GSBS Student Publications

Title

Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Biochemistry and Molecular Pharmacology

Date

2-17-2006

Document Type

Article

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Med Chem. 2006 Feb 23;49(4):1455-65. Link to article on publisher's site

DOI of Published Version

10.1021/jm0510023

Related Resources

Link to Article in PubMed

Journal Title

Journal of medicinal chemistry

PubMed ID

16480282