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-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.
Cruz-López
Olga
O
Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/Campus de Cartuja s/n, 18071 Granada, Spain.
Díaz-Mochón
Juan José
JJ
Campos
Joaquín M
JM
Entrena
Antonio
A
Núñez
María T
MT
Labeaga
Luis
L
Orjales
Aurelio
A
Gallo
Miguel A
MA
Espinosa
Antonio
A
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
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D006571:Heterocyclic Compounds; D007211:Indoles; D007659:Ketones