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

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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
Issue number17
Early online date28 Jul 2016
Publication statusPublished - 1 Sep 2016


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

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