Title
6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III: antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3
UMMS Affiliation
Graduate School of Biomedical Sciences; Department of Pharmacology and Molecular Toxicology; Department of Biochemistry and Molecular Pharmacology
Publication Date
1999-06-04
Document Type
Article
Disciplines
Life Sciences | Medicine and Health Sciences
Abstract
6-Anilinouracils (6-AUs) are dGTP analogues which selectively inhibit the DNA polymerase III of Bacillus subtilis and other Gram-positive bacteria. To enhance the potential of the 6-AUs as antimicrobial agents, a structure-activity relationship was developed involving substitutions of the uracil N3 position in two 6-AU platforms: 6-(3,4-trimethyleneanilino)uracil (TMAU) and 6-(3-ethyl-4-methylanilino)uracil (EMAU). Series of N3-alkyl derivatives of both 6-AUs were synthesized and tested for their ability to inhibit purified B. subtilis DNA polymerase III and the growth of B. subtilis in culture. Alkyl groups ranging in size from ethyl to hexyl enhanced the capacity of both platforms to bind to the polymerase, and with the exception of hexyl, they also significantly enhanced their antimicrobial potency. N3 substitution of the EMAU platform with more hydrophilic hydroxyalkyl and methoxyalkyl groups marginally enhanced anti-polymerase III activity but enhanced antibacterial potency severalfold. In sum, the results of these studies indicate that the ring N3 of 6-anilinouracils can tolerate substituents of considerable size and structural variety and, thus, can be manipulated to significantly enhance the antibacterial potency of this novel class of polymerase III-specific inhibitors.
DOI of Published Version
10.1021/jm980693i
Source
J Med Chem. 1999 Jun 3;42(11):2035-40. Link to article on publisher's site
Journal/Book/Conference Title
Journal of medicinal chemistry
Related Resources
PubMed ID
10354411
Repository Citation
Tarantino PM, Zhi C, Gambino J, Wright GE, Brown NC. (1999). 6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III: antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3. GSBS Student Publications. https://doi.org/10.1021/jm980693i. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1230