Synthesis of Substituted 6-Anilinouracils and Their Inhibition of DNA Polymerase IIIC and Gram-Positive Bacterial Growth
| Autor: | George E. Wright, Marjorie H. Barnes, Joseph Gambino, Michelle M. Butler, Chengxin Zhi, Zheng-yu Long, William A. LaMarr, Neal C. Brown, Wei-Chu Xu |
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| Rok vydání: | 2003 |
| Předmět: |
Stereochemistry
DNA polymerase Gram-positive bacteria Microbial Sensitivity Tests Bacillus subtilis Gram-Positive Bacteria Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Structure–activity relationship Enzyme Inhibitors Uracil Polymerase DNA Polymerase III Antibacterial agent Aniline Compounds biology biology.organism_classification Anti-Bacterial Agents Biochemistry chemistry biology.protein Molecular Medicine Antibacterial activity Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of Medicinal Chemistry. 46:2731-2739 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm020591z |
| Popis: | Certain substituted 6-anilinouracils are potent and selective inhibitors of Gram+ bacterial DNA polymerase IIIC (pol IIIC). In addition, analogues with 3-substituents in the uracil ring have potent antibacterial activity against Gram+ organisms in culture. In an attempt to find optimal anilino substituents for pol IIIC binding and optimal 3-substituents for antibacterial activity, we have prepared several series of 3-substituted-6-aminouracils and assayed their activity against pol IIIC from Bacillus subtilis and a panel of Gram+ and Gram- bacteria in culture. The 6-(3-ethyl-4-methylanilino) group and closely related substituent patterns maximized pol IIIC inhibition potency. Among a series of 3-(substituted-butyl)-6-(3-ethyl-4-methylanilino)uracils, basic amino substituents increased pol IIIC inhibition, but decreased antibacterial activity. The most potent antibacterials were simple hydroxybutyl and methoxybutyl derivatives, and hydrophobically substituted piperidinylbutyl derivatives. |
| Databáze: | OpenAIRE |
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