Abstract
Although the wide arsenal of drugs available to treat bacterial infections, emerging drug-resistant bacterial pathogens have recently highlighted an urgent need to find new more effective and less toxic therapeutic agents. Fluoroquinolones, including norfloxacin, are antibiotics showing a concentration-dependent bactericidal capacity due to the activity inhibition of DNA-gyrase and topoisomerase IV, which are enzymes essential for bacterial DNA replication. Naphthoquinones are secondary metabolites showing different biological activities, including cytotoxic, antibacterial and antifungal effects. In particular, the efficacy of natural and synthetic 1,4-naphthoquinone derivatives is likely due to their oxidizing/reducing capability, through which they destroy cellular targets as nucleic acids. Hybrid molecules are produced combining structural features of two or more bioactive compounds, in order to obtain new therapeutic agents able, not only to reduce undesirable side effects of the parent drugs, but also to inhibit more biological targets, hopefully with a better therapeutic property than the administration of combined single-target drugs. With the aim to apply this strategy in the study of new potential antimicrobial agents, we have synthesized four hybrid molecules by the reaction of norfloxacin with suitable quinones and their activities have been evaluated against both bacteria and fungi, in comparison with synthetic precursors. The experimental data are supported by docking calculations on S. aureus DNA-gyrase, discussing the interactions involved for each hybrid molecule, in comparison with norfloxacin and the original ligand moxifloxacin.
Highlights
In recent rational design of new drugs, molecular hybridization is a successful approach using scaffolds present in single therapeutically active agents, connected together in a new single structure by covalent bonds
We report here on the synthesis of new hybrid norfloxacin-quinone derivatives, their in vitro antimicrobial activities and a computational analysis of the complexes with S. aureus DNA-gyrase
Compounds 5-7 were synthesized by a nucleophilic substitution of norfloxacin (1) on the suitable quinones 2-4 [12,13] in dichloromethane solution at room temperature in the presence of triethylamine (Scheme 1)
Summary
In recent rational design of new drugs, molecular hybridization is a successful approach using scaffolds present in single therapeutically active agents, connected together in a new single structure by covalent bonds. The aim of this strategy is to obtain new molecules able to reduce undesirable side effects of the parent drugs, with the advantage of inhibiting more than one biological target simultaneously. After the first-generation quinolones mainly effective against Gram-(-) bacteria, fluoroquinolones were introduced They are more potent and show a broad spectrum of activities, but their use is limited by toxic effects, spontaneous mutation of targeted enzymes and an increased number of resistant pathogens. Norfloxacin is used to treat both humans and animals against Gram-(+). and Gram-(-) bacteria
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