Design and synthesis of N-(3-sulfamoylphenyl)amides as Trypanosoma brucei leucyl-tRNA synthetase inhibitors

Eur J Med Chem. 2021 May 5:217:113319. doi: 10.1016/j.ejmech.2021.113319. Epub 2021 Mar 8.

Abstract

The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC50 of 0.24 and 0.25 μM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.

Keywords: Leucyl-tRNA synthetase (LeuRS); N-(3-sulfamoylphenyl)amides; Trypanosoma brucei (T. brucei).

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / 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
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology

Substances

  • Amides
  • Antiprotozoal Agents
  • Enzyme Inhibitors
  • Leucine-tRNA Ligase