title: Design, syntheses, biological evaluation, and docking studies of 2-substituted 5-methylsulfonyl-1-phenyl-1H-indoles: potent and selective in vitro cyclooxygenase-2 inhibitors.
abstract: Four series of 5-methylsulfonyl-1-phenyl-1H-indole-2-carboxylic acid alkyl esters (family A), -2-carbonitriles (family B), -2-carboxamides (family C), and 2-benzoyl-5-methylsulfonyl-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-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-1H-indole and 2-(4-chlorophenyl)-5-methylsulfonyl-1-(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.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/Campus de Cartuja s/n, 18071 Granada, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-López
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Díaz-Mochón
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Campos
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena
authors.forename: María T
authors.initials: MT
authors.lastname: Núñez
authors.forename: Luis
authors.initials: L
authors.lastname: Labeaga
authors.forename: Aurelio
authors.initials: A
authors.lastname: Orjales
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D000465:Algorithms; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry; D008956:Models, Chemical; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D006571:Heterocyclic Compounds; D007211:Indoles; D007659:Ketones