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An endoperoxide-based hybrid approach to deliver falcipain inhibitors inside malaria parasites.

Abstract
The emergence of artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia has reinforced the urgent need to discover novel chemotherapeutic strategies to treat and control malaria. To address this problem, we prepared a set of dual-acting tetraoxane-based hybrid molecules designed to deliver a falcipain-2 (FP-2) inhibitor upon activation by iron(II) in the parasite digestive vacuole. These hybrids are active in the low nanomolar range against chloroquine-sensitive and chloroquine-resistant P. falciparum strains. We also demonstrate that in the presence of FeBr₂ or within infected red blood cells, these molecules fragment to release falcipain inhibitors with nanomolar protease inhibitory activity. Molecular docking studies were performed to better understand the molecular interactions established between the tetraoxane-based hybrids and the cysteine protease binding pocket residues. Our results further indicate that the intrinsic activity of the tetraoxane partner compound can be masked, suggesting that a tetraoxane-based delivery system offers the potential to attenuate the off-target effects of known drugs.
AuthorsRudi Oliveira, Ana S Newton, Rita C Guedes, Daniela Miranda, Richard K Amewu, Abhishek Srivastava, Jiri Gut, Philip J Rosenthal, Paul M O'Neill, Stephen A Ward, Francisca Lopes, Rui Moreira
JournalChemMedChem (ChemMedChem) Vol. 8 Issue 9 Pg. 1528-36 (Sep 2013) ISSN: 1860-7187 [Electronic] Germany
PMID23853126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chemical References
  • Antimalarials
  • Artemisinins
  • Cysteine Proteinase Inhibitors
  • Ferrous Compounds
  • Hemoglobins
  • Sulfones
  • Tetraoxanes
  • divinyl sulfone
  • Chloroquine
  • artemisinin
  • Cysteine Endopeptidases
  • falcipain
Topics
  • Antimalarials (chemistry, pharmacology, therapeutic use)
  • Artemisinins (chemical synthesis, chemistry)
  • Binding Sites
  • Chloroquine (pharmacology)
  • Cysteine Endopeptidases (chemistry, metabolism)
  • Cysteine Proteinase Inhibitors (pharmacology, therapeutic use)
  • Drug Resistance (drug effects)
  • Erythrocytes (drug effects, metabolism, parasitology)
  • Ferrous Compounds (chemistry)
  • Hemoglobins (metabolism)
  • Humans
  • Malaria (drug therapy)
  • Molecular Docking Simulation
  • Plasmodium falciparum (drug effects)
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Sulfones (chemistry)
  • Tetraoxanes (chemistry)

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