RESUMO
The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.
Assuntos
Antituberculosos/farmacologia , ATPases Bacterianas Próton-Translocadoras/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Tuberculose/tratamento farmacológico , Sequência de Aminoácidos , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , ATPases Bacterianas Próton-Translocadoras/química , ATPases Bacterianas Próton-Translocadoras/metabolismo , Diarilquinolinas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana , Quimioterapia Combinada , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mutação Puntual , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/química , Quinolinas/química , Quinolinas/farmacocinética , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.
