Synthesis and Antibacterial Activity of 3-Substituted-6-(3-ethyl-4-methylanilino)uracils
| Autor: | Zheng-yu Long, George E. Wright, Richard Storer, Karsten A. Holm, Neal C. Brown, Andrzej Manikowski, Donna J. Skow, Kimberly A. Foster, Serge Lamothe, Paul M. Tarantino, Irina Motorina, Michelle M. Butler, Chengxin Zhi, William A. LaMarr, Edward J. Dix |
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| Rok vydání: | 2005 |
| Předmět: |
Staphylococcus aureus
Hydrochloride Stereochemistry Microbial Sensitivity Tests Alkylation Gram-Positive Bacteria Chemical synthesis Mice Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Uracil Polymerase DNA Polymerase III Antibacterial agent Demethylation Aniline Compounds biology Staphylococcal Infections biology.organism_classification Anti-Bacterial Agents chemistry biology.protein Molecular Medicine Antibacterial activity Bacteria |
| Zdroj: | Journal of Medicinal Chemistry. 48:7063-7074 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm050517r |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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