Antimalarial Iron Chelator, FBS0701, Shows Asexual and Gametocyte Plasmodium falciparum Activity and Single Oral Dose Cure in a Murine Malaria Model

Iron chelators for the treatment of malaria have proven therapeutic activity in vitro and in vivo in both humans and mice, but their clinical use is limited by the unsuitable absorption and pharmacokinetic properties of the few available iron chelators. FBS0701, (S)3”-(HO)-desazadesferrithiocin-polyether [DADFT-PE], is an oral iron chelator currently in Phase 2 human studies for the treatment of transfusional iron overload. The drug has very favorable absorption and pharmacokinetic properties allowing for once-daily use to deplete circulating free iron with human plasma concentrations in the high µM range. Here we show that FBS0701 has inhibition concentration 50% (IC50) of 6 µM for Plasmodium falciparum in contrast to the IC50 for deferiprone and deferoxamine at 15 and 30 µM respectively. In combination, FBS0701 interfered with artemisinin parasite inhibition and was additive with chloroquine or quinine parasite inhibition. FBS0701 killed early stage P. falciparum gametocytes. In the P. berghei Thompson suppression test, a single dose of 100 mg/kg reduced day three parasitemia and prolonged survival, but did not cure mice. Treatment with a single oral dose of 100 mg/kg one day after infection with 10 million lethal P. yoelii 17XL cured all the mice. Pretreatment of mice with a single oral dose of FBS0701 seven days or one day before resulted in the cure of some mice. Plasma exposures and other pharmacokinetics parameters in mice of the 100 mg/kg dose are similar to a 3 mg/kg dose in humans. In conclusion, FBS0701 demonstrates a single oral dose cure of the lethal P. yoelii model. Significantly, this effect persists after the chelator has cleared from plasma. FBS0701 was demonstrated to remove labile iron from erythrocytes as well as enter erythrocytes to chelate iron. FBS0701 may find clinically utility as monotherapy, a malarial prophylactic or, more likely, in combination with other antimalarials

Assessment of antimalarial effect of ICL670A on in vitro cultures of Plasmodium falciparum

We tested in vitro the antimalarial properties of ICL670A, a newly developed iron chelator for the long-term oral treatment of iron overload. Ring-stage synchronized cultures of Plasmodium falciparum cultured in human erythrocytes were exposed to different concentrations of ICL670A and the conventional iron chelator, desferrioxamine B (DFO), for 48 h. Malarial growth was measured by incorporation of [3H]-hypoxanthine. ICL670A at 30 μmol/l had marked antimalarial activity that was observable by 6 h after beginning the exposure of ring-stage parasites to the agent. Over 48 h of culture, malarial growth was significantly lower with ICL670A than with DFO at concentrations of both 30 μmol/l (P = 0.008) and 60 μmol/l (P = 0.001). At 48 h, growth relative to control was 53% with ICL670A and 83% with DFO at concentrations of 30 μmol/l, and 20% with ICL670A and 26% with DFO at concentrations of 60 μmol/l. Standard 50% inhibitory concentrations (IC50s) were similar for ICL670A and DFO. Precomplexation with iron completely abolished the inhibitory effect of ICL670A, indicating that this new agent, like DFO, probably inhibits parasite growth via deprivation of iron from critical targets within the parasite. Further studies to address the question of the antimalarial potential of ICL670A in combination with classic antimalarials would be of interest

Effects of Root Extracts of Fagara zanthoxyloides on the In Vitro Growth and Stage Distribution of Plasmodium falciparum

The development of resistance by Plasmodium falciparum to conventional drugs poses a threat to malaria control. There is therefore a need to find new, effective, and affordable remedies for malaria, including those derived from plants. This study demonstrates that crude, reverse-phase high-pressure liquid chromatography (RP-HPLC)-semipurified, and RP-HPLC-purified root extracts of Fagara zanthoxyloides inhibit the growth of P. falciparum in vitro, with 50% inhibitory concentrations (IC(50)s) of 4.90, 1.00, and 0.13 μg/ml, respectively. Roots of F. zanthoxyloides, known as chewing sticks, are widely used for tooth cleaning in West Africa. Microscopic examination of Giemsa-stained slides showed a virtual absence of schizonts in ring-stage synchronized cultures treated with crude extracts at concentrations of 30 to 60 μg/ml during 36 to 48 h of incubation. These observations suggest that the active constituent in the extract may be cytotoxic for P. falciparum trophozoites, thereby inhibiting their development to the schizont stage. A pure bioreactive fraction was subsequently obtained from the chromatographic separations. When this fraction was mixed with pure fagaronine, the mixture coeluted as a single peak on the analytical RP-HPLC column, suggesting that fagaronine may be the active antimalarial constituent of Fagara root extracts. Additional experiments showed that fagaronine also inhibited P. falciparum growth, with an IC(50) of 0.018 μg/ml. The results of this study suggest that the antimalarial activity of fagaronine deserves further investigation

Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites

Iron (Fe) is crucial for cellular proliferation, and Fe chelators have shown activity at preventing the growth of the malarial parasite in cell culture and in animal and human studies. We investigated the anti-malarial activity of novel aroylhydrazone and thiosemicarbazone Fe chelators that show high activity at inhibiting the growth of tumour cells in cell culture [Blood 100 (2002) 666]. Experiments with the chelators were performed using the chloroquine-sensitive, 3D7, and chloroquine-resistant, 7G8, strains of Plasmodium falciparum in vitro. The new ligands were significantly more active in both strains than the Fe chelator in widespread clinical use, desferrioxamine (DFO). The most effective chelators examined were 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone and 2-hydroxy-1- naphthylaldehyde-4-phenyl-3-thiosemicarbazone. The anti-malarial activity correlates with anti-proliferative activity against neoplastic cells demonstrated in a previous study. Our studies suggest that this class of lipophilic chelators may have potential as useful agents for the treatment of malaria. © 2003 Elsevier Ltd. All rights reserved

Aminothiol multidentate chelators against Chagas disease

Three compounds of an aminothiol family of iron chelators were examined for activity against trypomastigote (human) and epimastigote (vector) forms of Trypanosoma cruzi: tetraethyl and tetramethyl derivatives of ethane-1,2- bis (N-1-amino-3-ethyl butyl-3-thiol) (BAT-TE and BAT-TM) and N\u27,N\u27,N\u27-tris- (2-methyl-2-mercaptopriopyl)-1.4.7-triazacyclonane (TAT). BAT-TE at 270 μM completely arrested the growth of trypomastigote forms in mouse blood stored at 4°C for 24 h (IC50 67.7 ± 7 μM), while BAT-TM arrested growth at 630 μM (IC50 158 ± 17 μM) and TAT at concentrations \u3e800 μM (IC50 415 ± 55 μM). In T. cruzi-infected mice, BAT-TE and BAT-TM had no antitrypanosomal activity in doses up to 200 mg/kg, whether the route of administration was intraperitoneal or oral, and TAT was not tested due to insufficient quantity. TAT had an IC50 of 52 ± 7 μM against the epimastigote forms while BAT-TM and BAT-TE were inhibitory only at concentrations \u3e250 μM. The trypanocidal activity of BAT derivatives in blood stored at 4°C makes these compounds potential candidates for the purpose of clearing donated blood of trypomastigotes. (C) 2000 Academic Press