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

doi:10.1016/j.bmcl.2020.127502

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.

Authors

Affiliations

¹ Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, CA 93407, USA. Electronic address: seagon@calpoly.edu.
² Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40508, USA.
³ Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, CA 93407, USA.
⁴ Promega Biosciences, 277 Granada Drive, San Luis Obispo, CA 93401, USA.
⁵ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Public Health, Tauro University, Vallejo, CA 94592, USA.
⁷ Department of Food Science and Technology, University of California Davis, Davis, CA 95616, USA.
⁸ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.

PMID: 32822760
DOI: 10.1016/j.bmcl.2020.127502

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.

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

Substances

Antimalarials
Carbolines
HSP90 Heat-Shock Proteins
tryptoline
Adenosine Triphosphate