in the formalin test.