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

doi:10.1016/j.bmcl.2018.05.049

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

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

37 Downloads (Pure)

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 language	English
Pages (from-to)	2998-3003
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	17
Early online date	26 May 2018
DOIs	https://doi.org/10.1016/j.bmcl.2018.05.049
Publication status	Published - 15 Sept 2018

Keywords

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

Access to Document

10.1016/j.bmcl.2018.05.049

McGarry-etal-BMCL2018-Design-synthesis-and-antibacterial-properties-of-pyrimidoAccepted author manuscript, 1.64 MBLicence: CC BY-NC-ND 4.0

Cite this

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

@article{ab30422b88234b19a4c0e3429903eecd,

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

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.",

keywords = "ESKAPE pathogens, anti-infectives, topoisomerases, DNA gyrase, pyrimido[45-b]indol-8-amine",

author = "McGarry, {David H.} and Cooper, {Ian R.} and Rolf Walker and Warrilow, {Catherine E.} and Mark Pichowicz and Ratcliffe, {Andrew J.} and Anne-Marie Salisbury and Savage, {Victoria J.} and Emmanuel Moyo and John Maclean and Andrew Smith and C{\'e}dric Charrier and Stokes, {Neil R.} and Lindsay, {David M.} and Kerr, {William J.}",

year = "2018",

month = sep,

day = "15",

doi = "10.1016/j.bmcl.2018.05.049",

language = "English",

volume = "28",

pages = "2998--3003",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

number = "17",

}

McGarry, DH, Cooper, IR, Walker, R, Warrilow, CE, Pichowicz, M, Ratcliffe, AJ, Salisbury, A-M, Savage, VJ, Moyo, E, Maclean, J, Smith, A, Charrier, C, Stokes, NR, Lindsay, DM & Kerr, WJ 2018, 'Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 17, pp. 2998-3003. https://doi.org/10.1016/j.bmcl.2018.05.049

TY - JOUR

T1 - Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

AU - McGarry, David H.

AU - Cooper, Ian R.

AU - Walker, Rolf

AU - Warrilow, Catherine E.

AU - Pichowicz, Mark

AU - Ratcliffe, Andrew J.

AU - Salisbury, Anne-Marie

AU - Savage, Victoria J.

AU - Moyo, Emmanuel

AU - Maclean, John

AU - Smith, Andrew

AU - Charrier, Cédric

AU - Stokes, Neil R.

AU - Lindsay, David M.

AU - Kerr, William J.

PY - 2018/9/15

Y1 - 2018/9/15

N2 - 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.

AB - 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.

KW - ESKAPE pathogens

KW - anti-infectives

KW - topoisomerases

KW - DNA gyrase

KW - pyrimido[45-b]indol-8-amine

UR - https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters

U2 - 10.1016/j.bmcl.2018.05.049

DO - 10.1016/j.bmcl.2018.05.049

M3 - Article

SN - 0960-894X

VL - 28

SP - 2998

EP - 3003

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 17

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this