RESUMO
Chemotypes comprising the d-annulated 1,3-dihydro-2H-1-benzazepin-2-one scaffold derived from the paullone structure were found to be potent vascular endothelial growth factor receptor 2 (VEGF-R2) kinase inhibitors. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were performed on a series of d-annulated benzazepinones with VEGF-R2 kinase inhibition activities. The comparative molecular field analysis and comparative molecular similarity indices analysis models using 32 molecules in the training set gave r(2)(cv) values of 0.811 and 0.769, r(2) values of 0.962 and 0.953, respectively. 3D contour maps generated from the two models revealed that the electron-withdrawing groups at R(1) and the bulky, electron-withdrawing as well as hydrogen bond donor groups at R(2) position are favourable; the bulky, hydrogen bond acceptor substituent at R(3) and the minor groups at R(4) position may benefit the potency. We have designed a series of novel VEGF-R2 inhibitors by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results may aid in designing of potential VEGF-R2 inhibitors with better activities.
Assuntos
Benzazepinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Benzazepinas/síntese química , Benzazepinas/química , Desenho Assistido por Computador , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The p38α mitogen-activated protein kinase (MAPK) has become an attractive target for the treatment of many diseases such as rheumatoid arthritis, inflammatory bowel disease and Crohn's disease. In this paper, 3D-QSAR and molecular docking studies were performed on 59 p38α MAPK inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to determine the structural requirements for potency in inhibiting p38α MAPK. The resulting model of CoMFA and CoMSIA exhibited good r(2) (cv) values of 0.725 and 0.609, and r(2) values of 0.961 and 0.905, respectively. Molecular docking was used to explore the binding mode between the inhibitors and p38α MAPK. We have accordingly designed a series of novel p38α MAPK inhibitors by utilizing the structure-activity relationship (SAR) results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provided a useful guide to design new compounds for p38α MAPK inhibitors.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/química , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Pirazóis/química , Relação Quantitativa Estrutura-Atividade , Sequência de Aminoácidos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Dados de Sequência Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologiaRESUMO
Rosiglitazone has shown promising anti-inflammation effect. To develop preferable anti-inflammatory agents, twenty-two rosiglitazone analogs were synthesized and their anti-inflammatory activity was evaluated. Among these compounds, 6i and 6k displayed excellent inhibitory activities on the production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Furthermore, 6i and 6k showed suppression effects on the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, and this suppression effects could be partially reversed by GW9662, which is a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Additionally, our docking results exhibited the well combination of 6i and 6k to PPARγ. So the anti-inflammation activity of 6i and 6k was due at least in part, to their interaction with PPARγ.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Benzilideno/farmacologia , Desenho de Fármacos , Furanos/farmacologia , Interleucina-6/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anilidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Linhagem Celular , Sobrevivência Celular , Furanos/síntese química , Furanos/química , Interleucina-6/biossíntese , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Pseudomonas aeruginosa (P. aeruginosa) colonize on most wounds and live as biofilm, which causes antibiotic resistance and wounds unhealed. To investigate the effects of 5-substituted 3,4-dihalo-5H-furan-2-one compounds on biofilm formation of P. aeruginosa, a set of 5-(aryl-1'-hydroxy-methyl)- or 5-(aryl-2-methylene)-3,4-dihalo-5H-furan-2-one compounds were designed and synthesized. Their inhibitory activities on biofilm formation of P. aeruginosa were studied by MIC assay, quantitative analysis of biofilm inhibition, and observation of biofilm formation with SEM. It was found that compounds 2i, 3f, 3i showed remarkable effects of biofilm formation inhibition on P. aeruginosa. Furthermore, molecular docking was performed to identify the key structural features of these compounds with the binding site of LasR receptor.