Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127502. doi: 10.1016/j.bmcl.2020.127502. Epub 2020 Aug 18.


A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.

Keywords: Malaria; Plasmodium falciparum; Structure activity relationship; Structure based design; Tetrahydro-β-carbolines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Binding Sites / drug effects
  • Carbolines / chemical synthesis
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Plasmodium falciparum / chemistry
  • Plasmodium falciparum / cytology
  • Plasmodium falciparum / drug effects*
  • Structure-Activity Relationship


  • Antimalarials
  • Carbolines
  • HSP90 Heat-Shock Proteins
  • tryptoline
  • Adenosine Triphosphate