Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors
Graduate School of Biomedical Sciences; Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Acute Toxicity Tests; Aniline Compounds; Animals; Anti-Bacterial Agents; DNA Gyrase; DNA Polymerase III; Drug Resistance, Bacterial; Gram-Positive Bacteria; Male; Mice; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Uracil; synthesis
Life Sciences | Medicine and Health Sciences
Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, 3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting "AU-FQ" hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU-FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.
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Citation: J Med Chem. 2006 Feb 23;49(4):1455-65. Link to article on publisher's site
Journal of medicinal chemistry
Zhi, Chengxin; Long, Zheng-yu; Manikowski, Andrzej; Comstock, Jeanne; Xu, Wei-Chu; Brown, Neal C.; Tarantino, Paul M.; Holm, Karsten A.; Dix, Edward J.; Wright, George E.; Barnes, Marjorie H.; Butler, Michelle Marie; Foster, Kimberly A.; LaMarr, William A.; Bachand, Benoit; Bethell, Richard; Cadilhac, Caroline; Charron, Sylvie; Lamothe, Serge; Motorina, Irina; and Storer, Richard, "Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors" (2006). GSBS Student Publications. 660.