Design, synthesis, and biological evaluation of N-acetyl-2-carboxybenzenesulfonamides: a novel class of cyclooxygenase-2 (COX-2) inhibitors

N-Acetyl-2-carboxybenzenesulfonamide (11), and a group of analogues possessing an appropriately substituted-phenyl substituent (4-F, 2,4-F2, 4-SO2Me, 4-OCHMe2) attached to its C-4, or C-5 position, were synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 inhibition studies showed that 11 is a more potent inhibitor (COX-1 IC50 = 0.06 μM; COX-2 IC50 = 0.25 μM) than aspirin (COX-1 IC50 = 0.35 μM; COX-2 IC50 = 2.4 μM), and like aspirin [COX-2 selectivity index (S.I.) = 0.14], 11 is a nonselective COX-2 inhibitor (COX-2 S.I. = 0.23). Regioisomers having a 2,4-difluorophenyl substituent attached to the C-4 (COX-2 IC50 = 0.087 μM; COX-2 S.I. >1149), or C-5 (COX-2 IC50 = 0.77 μM, SI > 130), position of 11 exhibited the most potent and selective COX-2 inhibitory activity relative to the reference drug celecoxib (COX-1 IC50 = 33.1 μM; COX-2 IC50 = 0.07 μM; COX-2 S.I. = 472). N-Acetyl-2-carboxybenzenesulfonamide (11, ED50 = 49 mg/kg), and its C-4 2,4-difluorophenyl derivative (ED50 = 91 mg/kg), exhibited superior antiinflammatory activity (oral dosing) in a carrageenan-induced rat paw edema assay compared to aspirin (ED50 = 129 mg/kg). These latter compounds exhibited comparable analgesic activity to the reference drug diflunisal, and superior analgesic activity compared to aspirin, in a 4% NaCl-induced abdominal constriction assay. A molecular modeling (docking) study indicated that the SO2NHCOCH3 substituent present in N-acetyl-2-carboxy-4-(2,4-fluorophenyl)benzenesulfonamide, like the acetoxy substituent in aspirin, is suitably positioned to acetylate the Ser530 hydroxyl group in the COX-2 primary binding site. The results of this study indicate that the SO2NHCOCH3 pharmacophore present in N-acetyl-2-carboxybenzenesulfonamides is a suitable bioisostere for the acetoxy (OCOMe) group in aspirin.

Figure optionsDownload as PowerPoint slide