2-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda6-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides as potent and selective peptide deformylase inhibitors

J Med Chem. 2001 Jun 7;44(12):1847-52. doi: 10.1021/jm000352g.

Abstract

Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Escherichia coli peptide deformylase (PDF) were obtained by rational optimization of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural information, gathered from Ni-PDF complexed with 1, suggested the preparation of two series of related hydroxamic acid analogues, 2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-N-hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides (B), among which potent PDF inhibitors (37, 42, and 48) were identified. Moreover, two selected compounds, one from each series, 36 and 41, showed good selectivity for PDF over several endoproteases including matrix metalloproteases. However, these compounds showed only weak antibacterial activity.

MeSH terms

  • Amidohydrolases*
  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / chemistry
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacteria / drug effects
  • Bacteria / isolation & purification
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Escherichia coli / enzymology*
  • Humans
  • Hydrogen Bonding
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Thiadiazines / chemical synthesis*
  • Thiadiazines / chemistry
  • Thiadiazines / pharmacology

Substances

  • Anti-Bacterial Agents
  • Hydroxamic Acids
  • Protease Inhibitors
  • Quinazolines
  • Thiadiazines
  • Aminopeptidases
  • Amidohydrolases
  • peptide deformylase