RESUMO
Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/ß, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/ε inhibitor development targeting neurodegenerative disorders and cancer.
Assuntos
Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase Idelta/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Quinazolinas/farmacologia , Caseína Quinase 1 épsilon/metabolismo , Caseína Quinase Idelta/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-AtividadeRESUMO
In this study we examined the suitability of the 3H-imidazo[4,5-b]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity in vitro. The results showed that compound 3f exhibited 2-fold selectivity with IC50 values of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compound 3f revealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.
