Mode of action of iron (III) chelators as antimalarials: I. Membrane permeation properties and cytotoxic activity.
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.
Lytton
S D
SD
Department of Biological Chemistry, Hebrew University, Jerusalem, Israel.
Mester
B
B
Dayan
I
I
Glickstein
H
H
Libman
J
J
Shanzer
A
A
Cabantchik
Z I
ZI
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
D000962:Antimalarials; D007502:Iron Chelating Agents; D003676:Deferoxamine