Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and gram-positive bacterial growth

Journal of Medicinal Chemistry

Volumn 46, Issue 13, 2003, Pages 2731-2739

  Zhi, Chengxin ^a   Long, Zheng Yu ^a   Gambino, Joseph ^a   Xu, Wei Chu ^a   Brown, Neal C ^b   Barnes, Marjorie ^b   Butler, Michelle ^c   LaMarr, William ^c   Wright, George E ^a  

^a GLSYNTHESIS INC   (United States)

^b UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^c MICROBIOTIX INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (4 HYDROXYBUTYL) 6 (3 ETHYL 4 METHYLANILINO)URACIL; 3 (4 METHOXYBUTYL) 6 (3 ETHYL 4 METHYLANILINO)URACIL; 6 (3 ETHYL 4 METHYLANILINO) DERIVATIVE; 6 ANILINOURACIL DERIVATIVE; ANTIINFECTIVE AGENT; DNA DIRECTED DNA POLYMERASE GAMMA; UNCLASSIFIED DRUG;

ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERIAL GROWTH; DRUG POTENCY; DRUG STRUCTURE; GRAM POSITIVE BACTERIUM; STRUCTURE ACTIVITY RELATION;

ANILINE COMPOUNDS; ANTI-BACTERIAL AGENTS; DNA POLYMERASE III; ENZYME INHIBITORS; GRAM-POSITIVE BACTERIA; HYDROPHOBICITY; MICROBIAL SENSITIVITY TESTS; STRUCTURE-ACTIVITY RELATIONSHIP; URACIL;

EID: 0038792271     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm020591z     Document Type: Article

References (17)

1. Tarantino, P.; Zhi, C.; Gambino, J.; Wright, G. E.; Brown, N. C. 6-Anilinouracil-based Inhibitors of Bacillus subtilis DNA Polymerase III: Antipolymerase and Antimicrobial Structure-Activity Relationships Based on Substitution at Uracil N3. J. Med. Chem. 1999, 42, 2035-2040.
2. Tarantino, P.; Zhi, C.; Wright, G. E.; Brown, N. C. Inhibitors of DNA Polymerase III as Novel Antimicrobial Agents against Gram-positive Eubacteria. Antimicr. Agents Chemother. 1999, 43, 1982-1987.
3. Braithwaite, D.; Ito, J. Compilation, alignment and phylogenetic relationships of DNA polymerases. Nucl. Acids Res. 1993, 21, 787-802.
4. Barnes, M. H.; Miller, S. D.; Brown, N. C. The DNA polymerases of Bacillus subtilis: identification of the replication-specific enzyme encoded by dnaE. J. Bacteriol. 2002, 184, 3834-3838.
5. Clements, J. E.; D'Ambrosio, J.; Brown, N. C. Inhibition of Bacillus subtilis deoxyribonucleic acid polymerase III by phenylhydrazinopyrimidines. Demonstration of a drug-induced deoxyribonucleic acid-enzyme complex. J. Biol. Chem. 1975, 250, 522-526.
6. Wright, G. E.; Brown, N. C. Inhibitors of Bacillus Subtilis DNA Polymerase III. 6-Anilinouracils and 6-(Alkylamino)uracils. J. Med. Chem. 1980, 23, 34-38.
7. Wright, G. E.; Gambino, J. J. Quantitative Structure-Activity Relationships of 6-Anilinouracils as Inhibitors of Bacillus Subtilis DNA Polymerase III. J. Med. Chem. 1984, 27, 181-185.
8. Brown, N. C.; Wright, G. E. DNA Polymerase III - A New Target for Antibiotic Development. Curr. Opin. Anti-Infect. Invest. Drugs 1999, 1, 45-48.
9. Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. Total synthesis of lycopodium alkaloids: (+)-lycopodine, (+)-lycodine and (+)lycodoline. J. Am. Chem. Soc. 1982, 104, 1054-1068.
10. Kirmse, W.; Jansen, U. Deamination reactions. 41. Reactions of aliphatic diazonium ions and carbocations with ethers. Chem. Ber. 1985, 118, 2607-2625.
11. Daly, J. S.; Giehl, T. J.; Brown, N. C.; Zhi, C.; Wright, G. E.; Ellison, R. T., III. In Vitro Antimicrobial Activities of Novel Anilinouracils Which Selectively Inhibit DNA Polymerase III of Gram-Positive Bacteria. Antimicrob. Agents Chemother. 2000, 44, 2217-2221.
12. Thomsen, A. D.; Lund, H. On the Friedel-Crafts Acylation of p-Methylacetanilide. Acta Chem. Scand. 1969, 23, 2930-2931.
13. Hammond, R.; Barnes, M.; Mack, S.; Mitchener, J.; Brown, N. Bacillus subtilis DNA polymerase III: complete sequence, overexpression and characterization of the polC gene. Gene 1991, 98, 29-36.
14. Barnes, M. H.; Brown, N. C. Antibody to B. subtilis DNA polymerase III: use in the purification of enzyme and the study of its structure. Nucl. Acids Res. 1979, 6, 1203-1219.
15. Wright, G. E.; Brown, N. C. Inhibition of Bacillus subtilis DNA Polymerase III by Arylhydrazinopyrimidines: Novel Properties of 2-Thiouracil Derivatives. Biochim. Biophys. Acta, 1976, 432, 37-48.
16. Wright, G. E.; Brown, N. C. Deoxyribonucleotide Analogues as Inhibitors and Substrates of DNA Polymerases. Pharmacol. Ther. 1990, 47, 447-497.
17. Love, E.; D'Ambrosio, J.; Dubnau, D.; Brown, N. C. Mapping of the gene specifying DNA polymerase III from Bacillus subtilis. Mol. Gen. Genet. 1976, 144, 313-321.