Abstract: A group of N-aryl- 4-(methylsulfonyl)aminobenzenesulfonamides, possessing a (methylsulfonyl) amino pharmacophore at the para-position of the one phenyl ring, in conjunction with another substituted phenyl ring (4-F, 4-H, 4-Me, 4-OMe) were evaluated as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-2 isozyme inhibition structure–activity studies identified 6e with 4-OMe substituent as a potent COX-2 inhibitor (IC50 = 1.59 μM) with a high COX-2 selectivity index (SI = 51.7) comparable to the reference drug celecoxib (COX-2 IC50 = 9.59 μM; COX-2 SI = 25.62). The structure-activity data acquired indicate that the sulfonamido moiety constitutes a suitable scaffold to design new acyclic N-aryl- 4-(methysulfonyl)aminobenzenesulfonamides derivatives with selective COX-2 inhibitory activity.