Design,synthesis and pharmacological evaluation of 4-2-alkylthio-5（4）-（4-substitutedphenyl）imidazole-4（5）ylbenzenesulfonamides as selective COX-2 inhibitors

摘要

＜正＞ 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 goodCOX-2 inhibitor activity,and which will exert anti-inflammatory activities in vivo.Methods:Benzenesulfonamide derivatives were designed and synthesized throughmulti-step chemical reactions.All the synthesized compounds were evaluated inan in vitro assay.The active compound 4a-af was selected for further evaluationin a carrageenan-induced rat paw edema model.Results:Docking studies showedthat compound 4 bind into the primary binding site of COX-2 with the sulfonamideSO2NH2 moiety interacting with the secondary pocket amino acid residues.In thein vitro assay,compound 4 inhibited COX-2 with an inhibition concentration IC50value of 1.23-8 nmol/L,compared to celecoxib with IC50 value of 1.5 nmol/L.Com-pound 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 latterexperiment,compound 4c was the most active compound.Conclusion:The anti-inflammatory effects obtained for compound 4a-4j could be due to the presenceof fluorine or hydrogen substituents in the para position of the phenyl ring ofthese compounds.