Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB.
J Med Chem
; 61(15): 6592-6608, 2018 Aug 09.
Article
em En
| MEDLINE
| ID: mdl-29944372
ABSTRACT
With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure-activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oxirredutases
/
Tiofenos
/
Morfolinas
/
Citocromos c
/
Mycobacterium tuberculosis
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido