Diazenedicarboxamides as inhibitors of D-alanine-D-alanine ligase (Ddl)

Bioorg Med Chem Lett. 2007 Apr 1;17(7):2047-54. doi: 10.1016/j.bmcl.2007.01.015. Epub 2007 Jan 17.

Abstract

D-Alanine-D-alanine ligase (Ddl) catalyzes the biosynthesis of an essential bacterial peptidoglycan precursor D-alanyl-D-alanine and it represents an important target for development of new antibacterial drugs. A series of semicarbazides, aminocarbonyldiazenecarboxylates, diazenedicarboxamides, and hydrazinedicarboxamides was synthesized and screened for inhibition of DdlB from Escherichia coli. Compounds with good inhibitory activity were identified, enabling us to deduce initial structure-activity relationships. Thirteen diazenedicarboxamides were better inhibitors than D-cycloserine and some of them also possess antibacterial activity, which makes them a promising starting point for further development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Carboxylic Acids / chemistry
  • Catalysis
  • Chemistry, Pharmaceutical / methods*
  • Crystallography, X-Ray
  • Cycloserine / chemistry
  • Drug Design
  • Escherichia coli / metabolism
  • Imides / chemistry*
  • Imides / pharmacology
  • Models, Chemical
  • Molecular Conformation
  • Peptide Synthases / antagonists & inhibitors*
  • Phosphorylation

Substances

  • Anti-Bacterial Agents
  • Carboxylic Acids
  • Imides
  • Adenosine Diphosphate
  • Cycloserine
  • Peptide Synthases
  • D-alanylalanine synthetase
  • diazene