RESUMO
A series of 1,5-diaryl-1,2,4-triazole derivatives were synthesized and evaluated as cyclooxygenase-2 (COX-2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b, 6b, 6c, 7c, 8b, 8d, 9c, and 9d have potent anti-inflammatory activity (P < 0.01), while compounds 6b, 6c, and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX-2 (COX-2 IC(50) = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX-2 IC(50) = 0.26 µM; SI = 0.015). In a rat carrageenan-induced paw edema assay, 6c exhibited moderate anti-inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX-2 in a similar mode to that of the known selective COX-2 inhibitor SC-558.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Triazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Carragenina , Celecoxib , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/síntese química , Modelos Animais de Doenças , Desenho de Fármacos , Inflamação/fisiopatologia , Concentração Inibidora 50 , Masculino , Camundongos , Ligação Proteica , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Triazóis/síntese químicaRESUMO
The cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression, and are involved in uncontrolled cell proliferation-a hallmark of cancer. This suggests that small molecular inhibitors of CDKs might be attractive as prospective antitumor agents. To explore the relationship between the structures of substituted isoquinoline-1,3-(2H,4H)-diones and their inhibition of CDK4, 3D-QSAR studies were performed on a dataset of 48 compounds. The bioactive conformation of template compound 34 was obtained by performing molecular docking into the ATP binding site of the homology model of CDK4 and ranking by highest consensus score, which was then used to build and align the rest of the molecules in the series. The constructed comparative molecular similarity indices analysis (CoMSIA) produces significantly better results than comparative molecular field analysis (CoMFA), with r(2)(cv) = 0.707 and r(2) = 0.988. The contours analysis provides useful information about the structural requirements for substituted isoquinoline-1,3-(2H,4H)-diones for CDK4 inhibitory activity.
