Pm. Tarantino et al., Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria, ANTIM AG CH, 43(8), 1999, pp. 1982-1987
6-Anilinouracils are selective inhibitors of DNA polymerase III, the enzyme
required for the replication of chromosomal DNA in gram-positive bacteria
(N. C. Brown, L, W. Dudycz, and G. E. Wright, Drugs Exp. Clin, Res. 12:555-
564, 1986), A new class of 6-anilinouracils based on N-3 alkyl substitution
of the uracil ring was synthesized and analyzed for activity as inhibitors
of the gram-positive bacterial DNA polymerase III and the growth of gram-p
ositive bacterial pathogens, Favorable in vitro properties of N-3-alkyl der
ivatives prompted the synthesis of derivatives in which the R group at N-3
was replaced with more-hydrophilic methoxyalkyl. and hydroxyalkyl groups. T
hese hydroxyalkyl and methoxyalkyl derivatives displayed Ki values in the r
ange from 0.4 to 2.8 mu M against relevant gram-positive bacterial DNA poly
merase IIIs and antimicrobial activity with MICs in the range from 0.5 to 1
5 mu g/ml against a broad spectrum of gram-positive bacteria, including met
hicillin-resistant staphylococci and vancomycin-resistant enterococci, Two
of these hydrophilic derivatives displayed protective activity in a simple
mouse model of lethal staphylococcal infection.