title: The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites.
abstract: We designed the N-methylanthranilic-desferrioxamine (MA-DFO) as a fluorescent iron (III) chelator with improved membrane permeation properties. Upon binding of iron (III), MA-DFO fluorescence is quenched, thus allowing traceability of drug-iron (III) interactions. MA-DFO is well tolerated by mammalian cells in culture. Its antimalarial activity is pronounced: IC50 values on in vitro (24-h) growth of Plasmodium falciparum were 3 +/- 1 microM for MA-DFO compared with 30 +/- 8 for DFO. The onset of growth inhibition of rings or trophozoites occurs 2-4 h after exposure to 13 microM MA-DFO. This effect is commensurate with MA-DFO permeation into infected cells. In a 24-h exposure to MA-DFO or DFO, trophozoites take up either compound to approximately 10% of the external concentration, rings to 5%, and noninfected cells to < 1%. Red cells encapsulated with millimolar concentrations of DFO or MA-DFO fully support parasite invasion and growth. We conclude that extracellular MA-DFO and DFO gain selective access into parasites by bypassing the host. The rate-limiting step is permeation through the parasite membrane, which MA-DFO accomplishes faster than DFO, in accordance with its higher hydrophobicity. These views are consistent with the proposed duct, which apparently provides parasitized cells with a window to the external medium.
authors.affiliation: Department of Biological Chemistry, Hebrew University of Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Loyevsky
authors.forename: S D
authors.initials: SD
authors.lastname: Lytton
authors.forename: B
authors.initials: B
authors.lastname: Mester
authors.forename: J
authors.initials: J
authors.lastname: Libman
authors.forename: A
authors.initials: A
authors.lastname: Shanzer
authors.forename: Z I
authors.initials: ZI
authors.lastname: Cabantchik
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers; D004910:Erythrocyte Membrane / Q000502:physiology; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D004337:Drug Carriers; C079357:N-methylanthranilic-desferrioxamine; D062367:ortho-Aminobenzoates; D003676:Deferoxamine