ABSTRACT
There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase-topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K(+) channel block. On the other hand, analog 49e displayed lower hERG K(+) channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , DNA Topoisomerases/metabolism , Drug Design , Gram-Positive Bacteria/drug effects , Pyrans/chemical synthesis , Pyrans/pharmacology , Animals , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacokinetics , Chemistry Techniques, Synthetic , DNA Gyrase/chemistry , DNA Gyrase/metabolism , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerase IV/chemistry , DNA Topoisomerase IV/metabolism , DNA Topoisomerases/chemistry , Female , Gram-Positive Bacteria/enzymology , Humans , Inhibitory Concentration 50 , Mice , Molecular Docking Simulation , Protein Conformation , Pyrans/metabolism , Pyrans/pharmacokinetics , Rats , Structure-Activity Relationship , Topoisomerase II Inhibitors , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/metabolism , Topoisomerase Inhibitors/pharmacokinetics , Topoisomerase Inhibitors/pharmacologyABSTRACT
A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.
