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Design, Syntheses, Biological Evaluation, and Docking Studies of 2‐Substituted 5‐Methylsulfonyl‐1‐Phenyl‐1 H ‐Indoles: Potent and Selective in vitro Cyclooxygenase‐2 Inhibitors
Author(s) -
CruzLópez Olga,
DíazMochón Juan José,
Campos Joaquín M.,
Entrena Antonio,
Núñez María T.,
Labeaga Luis,
Orjales Aurelio,
Gallo Miguel A.,
Espinosa Antonio
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600179
Subject(s) - docking (animal) , cyclooxygenase , in vitro , chemistry , stereochemistry , combinatorial chemistry , pharmacology , biochemistry , enzyme , medicine , nursing
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 n M ), and selective (respective selectivity indexes: >2163 and >2331) COX‐2 inhibitors.