Abstract
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.
Highlights
Drug design is made far more challenging when structural information about the biological target in question is lacking or the mechanism of action of a hit compound is unknown
While recent advances in the field of protein crystallography have allowed the structures of many challenging targets to be solved,[1] molecular modeling has traditionally been employed in such cases to allow the rational design and improvement of promising drug scaffolds.[2]
Visual examination of the binding poses predicted for each compound indicated that the N1-benzofused compounds would bind K. pneumoniae DNA gyrase in a similar manner to ciprofloxacin (Figure 2), though this did not appear to be the case with S. aureus (Figure S1)
Summary
Drug design is made far more challenging when structural information about the biological target in question is lacking or the mechanism of action of a hit compound is unknown. While recent advances in the field of protein crystallography have allowed the structures of many challenging targets to be solved,[1] molecular modeling has traditionally been employed in such cases to allow the rational design and improvement of promising drug scaffolds.[2]. Instead, modeling suites employ coarse grain molecular dynamics simulations for the majority of the biological target, with the more resource-intensive quantum mechanical simulations reserved for small, specific areas with which the drug is likely to directly interact.[3]. This compromise inevitably limits the utility of the data generated, the result being that drug discovery efforts are still primarily driven by in vitro and in vivo assays. We opine that the refinement of older, successful drug scaffolds developed in the premodeling era represents a task to which current modeling suites are well suited
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