7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity

Bioorg Med Chem Lett. 2011 Jul 15;21(14):4197-202. doi: 10.1016/j.bmcl.2011.05.093. Epub 2011 May 30.

Abstract

Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N(2)-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N(2)-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10μg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • DNA Polymerase III / antagonists & inhibitors*
  • DNA Polymerase III / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Escherichia coli / drug effects
  • Gram-Positive Bacteria / drug effects
  • Gram-Positive Bacteria / enzymology
  • Guanine / analogs & derivatives*
  • Guanine / chemistry
  • Guanine / pharmacology
  • Guanine / therapeutic use
  • Mice
  • Microbial Sensitivity Tests
  • Staphylococcal Infections / drug therapy

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Guanine
  • 3-deazaguanine
  • DNA Polymerase III