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

✍ Scribed by Olga Cruz-López; Juan José Díaz-Mochón; Joaquín M. Campos; Antonio Entrena; María T. Núñez; Luis Labeaga; Aurelio Orjales; Miguel A. Gallo; Antonio Espinosa

• Book ID: 102806401
• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 509 KB
• Volume: 2
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200600179

✦ Synopsis

Abstract

Four series of 5‐methylsulfonyl‐1‐phenyl‐1__H__‐indole‐2‐carboxylic acid alkyl esters (family A), ‐2‐carbonitriles (family B), ‐2‐carboxamides (family C), and 2‐benzoyl‐5‐methylsulfonyl‐1‐phenyl‐1__H__‐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‐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‐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)‐5‐methylsulfonyl‐1__H__‐indole and 2‐(4‐chlorophenyl)‐5‐methylsulfonyl‐1‐(4‐trifluoromethylphenyl)‐1__H__‐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.