Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils
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.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Graduate School of Biomedical Sciences
KeywordsAniline Compounds; Animals; Anti-Bacterial Agents; DNA Polymerase III; Gram-Positive Bacteria; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Uracil
Medicine and Health Sciences
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AbstractNumerous 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.
SourceJ Med Chem. 2005 Nov 3;48(22):7063-74. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/34006
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