Acta Pharmacologica Sinica 2007 August; 28 (8): 1254-1260; doi: 10.1111/j.1745-7254.2007.00619.x

Aim: To design and synthesize a series of benzenesulfonamide derivatives, 4-[2-alkylthio-5(4)-(4-substitutedphenyl)imidazole-4(5)-yl]benzenesulfonamides (4a-4j), which are intended to act as cyclooxygenase-2 (COX-2) inhibitors with good COX-2 inhibitor activity, and which will exert anti-inflammatory activities in vivo.

Methods: Benzenesulfonamide derivatives were designed and synthesized through multi-step chemical reactions. All the synthesized compounds were evaluated in an in vitro assay. The active compound 4a_4f was selected for further evaluation in a carrageenan-induced rat paw edema model.

Results: Docking studies showed that compound 4 bind into the primary binding site of COX-2 with the sulfonamide SO₂NH₂ moiety interacting with the secondary pocket amino acid residues. In the in vitro assay, compound 4 inhibited COX-2 with an inhibition concentration IC₅₀ value of 1.23-8 nmol/L, compared to celecoxib with IC₅₀ value of 1.5 nmol/L. Compound 4b and 4c had good potency and selectivity in comparison to the celecoxib. In the in vivo model, compound 4a-4f exhibited a moderate potency to inhibit 50% carrageenan-induced paw edema with value of 1.58-4.3 mg/kg. In the latter experiment, compound 4c was the most active compound.

Conclusion: The anti-inflammatory effects obtained for compound 4a-4j could be due to the presence of fluorine or hydrogen substituents in the para position of the phenyl ring of these compounds.

Keywords: cyclooxygenase-2 inhibitor; imidazole; alkylthio; celecoxib