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Antimicrob Agents Chemother. 2005 Mar;49(3):987-95.

Biological characterization of novel inhibitors of the gram-positive DNA polymerase IIIC enzyme.

Author information

1
Bayer HealthCare AG, Pharma Research EU, D-42096 Wuppertal, Germany.

Abstract

Novel N-3-alkylated 6-anilinouracils have been identified as potent and selective inhibitors of bacterial DNA polymerase IIIC, the enzyme essential for the replication of chromosomal DNA in gram-positive bacteria. A nonradioactive assay measuring the enzymatic activity of the DNA polymerase IIIC in gram-positive bacteria has been assembled. The 6-anilinouracils described inhibited the polymerase IIIC enzyme at concentrations in the nanomolar range in this assay and displayed good in vitro activity (according to their MICs) against staphylococci, streptococci, and enterococci. The MICs of the most potent derivatives were about 4 microg/ml for this panel of bacteria. The 50% effective dose of the best compound (6-[(3-ethyl-4-methylphenyl)amino]-3-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}uracil) was 10 mg/kg of body weight after intravenous application in a staphylococcal sepsis model in mice, from which in vivo pharmacokinetic data were also acquired.

PMID:
15728893
PMCID:
PMC549236
DOI:
10.1128/AAC.49.3.987-995.2005
[Indexed for MEDLINE]
Free PMC Article

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