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

Cooper, Ian R. and McCarroll, Andrew J. and McGarry, David and Kirkham, James and Pichowicz, Mark and Walker, Rolf and Warrilow, Catherine and Salisbury, Anne-Marie and Savage, Victoria J. and Moyo, Emmanuel and Forward, Henry and Cheung, Jonathan and Metzger, Richard and Gault, Zoe and Nelson, Gary and Hughes, Diarmaid and Cao, Sha and Maclean, John and Charrier, Cédric and Craighead, Mark and Best, Stuart and Stokes, Neil R. and Ratcliffe, Andrew 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). pp. 4179-83. ISSN 0960-894X

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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.