title: Design, synthesis, and characterization of novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram-positive activity.
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.
authors: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors: Jean-Philippe
authors: JP
authors: Surivet
authors: Cornelia
authors: C
authors: Zumbrunn
authors: Georg
authors: G
authors: Rueedi
authors: Christian
authors: C
authors: Hubschwerlen
authors: Daniel
authors: D
authors: Bur
authors: Thierry
authors: T
authors: Bruyère
authors: Hans
authors: H
authors: Locher
authors: Daniel
authors: D
authors: Ritz
authors: Wolfgang
authors: W
authors: Keck
authors: Peter
authors: P
authors: Seiler
authors: Christopher
authors: C
authors: Kohl
authors: Jean-Christophe
authors: JC
authors: Gauvin
authors: Azely
authors: A
authors: Mirre
authors: Verena
authors: V
authors: Kaegi
authors: Marina
authors: M
authors: Dos Santos
authors: Mika
authors: M
authors: Gaertner
authors: Jonathan
authors: J
authors: Delers
authors: Michel
authors: M
authors: Enderlin-Paput
authors: Maria
authors: M
authors: Boehme
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D026942:DNA Topoisomerases / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011714:Pyrans / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011714:Pyrans; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; D027101:DNA Topoisomerase IV; D026942:DNA Topoisomerases; D027081:DNA Gyrase