| Summary: | New selective COX-2 inhibitors were designed and synthesized by tethering 1,2,3-triazole and benzenesulfonamide pharmacophores to some NSAIDs. Compounds <b>6b</b> and <b>6j</b> showed higher in vitro COX-2 selectivity and inhibitory activity (IC<sub>50</sub> = 0.04 µM and S.I. = 329 and 312, respectively) than celecoxib (IC<sub>50</sub> = 0.05 µM and S.I. = 294). Compound <b>6e</b> revealed equipotent in vitro COX-2 inhibitory activity to celecoxib. Furthermore, <b>6b</b> and <b>6j</b> expressed more potent relief of carrageenan-induced paw edema thickness in mice than celecoxib, with ED<sub>50</sub> values of 11.74 µmol/kg and 13.38 µmol/kg vs. 16.24 µmol/kg, respectively. Compounds <b>6b</b> and <b>6j</b> inhibited the production of PGE2 with a % inhibition of PGE2 production of 90.70% and 86.34%, respectively, exceeding celecoxib’s percentage (78.62%). Moreover, <b>6b</b> and <b>6j</b> demonstrated a gastric safety profile comparable to celecoxib. In conclusion, compounds <b>6b</b> and <b>6j</b> better achieved the target goal as more potent and selective COX-2 inhibitors than celecoxib in vitro and in vivo.
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