title: A plant-derived morphinan as a novel lead compound active against malaria liver stages.
abstract: BACKGROUND
  The global spread of multidrug-resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s.
  
  
  RESULTS
  Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 muM, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 muM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 muM, TI 46, and IC50 42.4 muM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages.
  
  
  CONCLUSIONS
  A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs.
authors.affiliation: Laboratoire de Chimie et Biochimie des Substances Naturelles, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Maëlle
authors.initials: M
authors.lastname: Carraz
authors.forename: Akino
authors.initials: A
authors.lastname: Jossang
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Franetich
authors.forename: Anthony
authors.initials: A
authors.lastname: Siau
authors.forename: Liliane
authors.initials: L
authors.lastname: Ciceron
authors.forename: Laurent
authors.initials: L
authors.lastname: Hannoun
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.forename: François
authors.initials: F
authors.lastname: Frappier
authors.forename: Philippe
authors.initials: P
authors.lastname: Rasoanaivo
authors.forename: Georges
authors.initials: G
authors.lastname: Snounou
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D001681:Biological Assay; D002458:Cell Fractionation; D002478:Cells, Cultured; D022781:Hepatocytes / Q000469:parasitology; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008969:Molecular Sequence Data; D009019:Morphinans / Q000627:therapeutic use*; D008517:Phytotherapy; D024301:Plant Bark; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D010967:Plasmodium yoelii / Q000187:drug effects / Q000254:growth & development
chemical_list: D000962:Antimalarials; D009019:Morphinans; C517160:tazopsine