Antibacterial agent discovery using thymidylate synthase biolibrary screening

J Med Chem. 2006 Oct 5;49(20):5958-68. doi: 10.1021/jm051187d.

Abstract

Thymidylate synthase (TS, ThyA) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate to 2'-deoxythymidine 5'-monophosphate, an essential precursor for DNA synthesis. A specific inhibition of this enzyme induces bacterial cell death. As a second round lead optimization design, new 1,2-naphthalein derivatives have been synthesized and tested against a TS-based biolibrary, including human thymidylate synthase (hTS). Docking studies have been performed to rationalize the experimentally observed affinity profiles of 1,2-naphthalein compounds toward Lactobacillus casei TS and hTS. The best TS inhibitors have been tested against a number of clinical isolates of Gram-positive-resistant bacterial strains. Compound 3,3-bis(3,5-dibromo-4-hydroxyphenyl)-1H,3H-naphtho[1,2-c]furan-1-one (5) showed significant antibacterial activity, no in vitro toxicity, and dose-response effects against Staphylococcus epidermidis (MIC=0.5-2.5 microg/mL) clinical isolate strains, which are resistant to at least 17 of the best known antibacterial agents, including vancomycin. So far this compound can be regarded as a leading antibacterial agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry*
  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry*
  • Benzofurans / pharmacology
  • Chlorocebus aethiops
  • Citrobacter / drug effects
  • Cryptococcus neoformans / enzymology
  • Databases, Factual
  • Drug Resistance, Multiple, Bacterial
  • Enterococcus / drug effects
  • Enterococcus / isolation & purification
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Humans
  • Lacticaseibacillus casei / enzymology
  • Listeria monocytogenes / drug effects
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry*
  • Naphthalenes / pharmacology
  • Staphylococcus / drug effects
  • Staphylococcus / isolation & purification
  • Streptococcus / drug effects
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / chemistry*
  • Vero Cells

Substances

  • 1,1-bis(3,5-dibromo-4-hydroxyphenyl)-1H-naphtho(1,2-c)furan-3-one
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Benzofurans
  • Naphthalenes
  • Tetrahydrofolate Dehydrogenase
  • Thymidylate Synthase