Design, syntheses, biological evaluation, and docking studies of 2-substituted 5-methylsulfonyl-1-phenyl-1H-indoles: Potent and selective in vitro cyclooxygenase-2 inhibitors

Four series of 5-methylsulfonyl-1-phenyl-1H-indole-2-carboxylic acid alkyl esters (family A), -2-carbonitrites (family B), -2-carboxamides (family C and 2-benzoyl-5-methylsulfony)nyl-1-phenyl-1H-indoles (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- 11COX-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-position in the hydrophobic pocket of the enzyme and the 1-position phenyl ring in the trifluoromethyl zone. Among the group of compounds evaluated, 2-(4-chlorobenzoyl)-1-(4-chlorophenyl)-5methylsulfonyl-1H-indole and 2-(4-chlorophenyl)-5-methylsulfonyl-1-(4-trifluoromethylphenyl)-1H-indole emerged as the most potent (respective IC50, values: 46 and 43 nm), and selective (respective selectivity indexes: > 2163 and > 233 1) COX-2 inhibitors.