Design and structure-activity relationships of potent and selective inhibitors of undecaprenyl pyrophosphate synthase (UPPS): tetramic, tetronic acids and dihydropyridin-2-ones

Bioorg Med Chem Lett. 2008 Mar 15;18(6):1840-4. doi: 10.1016/j.bmcl.2008.02.009. Epub 2008 Feb 10.

Abstract

Based on a pharmacophore hypothesis substituted tetramic and tetronic acid 3-carboxamides as well as dihydropyridin-2-one-3-carboxamides were investigated as inhibitors of undecaprenyl pyrophosphate synthase (UPPS) for use as novel antimicrobial agents. Synthesis and structure-activity relationship patterns for this class of compounds are discussed. Selectivity data and antibacterial activities for selected compounds are provided.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / metabolism
  • Amides / chemical synthesis
  • Amides / pharmacology*
  • Cyclization
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / enzymology
  • Furans / chemical synthesis
  • Furans / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Polyisoprenyl Phosphates / metabolism
  • Protein Conformation
  • Pyrrolidinones / chemical synthesis
  • Pyrrolidinones / chemistry
  • Pyrrolidinones / pharmacology*
  • Sesquiterpenes / metabolism
  • Streptococcus pneumoniae / drug effects*
  • Streptococcus pneumoniae / growth & development
  • Structure-Activity Relationship

Substances

  • Amides
  • Enzyme Inhibitors
  • Furans
  • Polyisoprenyl Phosphates
  • Pyrrolidinones
  • Sesquiterpenes
  • tetramic acid
  • farnesyl pyrophosphate
  • Alkyl and Aryl Transferases
  • undecaprenyl pyrophosphate synthetase
  • tetronic acid