1 research outputs found
Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB
With
the emergence of multidrug-resistant strains of <i>Mycobacterium
tuberculosis</i> 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 <i>M. tuberculosis</i> 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 <i>c</i> oxidoreductase, part of the bc1-aa3-type cytochrome <i>c</i> oxidase complex that is responsible for driving oxygen-dependent
respiration