title: Mode of action of iron (III) chelators as antimalarials: I. Membrane permeation properties and cytotoxic activity.
abstract: We have designed two subfamilies of lipophilic iron (III) chelators previously termed reversed siderophores (RSFs). The agents display physicochemical properties that favor extraction of iron beyond membrane barriers of Plasmodium falciparum-infected red blood cells. We studied the in vitro antimalarial potency of RSFs and their relationship to the membrane permeation properties of these agents. The mode of RSF action involves: (1) fast access to intracellular compartments of parasitized cells; (2) selective and high-affinity chelation of iron (III) from parasitized cells; (3) fast exit from cells after iron (III) complexation; and (4) exertion of cell damage on parasites exposed for 3 to 5 hours to drugs, irrespective of the stage of parasite development. These results suggest that on reaching a critical intraerythrocyte target, RSFs induce an iron deficit that parasites in general, and rings in particular, have limited capacity to restore.
authors.affiliation: Department of Biological Chemistry, Hebrew University, Jerusalem, Israel.
authors.forename: S D
authors.initials: SD
authors.lastname: Lytton
authors.forename: B
authors.initials: B
authors.lastname: Mester
authors.forename: I
authors.initials: I
authors.lastname: Dayan
authors.forename: H
authors.initials: H
authors.lastname: Glickstein
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 / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000962:Antimalarials; D007502:Iron Chelating Agents; D003676:Deferoxamine