Optimization of 2-(1H-imidazo-2-yl)piperazines series of Trypanosoma brucei growth inhibitors as potential treatment for the second stage of HAT

Bioorg Med Chem Lett. 2020 Jun 15;30(12):127207. doi: 10.1016/j.bmcl.2020.127207. Epub 2020 Apr 21.

Abstract

A previous publication from our laboratory reported the identification of a new class of 2-(1H-imidazo-2-yl)piperazines as potent T. brucei growth inhibitors as potential treatment for Human African Trypanosomiasis (HAT). This work describes the structure-activity relationship (SAR) around the hit compound 1, which led to the identification of the optimized compound 18, a single digit nanomolar inhibitor (EC50 7 nM), not cytotoxic and with optimal in vivo profile that made it a suitable candidate for efficacy studies in a mouse model mimicking the second stage of disease.

Keywords: Antiparasitic; Human African Trypanosomiasis (HAT); Sleeping sickness; Trypanosoma brucei.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Growth Inhibitors / chemistry*
  • Growth Inhibitors / pharmacology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Isomerism
  • Morpholines / chemistry
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Quinolines / chemistry
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemistry*
  • Trypanocidal Agents / pharmacology
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosomiasis, African / drug therapy*

Substances

  • Growth Inhibitors
  • Morpholines
  • Piperazines
  • Quinolines
  • Trypanocidal Agents
  • thiamorpholine
  • quinoline