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

Abstract

Hydroxamate-based chelators of iron are potent inhibitors of in vitro growth of Plasmodium falciparum. Two types of such chelators, the natural desferrioxamine and the synthetic reversed siderophore RSF ileum2 , are prototypes of antimalarial agents whose action spectra differ in the speed of action, stage dependence, and degree of reversibility of effects. This work explores the possibility of improving the antimalarial efficacy of these agents by using them in various combinations on in vitro cultures of P. falciparum. Growth assessment was based both on total nucleic acid synthesis and on parasitemia. The results indicate that the synthetic reversed siderophore more than complements the antimalarial action of desferrioxamine when applied during either ring, trophozoite, or mixed stages. The combined drug effects were significantly higher than the additive effect of the individual drugs. Qualitatively similar results were obtained for both reversible effects and irreversible (i.e., sustained) effects. Following an 8-h window of exposure the combined drug treatment caused parasite growth arrest and prevented its recovery, even 3 days after the treatment. The fact that such a combination of iron chelators displays a wider action spectrum than either drug alone has implications for the design of chemotherapy regimens.

Synthesis of carbohydrate-based artificial siderophores and their biological applications

“…39 Retro-hydroxamate siderophores are analogues in which the position of the hydroxamate nitrogen and carbon are interchanged relative to their position in the natural siderophore and have found application as antimalarial agents. [40][41][42][43] The first synthetic analogues of hydroxamate siderophores based on methyl a-D-glucopyranoside, methyl a-D-galactopyranoside, methyl a-Dribopyranoside and methyl a-D-xylopyranoside were in fact retro-hydroxamates and were reported by Heggemann et al 15 The two hexoses were first protected with a trityl group at C-6, so that all four monosaccharides studied have only three free OH groups (OH-2, 3 and 4). The corresponding retro-trishydroxamates with different spacer groups were prepared by Steglich esterification with N-benzoyloxy-N-methylglutaric acid (30-33a), N-benzyloxy-N-methylsuccinic acid (30-33b), N-benzyloxy-N-methylglutaric acid (30-33c) and N-benzyloxy-N-butylglutaric acid (30d), using dicyclohexyl-carbodiimide (DCC) and N,N-dimethylaminopyridine (DMAP) in dichloromethane.…”

Recent developments and rationale towards new strategies for malarial chemotherapy

“…Iron chelation treatments of malaria-parasite infected erythrocytes selectively intervenes with the iron-depen dent metabolism of malaria parasites, and have been shown to abolish plasmodial growth IN VITRO and reduce malaria infection in mice (Fritsch ET AL., 1985), monkeys (Pollack ET AL., 1987) and in clinical cases in humans (Traore ET AL., 1991;Bunnag ET AL., 1992, Gordeuk ET AL., 1992, Gordeuk ET AL., 1993. The IN VITRO antimalarial action of desferoxamine (DFO) is mani fested after 8-10 h of continuous exposure of P. FAL CIPARUM trophozoites to the drugs (Golenser ET AL., 1995).…”

“…These modes of action also have some implications for their future as curative anti malarial agents. A combination of fast-acting sidero phores (which are able to penetrate ring-infected red cells), and slow-acting DFO derivatives (which are only permeable at the early trophozoite/schizont stages), was found to provide a new and efficient means of arresting P. falciparum growth in vitro (Golenser et al, 1995;Tsafack et al, 1995).…”

Intramolecular monodealkylation during the attempted synthesis of diethylphosphonoacetohydroxamic acid

“…In addition, there exist reports on hydroxamic acids having antimalarial [6] and anticancer [7] activity as well as synergism with some anti-AIDS drugs [8]. In contrast to the multitude of existing hydroxamic acids of various structures, there are only a few reports on molecules containing hydroxamic groups along with phosphorus containing functions [9].…”