Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils
Graduate School of Biomedical Sciences; Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Aniline Compounds; Animals; Anti-Bacterial Agents; DNA Polymerase III; Gram-Positive Bacteria; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Uracil
Life Sciences | Medicine and Health Sciences
Numerous 3-substituted-6-(3-ethyl-4-methylanilino)uracils (EMAU) have been synthesized and screened for their capacity to inhibit the replication-specific bacterial DNA polymerase IIIC (pol IIIC) and the growth of Gram+ bacteria in culture. Direct alkylation of 2-methoxy-6-amino-4-pyrimidone produced the N3-substituted derivatives, which were separated from the byproduct 4-alkoxy analogues. The N3-substituted derivatives were heated with a mixture of 3-ethyl-4-methylaniline and its hydrochloride to effect displacement of the 6-amino group and simultaneous demethylation of the 2-methoxy group to yield target compounds in good yields. Certain intermediates, e.g. the 3-(iodoalkyl) compounds, were converted to a variety of (3-substituted-alkyl)-EMAUs by displacement. Most compounds were potent competitive inhibitors of pol IIIC (K(i)s 0.02-0.5 microM), and those with neutral, moderately polar 3-substituents had potent antibacterial activity against Gram+ organisms in culture (MICs 0.125-10 microg/mL). Several compounds protected mice from lethal intraperitoneal (ip) infections with S. aureus (Smith) when given by the ip route. A water soluble derivative, 3-(4-morpholinylbutyl)-EMAU hydrochloride, given subcutaneously, prolonged the life of infected mice in a dose dependent manner.
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Citation: J Med Chem. 2005 Nov 3;48(22):7063-74. Link to article on publisher's site
DOI of Published Version
Journal of medicinal chemistry
Zhi, Chengxin; Long, Zheng-yu; Manikowski, Andrzej; Brown, Neal C.; Tarantino, Paul M.; Holm, Karsten A.; Dix, Edward J.; Wright, George E.; Foster, Kimberly A.; Butler, Michelle Marie; LaMarr, William A.; Skow, Donna J.; Motorina, Irina; Lamothe, Serge; and Storer, Richard, "Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils" (2005). GSBS Student Publications. 659.