Isomeric acetoxy analogs of celecoxib and their evaluation as cyclooxygenase inhibitors

A group of celecoxib analogs having a SO2NH2 (9a–f), or SO2Me (12a–f), COX-2 pharmacophore at the para-position of the N-1 phenyl ring in conjunction with a C-5 phenyl ring having a variety of substituents (4-, 3-, 2-OAc; 4-Me,2-OAc, 4-Me,3-OAc, 4-F,2-OAc) was synthesized for evaluation as cyclooxygenase (COX) inhibitors of the COX-1/COX-2 isozymes. Within this group of compounds, 1-(4-aminosulfonylphenyl)-3-trifluoromethyl-5-(2-acetoxy-4-fluorophenyl)pyrazole (9f) emerged as the most potent (COX-1 IC50 = 0.7 μM; COX-2 IC50 = 0.015 μM) and selective (COX-2 selectivity index = 47) inhibitor agent that exhibited good anti-inflammatory activity (ED50 = 42.3 mg/kg) which was lower than the reference drug celecoxib (ED50 = 10.8 mg/kg), but greater than ibuprofen (ED50 = 67.4 mg/kg) and aspirin (ED50 = 128.7 mg/kg). Molecular modeling studies for 9f showed that the SO2NH2 group assumes a position within the secondary pocket of the COX-2 active site wherein the SO2NH2 oxygen atom is hydrogen bonded to the H90 residue (2.90 Å), the SO2NH2 nitrogen atom forms a hydrogen bond with L352 (N⋯O = 2.80 Å), and the acetyl group is positioned in the vicinity of the S530 residue where the acetyl oxygen atom undergoes hydrogen bonding to L531 (2.99 Å).

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