Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors

Bioorg Med Chem Lett. 2020 Apr 15;30(8):127052. doi: 10.1016/j.bmcl.2020.127052. Epub 2020 Feb 22.

Abstract

The identification of a new series of growth inhibitors of Trypanosoma cruzi, the causative agent of Chagas' disease, is described. In vitro screening of a subset of compounds from our in-house compound collection against the parasite led to the identification of hit compound 1 with low micromolar inhibition of T. cruzi growth. SAR exploration on the hit compound led to the identification of compounds that show nanomolar parasite growth inhibition (T. cruzi EC50 ≤ 100 nM) and no cytotoxicity in human cells (HeLa CC50 > 50 μM). Further investigation identified CYP51 inhibition (compound 11 CYP51 IC50 52 nM) as a possible mechanism of action of this new class of anti-parasitic agents.

Keywords: 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridine; Anti-parasitic; CYP51 inhibitor; Chagas disease; Trypanosoma cruzi.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Growth Inhibitors / chemical synthesis
  • Growth Inhibitors / chemistry
  • Growth Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects*

Substances

  • Growth Inhibitors
  • Pyridines
  • Trypanocidal Agents
  • pyridine