Design and synthesis of α-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA synthetase inhibitors

Eur J Med Chem. 2020 Jan 1:185:111827. doi: 10.1016/j.ejmech.2019.111827. Epub 2019 Oct 31.

Abstract

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei, is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy-N-sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC50 of 0.70 μM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents.

Keywords: Anti-trypanosomal agent; Human African trypanosomiasis (HAT); Leucyl-tRNA synthetase (LeuRS); Structure-activity relationship; α-phenoxy-N-Sulfonylphenyl acetamides.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Leucine-tRNA Ligase / antagonists & inhibitors*
  • Leucine-tRNA Ligase / metabolism
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology

Substances

  • Acetamides
  • Enzyme Inhibitors
  • Trypanocidal Agents
  • Leucine-tRNA Ligase