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

Authors
  • Eagon, Scott1
  • Hammill, Jared T2
  • Bach, Jordan3
  • Everson, Nikalet4
  • Sisley, Tyler A5
  • Walls, Michael J6
  • Durham, Sierra7
  • Pillai, Dylan R8
  • Falade, Mofolusho O2
  • Rice, Amy L2
  • Kimball, Joshua J4
  • Lazaro, Horacio4
  • DiBernardo, Celine3
  • Kiplin Guy, R2
  • 1 Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, CA 93407, USA. Electronic address: [email protected]
  • 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. , (Canada)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Aug 18, 2020
Volume
30
Issue
21
Pages
127502–127502
Identifiers
DOI: 10.1016/j.bmcl.2020.127502
PMID: 32822760
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020 Elsevier Ltd. All rights reserved.

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