GSBS Student Publications

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

Date

6-4-1999

Document Type

Article

Medical Subject Headings

Anti-Bacterial Agents; Bacillus subtilis; DNA Polymerase III; Enzyme Inhibitors; Microbial Sensitivity Tests; Structure-Activity Relationship; Uracil

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.

Rights and Permissions

Citation: J Med Chem. 1999 Jun 3;42(11):2035-40. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

Journal of medicinal chemistry

PubMed ID

10354411