A group of rofecoxib analogs, having a sulfonylazide (SO 2 N 3 ) substituent in place of the methanesulfonyl (SO 2 CH 3 ) pharmacophore at the meta-position viz 3-( 4-methyl, 4-methoxy, or 4-ethoxyphenyl)-4-(3-sulf o n y l a z i d o p h e n y l ) -2 ( 5H)furanone (7 a -c) and p a r a-position v i z 3 -p h e n y l -4 -( 4 -s u l f o n y l a z i d o p h e n y l ) - 2(5H)furanone (7d), 3-(4-fluoro, or 4-chlorophenyl)-4-(4-sulfonylazidophenyl)-2(5H)furanone (7e-f) of the C-4 phenyl ring, and 4-(1-oxido-4-pyridyl)-3-phenyl-2(5H)furanone (12) were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 enzyme inhibition studies showed that 3-phenyl-4-(4-sulfonylazidophenyl)-2(5H)furanone (7d) inhibited COX-1 selectively (COX-1 IC 50 = 0.6659 µM; COX-2 IC 50 > 100 µM) and 3-(4-fluorophenyl)-4-(4-sulfonylazidophenyl)-2(5H)furanone (7e) inhibited both enzymes (COX-1 IC 50 = 0.8494 µM; COX-2 IC 50 = 1.7661 µM). A molecular modeling study was performed where 3-(4-fluorophenyl)-4-(4-sulfonylazidophenyl)-2(5H)furanone (7e) was docked in the active site of murine COX-2 isozyme, which showed that the sulfonylazido group inserts deep into the 2º-pocket of COX-2 where it undergoes both H-bonding (Gln 192 , Phe 518 ) and weak electrostatic (Arg 513 ) interactions.