Novel non-nucleobase inhibitors of Staphylococcus aureus DNA polymerase IIIC.
The preparation and biological evaluation of 5-substituted-6-hydroxy-2-(anilino)pyrimidinones as a new class of DNA polymerase IIIC inhibitors, required for the replication of chromosomal DNA in Gram-positive bacteria, are described. These new dGTP competitive inhibitors displayed good levels of in vitro inhibition and antibacterial activity against Staphylococcus aureus. A new class of dATP competitive inhibitors, 6-substituted-2-amino-5-alkyl-pyrimidin-4-ones, whose antibacterial activity was unaffected by serum, were identified.
Rose
Yannick
Y
Targanta Therapeutics Inc., 7170 Frederick-Banting, 2nd Floor, Montréal, Québec, Canada H4S 2A1. yrose@targanta.com
Ciblat
Stéphane
S
Reddy
Ranga
R
Belley
Adam C
AC
Dietrich
Evelyne
E
Lehoux
Dario
D
McKay
Geoffrey A
GA
Poirier
Hugo
H
Far
Adel Rafai
AR
Delorme
Daniel
D
D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D004258:DNA Polymerase III