RESUMO
Based on an (aminoaryl)benzothiazole quinazoline hit structure for kinase inhibition, a systematic optimization program resulted in a lead structure allowing for inhibitory activities in cellular phosphorylation assays in the low nanomolar range.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Aurora Quinases , Linhagem Celular Tumoral , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
Recent research has provided evidence that interference with bacterial cell-to-cell signaling is a promising strategy for the development of novel antimicrobial agents. Here we report on the computer-aided design of novel compounds that specifically inhibit an N-acyl-homoserine lactone-dependent communication system that is widespread among members of the genus Burkholderia. This genus comprises more than 30 species, many of which are important pathogens of animals and humans. Over the past few years, several Burkholderia species, most notably Burkholderia cenocepacia, have emerged as important opportunistic pathogens causing severe pulmonary deterioration in persons with cystic fibrosis. As efficient treatment of Burkholderia infections is hampered by the inherent resistance of the organisms to a large range of antibiotics, novel strategies for battling these pathogens need to be developed. Here we show that compounds targeting the B. cenocepacia signaling system efficiently inhibit the expression of virulence factors and attenuate the pathogenicity of the organism.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Infecções por Burkholderia/microbiologia , Burkholderia cepacia/fisiologia , Desenho de Fármacos , Transdução de Sinais/efeitos dos fármacos , Antibacterianos/farmacologia , Burkholderia cepacia/genética , Desenho Assistido por Computador , Regulação Bacteriana da Expressão Gênica , Transdução de Sinais/fisiologiaRESUMO
A novel series of DHODH inhibitors was developed based on a lead which was obtained by a docking procedure and a medicinal chemistry exploration. The activity of the initial lead was improved by a QSAR method to yield low nanomolar inhibitors.
Assuntos
Inibidores Enzimáticos/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismoRESUMO
A new naphthylisoquinoline alkaloid, ancistrolikokine D, and the likewise 5,8'-coupled alkaloid ancistroealaine A, as well as two further, biosynthetically related, but nitrogen-free natural products, ancistronaphthoic acid B and cis-isoshinanolone, have been isolated from Ancistrocladus likoko J. LEACUTE;ONARD (Ancistrocladaceae). The 5,8'-coupling of the new alkaloids and of the alkaloids isolated earlier hints at a close phylogenetic relationship of A. likoko to other Central African Ancistrocladus species. The compounds show moderate activities against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei rhodesiense.
Assuntos
Alcaloides/isolamento & purificação , Anti-Infecciosos/isolamento & purificação , Caryophyllaceae/química , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Naftalenos/química , Naftóis/isolamento & purificação , Alcaloides/química , Alcaloides/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , República Democrática do Congo , Concentração Inibidora 50 , Isoquinolinas/farmacologia , Leishmania donovani/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Naftóis/química , Naftóis/farmacologia , Raízes de Plantas/química , Plasmodium falciparum/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Trypanosoma/efeitos dos fármacosRESUMO
From the root bark of Triphyophyllum peltatum, the new naphthylisoquinoline alkaloid 5'-O-demethyldioncophylline A has been isolated. Its otherwise difficult separation from the largely dominating main alkaloid, dioncophylline A, was greatly facilitated by a bromination-benzylation procedure. From the resulting derivative, a crystal structure analysis with an anomalous X-ray diffraction was achieved, allowing confirmation of the full absolute stereostructure of the new alkaloid. The structure was further corroborated by a partial synthesis from dioncopeltine A. The natural product was shown to exhibit antimalarial activity against erythrocytic forms of Plasmodium falciparum.
