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

J Med Chem. 2003 Jun 19;46(13):2731-9. doi: 10.1021/jm020591z.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / pharmacology
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • DNA Polymerase III / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Gram-Positive Bacteria / drug effects*
  • Hydrophobic and Hydrophilic Interactions
  • Microbial Sensitivity Tests
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis*
  • Uracil / pharmacology

Substances

  • Aniline Compounds
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Uracil
  • DNA Polymerase III