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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.


Laura A T Cleghorn, Peter C Ray, Joshua Odingo, Anuradha Kumar, Heather Wescott, Aaron Korkegian, Thierry Masquelin, Abraham Lopez Moure, Caroline Wilson, Susan Davis, Margaret Huggett, Penelope Turner, Alasdair Smith, Ola Epemolu, Fabio Zuccotto, Jennifer Riley, Paul Scullion, Yoko Shishikura, Liam Ferguson, Joaquin Rullas, Laura Guijarro, Kevin D Read, Simon R Green, Phil Hipskind, Tanya Parish, Paul G Wyatt. Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB. Journal of medicinal chemistry. 2018 Aug 09;61(15):6592-6608

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PMID: 29944372

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