Inhibitors of Bacillus subtilis DNA polymerase III. 6-Anilinouracils and 6-(alkylamino)uracils

J Med Chem. 1980 Jan;23(1):34-8. doi: 10.1021/jm00175a007.


Substituted 6-anilinouracils were found to be potent inhibitors of the replication-specific enzyme, DNA polymerase III, from Bacillus subtilis. Inhibition potency was maximized by inclusion of small alkyl groups or halogens in the meta and para positions of the phenyl ring; polar substituents decreased activity considerably. Qualitative structure--activity relationships indicated that the meta position can tolerate larger groups, suggesting that this position may be suitable for the introduction of a group capable of irreversibly binding to the enzyme. Several 6-(alkylamino)uracils were weak inhibitors of DNA polymerases III; the optimum alkyl groups for enzyme binding were n-pentyl and n-hexyl, which apparently can occupy the planar enzyme binding site. The varied activities of 6-anilinouracils on a mutant DNA polymerase, resistant to 6-(phenylhydrazino)- and 6-(benzylamino)uracils bearing a p-OH or NH2 group, have altered previous postulates for the structural basis of inhibitor resistance and have permitted construction of a refined model for inhibitor conformation in the latter series.

Publication types

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

MeSH terms

  • Bacillus subtilis / drug effects
  • Bacillus subtilis / enzymology*
  • Bacillus subtilis / genetics
  • Binding Sites
  • DNA Polymerase III / antagonists & inhibitors*
  • Mutation
  • Nucleic Acid Synthesis Inhibitors*
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis
  • Uracil / pharmacology


  • Nucleic Acid Synthesis Inhibitors
  • Uracil
  • DNA Polymerase III