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 erythro- cytes. 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 — (l-N-ethoxycarbonylmethyl- pyridoxlidenium]-2-2'-pyridyl] hydrazine bromide — (code named L2-9). 2h exposure to 20μM 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.