New DNA polymerase IIIC inhibitors: 3-subtituted anilinouracils with potent antibacterial activity in vitro and in vivo.
The development of resistance has rendered several antibiotics clinically ineffective, and there is an urgent medical need for potent and safe antibacterials with a novel and valid mode of action. To avoid cross-resistance, they should preferably inhibit targets that are not addressed by established antibiotics. In this respect, 6-anilinouracils represent a promising lead structure. They target the Gram-positive DNA polymerase IIIC, a target that is associated with a bactericidal mode of action. Moreover, they have no cross-resistance to marketed antibiotics. This paper describes the synthesis and biological characterization of structurally novel anilinouracils, some of which display potent in vivo efficacy in murine models of bacterial septicemia.
Svenstrup
Niels
N
Global Drug Discovery, Bayer Schering Pharma, Bayer HealthCare AG, 42096 Wuppertal, Germany. Niels.Svenstrup@BayerHealthcare.com
Ehlert
Kerstin
K
Ladel
Christoph
C
Kuhl
Alexander
A
Häbich
Dieter
D
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008826:Microbial Sensitivity Tests; D023421:Models, Animal; D014498:Uracil / Q000031:analogs & derivatives*
D000900:Anti-Bacterial Agents; D014498:Uracil; D004258:DNA Polymerase III