N1-Benzofused Modification of Fluoroquinolones Reduces
Activity Against Gram-Negative Bacteria
Posted on 2020-05-19 - 00:13
The
fluoroquinolone class of antibiotics has 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. Because 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 hypothesized that an electron-rich benzofused N1 substituent could
enhance this interaction. Molecular modeling 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 synthesized 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 permeabilizer polymyxin B nonapeptide and compound efflux via resistance–nodulation–division-family
efflux transporters was evaluated using the known efflux pump inhibitor
phenylalanine–arginine β-naphthylamide. 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 because
of poor solubility profiles whereas compounds with intermediate hydrophobicity
were inactive because of impaired outer membrane penetration, and
reduced inhibition of topoisomerase targets, the latter in contrast
to modeling predictions. This study adds new information to the fluoroquinolone
SAR and suggests limited utility of large hydrophobic substituents
at the N1 position of fluoroquinolones.
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Laws, Mark; Hind, Charlotte; Favaron, Andrea; Jamshidi, Shirin; Evans, Bonnie; Clifford, Melanie; et al. (2020). N1-Benzofused Modification of Fluoroquinolones Reduces
Activity Against Gram-Negative Bacteria. ACS Publications. Collection. https://doi.org/10.1021/acsomega.9b03910