Novel Fluoroquinolone Hybrids:Design, Synthesis And Evaluation As Antibacterial Agents

Based on the multi-target drug design and hybrid strategy for drug research anddevelopment, two series of multi-target antibacterial agents were designed andsynthesized. Twenty-seven3-arylfuran-2(5H)-one-fluoroquinolones were demonstratedas inhibitors against both DNA gyrase and tyrosyl-tRNA synthetase (TyrRS).Twenty-one flavonoid-fluoroquinolone hybrids were confirmed as dual mode inhibitorsof efflux pump and DNA gyrase. The results show that some obtained hybrids of bothseries displayed excellent antibacterial activity.In the terms of3-arylfuran-2(5H)-one-fluoroquinolone hybrids, most of the testedcompounds exhibited merits from both parents, displaying a broad spectrum of activityagainst resistant strains including both Gram-negative and Gram-positive bacteria. Themost potent compound A11which is the3-(2-fluorophenyl)-2(5H)-one-ciprofloxacinhybrid shows MIC50of0.11μg/mL against multiple drug resistant E. coli inantibacterial assay, being about51-fold more potent than ciprofloxacin. The enzymeassays reveal that A11is a potent multi-target inhibitor with IC50of1.15±0.07μMagainst DNA gyrase and0.12±0.04μM against TyrRS, respectively. These inspiringresults strongly suggest that A11deserves to further research as a novel antibiotic.Such excellent results can also be found among the flavonoid-fluoroquinolonehybrids. Most of flavonoid-fluoroquinolones showed outstanding antibacterial activityagainst drug-resistant microorganisms. The narigenin-ciprofloxacin (MIC500.71μg/mL,0.0.62μg/mL,0.29μg/mL and0.14μg/mL) is the most active, showing8,43,23and88times better activity than ciprofloxacin (MIC505.65μg/mL,2.70μg/mL,6.82μg/mLand32.4μg/mL) against E. coli ATCC35218, B. subtilis ATCC6633, S. aureus ATCC25923and C. albicans ATCC90873, respectively. DNA supercoiling assays of twoactive analogues revealed potent inhibition of the DNA gyrase, confirming the desiredmode of action. Molecular docking study disclosed that the introduced flavonoid moietyto the floxacin moiety not only provides several additional interactions but also does notdisturb the binding mode of the floxacin moiety. Our data also demonstrated that a hightolerance for structural variations at the C-7position.The structure-activity relationships of the two series of hybrids were well describedthrough the further analysis of the activity evaluation results. Furthermore, the study ofmolecular docking revealed the binding modes of these molecules with DNA gyrase andTyrRS. These findings provide a powerful set of tools for structural optimization.