Reversed siderophores act as antimalarial agents.

Abstract

We describe here a family of biomimetic iron carriers that display high binding efficiency for ferric ions and favorable permeation properties across erythrocytic membranes. These carriers inhibit in vitro growth of Plasmodium falciparum by scavenging intracellular iron. The chemical features were realized by reproducing the iron-binding cavities of natural iron carriers (siderophores) and by systematic substitutions of their hydrophilic envelopes for more hydrophobic ones. In contrast to natural carriers, which participate in receptor-mediated iron uptake in cells and act as growth promoters, our synthetic carriers were designed to penetrate cellular membranes by diffusion, scavenge intracellular iron, and thereby act as growth inhibitors. Based on these properties we designate the compounds reversed siderophores and refer to the specific analogs of the natural ferrichrome as synthetic ferrichromes. The antimalarial activity of the synthetic ferrichromes correlated with their lipophilicity, and this antimalarial activity was averted when the chelators were applied as iron(lI) complexes. The sites of synthetic ferrichrome action reside in the intraerythrocytic parasite and not in serum or on normal erythrocyte components. The agents were effective against all stages of parasite growth and against a variety of multidrug-resistant strains of P. falkiparum. The most potent agent of this synthetic ferrichrome series, SF1-ileu, was not toxic to mammalian cells in culture and was 15-fold more potent and 20-fold faster acting than desferrioxamine. Taken in toto, these agents constitute a series of promising candidates for future use in malaria chemotherapy.Other types of antimalarial agents are urgently needed to combat the global expansion of malaria. This expansion and the resurgence of drug resistance in various regions of the world have prompted the development of innovative chemotherapeutic strategies (see refs. 1-4 for reviews). Because iron is an essential element for virtually all living species (5), the development of compounds that can exert differential sequestration of essential iron(III) could prove useful for arresting parasite growth, including strains of Plasmodium falciparum of demonstrable drug-resistance nature. Previous attempts to use natural and synthetic iron binders as in vitro and in vivo growth inhibitors of intraerythrocytic parasites scored some success (6-14). However, each class of compounds thus far examined has had some drawbacks. The hydroxamate-based natural siderophores, which are highly specific chelators, are only moderately efficient antimalarials because oftheir poor permeability into infected erythrocytes, their putative site of action (14). Synthetic dithiocarbamates and hydroxyquinolines, on the other hand, proved efficacious, apparently because of a combination of high permeation features and metal complexation; however, their propensity for forming cytotoxic metal complexes might curtail their use in vivo (6-10). Synthetic catecholates, which acted as specific iron sc...

Antimalarial action of hydroxamate-based iron chelators and potentiation of desferrioxamine action by reversed siderophores

“…These seemingly contradictory properties of potential drugs which on the one hand act rapidly and on the other hand cause a long lasting inhibition could be accomplished either by application of permeant prodrugs which produce intracellular impermeant drugs or by application of a combination of drugs with different action profiles, as shown in the present study. For the case of malaria parasites, the combined action of such drugs was anticipated to outperform the sum of the individual effects (15,16,22,26). Where the mechanism of drug action is known, a scheme of synergistic action can be drawn (16).…”

“…Iron chelators are a class of agents which have proven useful as antimalarial agents in vitro (2,9,15,(18)(19)(20)(21)(22)(23), in rodent models (6), in primate hosts (17), and in humans (reviewed in reference 8). For the hydroxamate-type chelators, the biological action has been attributed to chelation of internal iron pools (9,13,19) and, in turn, to interference with the supply of iron to different parasite components (27), possibly to ribonucleotide reductase (1,10,27).…”

The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites.

“…All this evidence implies that DFO gains a slow and limited access to the mature stages of erythrocytic parasites where it exerts cytotoxic action on still unidentified parasite targets. Interestingly, unlike its cytostatic effect on various mammalian cells in culture (13)(14)(15), the antimalarial effect of DFO in vitro might be similar to those of highly permeant reversed siderophores (RSFs) (10), which cause irreversible inhibition of parasite growth ( 10). The most hydrophobic members ofthis genre, when compared with DFO as antimalarials, displayed demonstrably faster (five-O0-fold) action, 10-fold lower IC50, multistage activity, and no damage to mammalian cells in culture ( 10,15).…”

“…The information available indicates that DFO acts without affecting serum (4,10) or normal red cell iron pools (3,10), that it gains a restricted access to infected cells ( 11 ), and that its antimalarial action is manifested only in the advanced stages of parasite development and only after prolonged exposure of cells to drug (3,12). All this evidence implies that DFO gains a slow and limited access to the mature stages of erythrocytic parasites where it exerts cytotoxic action on still unidentified parasite targets.…”

“…The IC50 values of drugs on parasite growth were calculated from the profiles of parasite growth using the Dixon method ( 15) as published elsewhere ( 10).…”