Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532

Bioorg Med Chem. 2021 Jan 15:30:115964. doi: 10.1016/j.bmc.2020.115964. Epub 2020 Dec 29.

Abstract

Infectious diseases caused by resistant Gram-negative bacteria have become a serious problem, and the development of therapeutic drugs with a novel mechanism of action and that do not exhibit cross-resistance with existing drugs has been earnestly desired. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a drug target that has been studied for a long time. However, no LpxC inhibitors are available on the market at present. In this study, we sought to create a new antibacterial agent without a hydroxamate moiety, which is a common component of the major LpxC inhibitors that have been reported to date and that may cause toxicity. As a result, a development candidate, TP0586532, was created that is effective against carbapenem-resistant Klebsiella pneumoniae and does not pose a cardiovascular risk.

Keywords: Antibacterial agent; Gram-negative bacteria; Lead optimization; LpxC; Non-hydroxamate; carbapenem-resistant Enterobacteriaceae.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects*
  • Escherichia coli / enzymology
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Klebsiella pneumoniae / drug effects*
  • Klebsiella pneumoniae / enzymology
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Imidazoles
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase