Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

David H. McGarry, Ian R. Cooper, Rolf Walker, Catherine E. Warrilow, Mark Pichowicz, Andrew J. Ratcliffe, Anne-Marie Salisbury, Victoria J. Savage, Emmanuel Moyo, John Maclean, Andrew Smith, Cédric Charrier, Neil R. Stokes, David M. Lindsay, William J. Kerr

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Abstract

According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.
Original languageEnglish
Pages (from-to)2998-3003
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number17
Early online date26 May 2018
DOIs
Publication statusPublished - 15 Sep 2018

Keywords

  • ESKAPE pathogens
  • anti-infectives
  • topoisomerases
  • DNA gyrase
  • pyrimido[45-b]indol-8-amine

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    McGarry, D. H., Cooper, I. R., Walker, R., Warrilow, C. E., Pichowicz, M., Ratcliffe, A. J., Salisbury, A-M., Savage, V. J., Moyo, E., Maclean, J., Smith, A., Charrier, C., Stokes, N. R., Lindsay, D. M., & Kerr, W. J. (2018). Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase. Bioorganic and Medicinal Chemistry Letters, 28(17), 2998-3003. https://doi.org/10.1016/j.bmcl.2018.05.049