title: Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth.
abstract: 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.
authors.affiliation: GLSynthesis Inc., One Innovation Drive, Worcester, Massachusetts 01605, USA.
authors.forename: Chengxin
authors.initials: C
authors.lastname: Zhi
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Long
authors.forename: Joseph
authors.initials: J
authors.lastname: Gambino
authors.forename: Wei-Chu
authors.initials: WC
authors.lastname: Xu
authors.forename: Neal C
authors.initials: NC
authors.lastname: Brown
authors.forename: Marjorie
authors.initials: M
authors.lastname: Barnes
authors.forename: Michelle
authors.initials: M
authors.lastname: Butler
authors.forename: William
authors.initials: W
authors.lastname: LaMarr
authors.forename: George E
authors.initials: GE
authors.lastname: Wright
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D014498:Uracil; D004258:DNA Polymerase III