Inhibitors of Bacillus subtilis DNA polymerase III. 6-Anilinouracils and 6-(alkylamino)uracils.
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.
D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D001665:Binding Sites; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D019384:Nucleic Acid Synthesis Inhibitors; D014498:Uracil; D004258:DNA Polymerase III