title: 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.
authors.affiliation: iMed.UL and Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, Lisbon 1649-003, Portugal.
authors.forename: Rudi
authors.initials: R
authors.lastname: Oliveira
authors.forename: Ana S
authors.initials: AS
authors.lastname: Newton
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Daniela
authors.initials: D
authors.lastname: Miranda
authors.forename: Richard K
authors.initials: RK
authors.lastname: Amewu
authors.forename: Abhishek
authors.initials: A
authors.lastname: Srivastava
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Francisca
authors.initials: F
authors.lastname: Lopes
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D002738:Chloroquine / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D005296:Ferrous Compounds / Q000737:chemistry; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*; D045568:Tetraoxanes / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015853:Cysteine Proteinase Inhibitors; D005296:Ferrous Compounds; D006454:Hemoglobins; D013450:Sulfones; D045568:Tetraoxanes; C009873:divinyl sulfone; D002738:Chloroquine; C031327:artemisinin; D003546:Cysteine Endopeptidases; C099607:falcipain
keywords: antimalarial agents; falcipains; hybrids; peroxides; vinyl sulfones