Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors

Ian R. Cooper, Andrew J. McCarroll, David McGarry, James Kirkham, Mark Pichowicz, Rolf Walker, Catherine Warrilow, Anne-Marie Salisbury, Victoria J. Savage, Emmanuel Moyo, Henry Forward, Jonathan Cheung, Richard Metzger, Zoe Gault, Gary Nelson, Diarmaid Hughes, Sha Cao, John Maclean, Cédric Charrier, Mark Craighead & 3 others Stuart Best, Neil R. Stokes, Andrew J. Ratcliffe

Research output: Contribution to journalArticle

6 Citations (Scopus)
45 Downloads (Pure)

Abstract

There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.

Original languageEnglish
Pages (from-to)4179-83
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number17
Early online date28 Jul 2016
DOIs
Publication statusPublished - 1 Sep 2016

Fingerprint

Topoisomerase II Inhibitors
Type II DNA Topoisomerase
Pathogens
Structure-Activity Relationship
Ciprofloxacin
Gram-Negative Bacteria
Escherichia coli
Bacteria
Safety
Infection
Pharmaceutical Preparations
In Vitro Techniques

Keywords

  • ESKAPE pathogens
  • anti-infectives
  • topoisomerases
  • DNA gyrase
  • isothiazolone
  • multi-drug resistant pathogens
  • bacterial resistance

Cite this

Cooper, Ian R. ; McCarroll, Andrew J. ; McGarry, David ; Kirkham, James ; Pichowicz, Mark ; Walker, Rolf ; Warrilow, Catherine ; Salisbury, Anne-Marie ; Savage, Victoria J. ; Moyo, Emmanuel ; Forward, Henry ; Cheung, Jonathan ; Metzger, Richard ; Gault, Zoe ; Nelson, Gary ; Hughes, Diarmaid ; Cao, Sha ; Maclean, John ; Charrier, Cédric ; Craighead, Mark ; Best, Stuart ; Stokes, Neil R. ; Ratcliffe, Andrew J. / Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 17. pp. 4179-83.
@article{abc1d2d0e5f745dabdef86cb3311b020,
title = "Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors",
abstract = "There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.",
keywords = "ESKAPE pathogens, anti-infectives, topoisomerases, DNA gyrase, isothiazolone , multi-drug resistant pathogens, bacterial resistance",
author = "Cooper, {Ian R.} and McCarroll, {Andrew J.} and David McGarry and James Kirkham and Mark Pichowicz and Rolf Walker and Catherine Warrilow and Anne-Marie Salisbury and Savage, {Victoria J.} and Emmanuel Moyo and Henry Forward and Jonathan Cheung and Richard Metzger and Zoe Gault and Gary Nelson and Diarmaid Hughes and Sha Cao and John Maclean and C{\'e}dric Charrier and Mark Craighead and Stuart Best and Stokes, {Neil R.} and Ratcliffe, {Andrew J.}",
note = "Copyright {\circledC} 2016 Elsevier Ltd. All rights reserved.",
year = "2016",
month = "9",
day = "1",
doi = "10.1016/j.bmcl.2016.07.061",
language = "English",
volume = "26",
pages = "4179--83",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
number = "17",

}

Cooper, IR, McCarroll, AJ, McGarry, D, Kirkham, J, Pichowicz, M, Walker, R, Warrilow, C, Salisbury, A-M, Savage, VJ, Moyo, E, Forward, H, Cheung, J, Metzger, R, Gault, Z, Nelson, G, Hughes, D, Cao, S, Maclean, J, Charrier, C, Craighead, M, Best, S, Stokes, NR & Ratcliffe, AJ 2016, 'Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 17, pp. 4179-83. https://doi.org/10.1016/j.bmcl.2016.07.061

Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors. / Cooper, Ian R.; McCarroll, Andrew J.; McGarry, David; Kirkham, James; Pichowicz, Mark; Walker, Rolf; Warrilow, Catherine; Salisbury, Anne-Marie; Savage, Victoria J.; Moyo, Emmanuel; Forward, Henry; Cheung, Jonathan; Metzger, Richard; Gault, Zoe; Nelson, Gary; Hughes, Diarmaid; Cao, Sha; Maclean, John; Charrier, Cédric; Craighead, Mark; Best, Stuart; Stokes, Neil R.; Ratcliffe, Andrew J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 17, 01.09.2016, p. 4179-83.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors

AU - Cooper, Ian R.

AU - McCarroll, Andrew J.

AU - McGarry, David

AU - Kirkham, James

AU - Pichowicz, Mark

AU - Walker, Rolf

AU - Warrilow, Catherine

AU - Salisbury, Anne-Marie

AU - Savage, Victoria J.

AU - Moyo, Emmanuel

AU - Forward, Henry

AU - Cheung, Jonathan

AU - Metzger, Richard

AU - Gault, Zoe

AU - Nelson, Gary

AU - Hughes, Diarmaid

AU - Cao, Sha

AU - Maclean, John

AU - Charrier, Cédric

AU - Craighead, Mark

AU - Best, Stuart

AU - Stokes, Neil R.

AU - Ratcliffe, Andrew J.

N1 - Copyright © 2016 Elsevier Ltd. All rights reserved.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.

AB - There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.

KW - ESKAPE pathogens

KW - anti-infectives

KW - topoisomerases

KW - DNA gyrase

KW - isothiazolone

KW - multi-drug resistant pathogens

KW - bacterial resistance

U2 - 10.1016/j.bmcl.2016.07.061

DO - 10.1016/j.bmcl.2016.07.061

M3 - Article

VL - 26

SP - 4179

EP - 4183

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 17

ER -