King's College London

Research portal

N1-Benzofused Modification of Fluoroquinolones Reduces Activity Against Gram-Negative Bacteria

Research output: Contribution to journalArticle

Mark Laws, Charlotte K. Hind, Andrea Favoran, Shirin Jamshidi, Bonnie Evans, Melanie Clifford, J. Mark Sutton, Miraz Rahman

Original languageEnglish
Article numberacsomega.9b03910
Pages (from-to)11923–11934
Number of pages12
JournalACS Omega
Issue number21
Publication statusPublished - 18 May 2020


King's Authors


The fluoroquinolone class of antibiotics have a well-established structure-activity relationship (SAR) and a long history in the clinic, but the effect of electron-rich benzofused substituents at the N1 position remains poorly explored. Since groups at this position are part of the topoisomerase-DNA binding complex and form a hydrophobic interaction with the major groove of DNA, it was hypothesised that an electron-rich benzofused N1 substituent could enhance this interaction. Molecular modelling techniques were employed to evaluate the binding of certain N1-modified fluoroquinolones to DNA gyrase targets from both Staphylococcus aureus and Klebsiella pneumoniae species compared with ciprofloxacin and norfloxacin. Seven N1-modified fluoroquinolones were subsequently synthesised and tested against a panel of Gram-negative pathogens to determine minimum inhibitory concentration (MIC) values. Gram-negative outer membrane penetration was investigated using the membrane permeabiliser polymyxin B nonapeptide (PMBN) and compound efflux via RND-family efflux transporters was evaluated using the known efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PAβN). Additionally, the target inhibitory activity of representative compound 6e was determined in a cell-free environment. A correlation between N1 substituent hydrophobicity and activity was observed across the MIC panel, with compound activity decreasing with increased hydrophobicity. Those compounds with highest hydrophobicity were inactive due to poor solubility profiles whereas compounds with intermediate hydrophobicity were inactive due to impaired outer membrane penetration and reduced inhibition of topoisomerase targets, the latter in contrast to modelling predictions. This study adds new information to the fluoroquinolone SAR and suggests limited utility of large hydrophobic substituents at the N1 position of fluoroquinolones.

Download statistics

No data available

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454