Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB

Laura Cleghorn, Peter Ray, Joshua Odingo, Anuradha Kumar, Heather Wescott, Aaron Korkegian, Thierry Masquelin, Abraham Lopez Moure, Caroline Wilson, Susan Davis, Margaret Huggett, Penelope Turner, Alasdair Smith, Rafiu Epemolu, Fabio Zuccotto, Jennifer Riley, Stanley Scullion, Yoko Shishikura, Liam Ferguson, Joaquin RullasLaura Guijarro, Kevin Read, Simon Green, Phil Hipskind, Tanya Parish, Paul Wyatt

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Abstract

With the emergence of multi-drug 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. Optimised 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.
Original languageEnglish
Pages (from-to)6592-6608
Number of pages17
JournalJournal of Medicinal Chemistry
Volume61
Issue number15
Early online date26 Jun 2018
DOIs
Publication statusPublished - 9 Aug 2018

Keywords

  • Morpholino-thiophenes
  • Tuberculosis
  • SAR
  • Respiratioin target
  • QcrB
  • thiophene
  • phenyl and pyridyl bioisosteric replacements

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    Cleghorn, L., Ray, P., Odingo, J., Kumar, A., Wescott, H., Korkegian, A., Masquelin, T., Lopez Moure, A., Wilson, C., Davis, S., Huggett, M., Turner, P., Smith, A., Epemolu, R., Zuccotto, F., Riley, J., Scullion, S., Shishikura, Y., Ferguson, L., ... Wyatt, P. (2018). Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB. Journal of Medicinal Chemistry, 61(15), 6592-6608. https://doi.org/10.1021/acs.jmedchem.8b00172