title: Biological characterization of novel inhibitors of the gram-positive DNA polymerase IIIC enzyme.
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.
authors.affiliation: Bayer HealthCare AG, Pharma Research EU, D-42096 Wuppertal, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuhl
authors.forename: Niels
authors.initials: N
authors.lastname: Svenstrup
authors.forename: Christoph
authors.initials: C
authors.lastname: Ladel
authors.forename: Michael
authors.initials: M
authors.lastname: Otteneder
authors.forename: Annegret
authors.initials: A
authors.lastname: Binas
authors.forename: Guido
authors.initials: G
authors.lastname: Schiffer
authors.forename: Michael
authors.initials: M
authors.lastname: Brands
authors.forename: Thomas
authors.initials: T
authors.lastname: Lampe
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
authors.forename: Helga
authors.initials: H
authors.lastname: Rübsamen-Waigmann
authors.forename: Dieter
authors.initials: D
authors.lastname: Haebich
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ehlert
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D017208:Rats, Wistar; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004247:DNA; D004258:DNA Polymerase III
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