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; Stuart Best; Neil R. Stokes; Andrew J. Ratcliffe

doi:10.1016/j.bmcl.2016.07.061

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 CraigheadStuart Best, Neil R. Stokes, Andrew J. Ratcliffe

Pure And Applied Chemistry

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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 language	English
Pages (from-to)	4179-83
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	17
Early online date	28 Jul 2016
DOIs	https://doi.org/10.1016/j.bmcl.2016.07.061
Publication status	Published - 1 Sept 2016

Keywords

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

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10.1016/j.bmcl.2016.07.061

Cooper-etal-BMCL2016-ovel-isothiazolone-class-of-bacterial-type-II-topoisomerase-inhibitorsAccepted author manuscript, 594 KBLicence: CC BY-NC-ND 4.0

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Cooper, I. R., McCarroll, A. J., McGarry, D., Kirkham, J., Pichowicz, M., Walker, R., Warrilow, C., Salisbury, A.-M., Savage, V. J., Moyo, E., Forward, H., Cheung, J., Metzger, R., Gault, Z., Nelson, G., Hughes, D., Cao, S., Maclean, J., Charrier, C., ... Ratcliffe, A. J. (2016). Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors. Bioorganic and Medicinal Chemistry Letters, 26(17), 4179-83. https://doi.org/10.1016/j.bmcl.2016.07.061

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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.\}",

year = "2016",

month = sep,

day = "1",

doi = "10.1016/j.bmcl.2016.07.061",

language = "English",

volume = "26",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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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

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.

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

C2 - 27499455

SN - 0960-894X

VL - 26

SP - 4179

EP - 4183

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 17

ER -

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

Abstract

Keywords

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