The synthesis and evaluation of quinolinequinones as anti-mycobacterial agents

  • Bioorg Med Chem. 2019 Aug 15;27(16):3532-3545. doi: 10.1016/j.bmc.2019.06.002.
Kristiana T Santoso  1 ,  Ayana Menorca  2 ,  Chen-Yi Cheung  2 ,  Gregory M Cook  3 ,  Bridget L Stocker  4 ,  Mattie S M Timmer  5
Affiliations
  • 1. School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
  • 2. Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
  • 3. Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
  • 4. School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand. Electronic address: [email protected].
  • 5. School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand. Electronic address: [email protected].
PMID: 31262663 DOI: 10.1016/j.bmc.2019.06.002
Abstract

A library of thirty-two quinolinequinones (QQs) with various amine substituents at the 6- and 7-positions were synthesised efficiently and in good yields for evaluation as potential anti-tuberculosis agents. Mycobacterium tuberculosis growth inhibition assays demonstrated that QQs bearing moderate length alkyl chains (i.e. heptylphenylamino- and octylamino-QQs), and aryl groups (i.e. phenylethylamino- and benzylamino-QQs) exhibited encouraging inhibitory activity, while QQ analogue 7-chloro-6-propargylamino-quinoline-5,8-dione (16b) had excellent inhibitory activity (MIC = 8 μM). The cLogP values and redox activities of the QQs were determined, and neither readout correlated with the anti-mycobacterial activities of the compounds. Notwithstanding, mode of action studies of 16b revealed that treatment of M. tuberculosis with this compound led to activation of NADH-dependent oxygen consumption suggesting a redox cycling mechanism. To this end, the promising anti-mycobacterial activity of several QQs and their ability to perturb oxygen management leading to an uncontrolled respiratory burst, as identified in this work and by Others, demonstrates the merit of further optimising the anti-mycobacterial activity of this readily synthesised class of compound.

Keywords
Organic synthesis; Quinolinequinones; Tuberculosis.
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