Design,Syntheses,Biological Evaluation,and Docking Studies of 2-Substituted 5-Methylsulfonyl-1-Phenyl-1H-lndoles: Potent and Selective in vitro Cyclooxygenase-2 Inhibitors

摘要

Four series of 5-methylsulfonyl-1-phenyl-1H-indole-2-carboxylic acid alkyl esters (family A),-2-carbonitriles (family B),-2-carboxa-mides (family C),and 2-benzoyl-5-methylsulfonyl-l-phenyl-1H-in-doles (family D) were prepared and evaluated for their ability to inhibit purified cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1).Family D compounds have the best COX-1/COX-2 inhibition ratios and potencies.According to docking studies,these molecules appear to bind the COX-2 binding site differently than indomethacin,with the insertion of the substituent at the 2-posi-tion in the hydrophobic pocket of the enzyme and the 1 -position phenyl ring in the trifiuoromethyl zone.Among the group of compounds evaluated,2-(4-chlorobenzoyl)-1-(4-chlorophenyl)-5-methylsulfonyl-1 H-indole and 2-(4-chlorophenyl)-5-methylsulfon-yl-l-(4-trifluoromethylphenyl)-1H-indole emerged as the most potent (respective IC_(50) values: 46 and 43 nM),and selective (respective selectivity indexes: >2163 and >2331) COX-2 inhibitors.