Growth inhibition of Plasmodium falciparum involving carbon centered iron-chelate radical (L., X-)-Fe(III) based on pyridoxal-betaine. A novel type of antimalarials active against chloroquine-resistant parasites.
Malaria parasites have been shown to be more susceptible to oxidative stress than their host erythrocytes. In the present work, a chloroquine resistant malaria parasite, Plasmodium falciparum (FCR-3) was found to be susceptible in vitro to a pyridoxal based iron chelator--(1-[N-ethoxycarbonylmethylpyridoxlidenium]-2-[2'-pyridyl ] hydrazine bromide--(code named L2-9). 2h exposure to 20 microM L2-9 was sufficient to irreversibly inhibit parasite growth. Desferrioxamine blocked the drug effect, indicating the requirement for iron. Oxygen however, was not essential. Spectrophotometric analysis showed that under anoxic conditions, L2-9-Fe(II) chelate undergoes an intramolecular redox reaction which presumably involves a one electron transfer and is expected to result in the formation of free radical. Spin trapping coupled to electron spin resonance (ESR) studies of L2-9-iron chelate showed that L2-9-Fe(II) produced free radicals both in the presence and absence of cells, while L2-9-Fe(III) produced free radicals only in the presence of actively metabolising cells.
Iheanacho
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Kuvin Centre for the Study of Infectious and Tropical Diseases, Jerusalem, Israel.
Sarel
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Samuni
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Avramovici-Grisaru
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Spira
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D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004351:Drug Resistance; D004578:Electron Spin Resonance Spectroscopy; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013053:Spectrophotometry
D000962:Antimalarials; D006834:Hydrazines; D007502:Iron Chelating Agents; D016877:Oxidants; C065491:CGP 43902A; D002738:Chloroquine; D007501:Iron; D003676:Deferoxamine