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

McGarry, David H. and Cooper, Ian R. and Walker, Rolf and Warrilow, Catherine E. and Pichowicz, Mark and Ratcliffe, Andrew J. and Salisbury, Anne-Marie and Savage, Victoria J. and Moyo, Emmanuel and Maclean, John and Smith, Andrew and Charrier, Cédric and Stokes, Neil R. and Lindsay, David M. and Kerr, William 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). pp. 2998-3003. ISSN 0960-894X

[img]
Preview
Text (McGarry-etal-BMCL2018-Design-synthesis-and-antibacterial-properties-of-pyrimido)
McGarry_etal_BMCL2018_Design_synthesis_and_antibacterial_properties_of_pyrimido.pdf
Accepted Author Manuscript
License: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 logo

Download (1MB)| Preview

    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.