Design, synthesis, and biological evaluation of N-acetyl-2-(or 3-)carboxymethylbenzenesulfonamides as cyclooxygenase isozyme inhibitors

A group of N -acetyl-2-(or 3-)carboxymethylbenzenesulfonamides, possessing either a F or a substituted-phenyl ring substituent (4-F, 2,4-F 2 , 4-SO 2 Me, 4-OCHMe 2 ) attached to its C-4 or C-6 position, was prepared using a palladium-catalyzed Suzuki cross-coupling reaction for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. Although N -acetyl-3-carboxymethyl-6-fluorobenzenesulfonamide [ 14 , COX-1 IC 50 = 2.26 μM; COX-2 IC 50 = 0.012 μM; COX-2 selectivity index (SI) = 188] and N -acetyl-3-carboxymethyl-6-(4-isopropoxyphenyl)benzenesulfonamide ( 20c , COX-1 IC 50 >100 μM; COX-2 IC 50 = 0.15 μM; COX-2 SI >667) exhibited potent in vitro COX-2 inhibitory activity and high COX-2 selectivity, both compounds were inactive anti-inflammatory agents in a carrageenan-induced rat paw edema assay. In contrast, the less potent and less selective COX-2 inhibitors N -acetyl-2-carboxymethyl-4-fluorobenzenesulfonamide ( 12 , COX-1 IC 50 = 4.25 μM; COX-2 IC 50 = 0.978 μM; COX-2 SI = 4.3), N -acetyl-2-carboxymethyl-4-(2,4-difluorophenyl)benzenesulfonamide ( 17c , COX-1 IC 50 = 1.02 μM; COX-2 IC 50 = 1.00 μM; COX-2 SI = 1.02), and N -acetyl-3-carboxymethyl-6-(4-methanesulfonylphenyl)benzenesulfonamide ( 20e , COX-1 IC 50 = 0.109 μM; COX-2 IC 50 = 1.14 μM; COX-2 SI = 0.095) exhibited moderate anti-inflammatory activity where a 75 mg/kg oral dose reduced inflammation 26%, 14%, and 20%, respectively, at 3 h postdrug administration relative to the reference drug aspirin where a 50 mg/kg oral dose reduced inflammation by 25% at 3 h postdrug administration.