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

Scott Eagon, Jared T. Hammill, Jordan Bach, Nikalet Everson, Tyler A. Sisley, Michael J. Walls, Sierra Durham, Dylan R. Pillai, Mofolusho O. Falade, Amy L. Rice, Joshua J. Kimball, Horacio Lazaro, Celine DiBernardo, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Article number127502
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number21
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
This work was supported by the Center for Applied Biotechnology at California Polytechnic State University, the Bill and Linda Frost Fund and Grand Challenges Canada .

Publisher Copyright:
© 2020 Elsevier Ltd

Keywords

  • Malaria
  • Plasmodium falciparum
  • Structure activity relationship
  • Structure based design
  • Tetrahydro-β-carbolines

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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