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

Research output: Contribution to journalArticle

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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

Fingerprint

Thiophenes
Morpholinos
Mycobacterium tuberculosis
Electron Transport Complex IV
Structure-Activity Relationship
Cytochromes c
Pharmaceutical Preparations
Libraries
Oxidoreductases
Respiration
Oxygen
Infection

Keywords

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

Cite this

Cleghorn, Laura ; Ray, Peter ; Odingo, Joshua ; Kumar, Anuradha ; Wescott, Heather ; Korkegian, Aaron ; Masquelin, Thierry ; Lopez Moure, Abraham ; Wilson, Caroline ; Davis, Susan ; Huggett, Margaret ; Turner, Penelope ; Smith, Alasdair ; Epemolu, Rafiu ; Zuccotto, Fabio ; Riley, Jennifer ; Scullion, Stanley ; Shishikura, Yoko ; Ferguson, Liam ; Rullas, Joaquin ; Guijarro, Laura ; Read, Kevin ; Green, Simon ; Hipskind, Phil ; Parish, Tanya ; Wyatt, Paul. / Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 15. pp. 6592-6608.
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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.",
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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, Rullas, J, Guijarro, L, Read, K, Green, S, Hipskind, P, Parish, T & Wyatt, P 2018, 'Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB', Journal of Medicinal Chemistry, vol. 61, no. 15, pp. 6592-6608. https://doi.org/10.1021/acs.jmedchem.8b00172

Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB. / Cleghorn, Laura; Ray, Peter; Odingo, Joshua; Kumar, Anuradha; Wescott, Heather; Korkegian, Aaron; Masquelin, Thierry; Lopez Moure, Abraham; Wilson, Caroline; Davis, Susan; Huggett, Margaret; Turner, Penelope; Smith, Alasdair; Epemolu, Rafiu; Zuccotto, Fabio; Riley, Jennifer; Scullion, Stanley; Shishikura, Yoko; Ferguson, Liam; Rullas, Joaquin; Guijarro, Laura; Read, Kevin; Green, Simon; Hipskind, Phil; Parish, Tanya (Lead / Corresponding author); Wyatt, Paul (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 61, No. 15, 09.08.2018, p. 6592-6608.

Research output: Contribution to journalArticle

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T1 - Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB

AU - Cleghorn, Laura

AU - Ray, Peter

AU - Odingo, Joshua

AU - Kumar, Anuradha

AU - Wescott, Heather

AU - Korkegian, Aaron

AU - Masquelin, Thierry

AU - Lopez Moure, Abraham

AU - Wilson, Caroline

AU - Davis, Susan

AU - Huggett, Margaret

AU - Turner, Penelope

AU - Smith, Alasdair

AU - Epemolu, Rafiu

AU - Zuccotto, Fabio

AU - Riley, Jennifer

AU - Scullion, Stanley

AU - Shishikura, Yoko

AU - Ferguson, Liam

AU - Rullas, Joaquin

AU - Guijarro, Laura

AU - Read, Kevin

AU - Green, Simon

AU - Hipskind, Phil

AU - Parish, Tanya

AU - Wyatt, Paul

N1 - The work was funded in part by the Bill and Melinda Gates Foundation & Wellcome Trust grant awards to University of Dundee - A Centre of Excellence for Lead Optimisation for Diseases of the Developing World (OPP1066891& 100195/Z/12/Z).

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N2 - 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.

AB - 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.

KW - Morpholino-thiophenes

KW - Tuberculosis

KW - SAR

KW - Respiratioin target

KW - QcrB

KW - thiophene

KW - phenyl and pyridyl bioisosteric replacements

U2 - 10.1021/acs.jmedchem.8b00172

DO - 10.1021/acs.jmedchem.8b00172

M3 - Article

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SP - 6592

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