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. 2013 Mar 20;5(177):177ra37.
doi: 10.1126/scitranslmed.3005029.

Quinolone-3-diarylethers: A New Class of Antimalarial Drug

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Free PMC article

Quinolone-3-diarylethers: A New Class of Antimalarial Drug

Aaron Nilsen et al. Sci Transl Med. .
Free PMC article

Abstract

The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3-diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.

Figures

Figure 1
Figure 1
Chemical structures of compounds used or referred to in this study. Atovaquone and GW8445520 are antimalarial drugs that are known to target the Plasmodium cytochrome bc1 complex. Discovery of endochin as an antimalarial dates back to the 1940’s when it was shown to be effective against several avian plasmodial species but lacked activity against mammalian species. A new structural class of antimalarial agents is represented by ELQ-271, ELQ-300 and P4Q-391, 4(1H)-quinolones bearing a diarylether side chain at the 3-position of the quinolone core. ELQ-300 and P4Q-391 were developed further and tested in a number of rodent models of malaria.
Figure 2
Figure 2
Ex vivo activity of ELQ-300 and P4Q-391 against Plasmodium clinical field isolates. (A) Ex vivo susceptibility of different Plasmodium species to ELQ-300 and P4Q-391 compared with that for other antimalarials such as chloroquine. (B) Ex vivo susceptibility (median IC50s) of P. falciparum (closed circles) and P. vivax (open circles) to ELQ-300 and P4Q-391 compared to other antimalarials. P values calculated using *Wilcoxon rank sum test.
Figure 3
Figure 3
Comparative effect of ELQ-271 and ELQ-300 on the intracellular level of ATP in two different mammalian cell lines. The ability of ELQ-271 and ELQ-300 to deplete ATP levels in two rat cell lines in galactose medium was evaluated with antimycin A and cycloheximide as positive and negative controls, respectively. As shown in the figure while ELQ-271 caused a concentration dependent decline in ATP levels (indicating that it was inhibiting host electron transport processes), ELQ-300 did not have a measureable adverse effect on ATP levels in either cell line with an IC50 level above 100µM.
Figure 4
Figure 4
EC50 curves for ELQ-300 and P4Q-391 vs. P. falciparum cytochrome bc1. Cytochrome c reductase activity was monitored by spectroscopic analysis with a dual wavelength spectrophotometer in dual mode (550 nm – 541 nm). The assay was performed at 35°C in a stirred cuvette with 2,3-dimethoxy-5-methyl-6-decyl-1,4 benzohydroquinone (decylubiquinol) and horse heart cytochrome c in a buffered solution. Reactions were initiated by addition of hemozoin-free mitochondrial preparations.
Figure 5
Figure 5
ELQ-300 activity compared with atovaquone activity against P. yoelii murine malaria. (A) Dose response for ELQ-300 versus atovaquone. Groups of n=4 mice/group were infected with 6.4×106 P. yoelii-infected erythrocytes. Drug treatment started 1 hour after infection and was administered on days 1-4. (B) Whole blood and plasma concentrations of ELQ-300 (nM) after oral gavage administration (target dose = 0.1 mg/kg) to P. yoelii infected CD-1 mice (n = 4 for each time point). Blood samples were taken after the last dose (day 4).
Figure 6
Figure 6
Efficacy of ELQ-300 against the human malaria parasite in the immune-deficient (SCID) humanized mouse model of P. falciparum. A group of 3 mice treated with vehicle and another group of 11 mice treated with different doses of ELQ-300 were analyzed to estimate ED90 and AUCED90 as parameters of efficacy. (A) Parasitemia in individual mice treated with different doses of ELQ-300 during the efficacy assay. Each symbol represents an individual mouse. (B) Concentrations of ELQ-300 in the blood of each individual mouse in the efficacy study measured for 24 h after the initial oral dose administration. Each symbol represents an individual mouse. (C) Graphic estimation of AUCED90 for ELQ-300. Data are the area under the curve for ELQ-300 in blood during the first 24 h after first oral dose administration (AUC0→23h) vs log10 [parasitemia at day 7] for each individual mouse in the efficacy study. (D) Microscopic and flow cytometry analysis of P. falciparum present in peripheral blood of mice treated with vehicle or ELQ-300. Samples were taken 48 h after the start of treatment (i.e., 1 cycle of exposure to drug). Flow cytometry dot plots from samples of peripheral blood show P. falciparum infected human erythrocytes inside of the polygonal regions. Images in the right hand panels show Giemsa-stained bloodstream parasites present at the 48 h time point. Blood films from control untreated animals show normal staining and appearance while the parasites in ELQ-300 treated animals stain poorly and exhibit altered morphology.
Figure 7
Figure 7
Whole animal bioluminescence imaging of mice infected with luciferase transfected P. berghei sporozoites. Mice were treated with different doses of ELQ-300, P4Q-391 or atovaquone. Animals (n=5 per group) received a single dose by gavage one hour following inoculation with sporozoites. Representative images taken at 44 h after infection are shown. Bioluminescent signal was detected in control untreated animals with the highest intensity noted in the area overlaying the liver, consistent with the presence of liver-stage parasites. Notice that while all three drugs exhibited a dose-dependent effect on liver stages, ELQ-300 fully protected mice against P. berghei liver stage infection at doses as low as 0.03 mg/kg.
Figure 8
Figure 8
ELQ-300 (filled circles) and P4Q-391 (open triangles) were administered intravenously and orally to non-fasted male Swiss outbred mice. The intravenous dose (0.1 mg/kg) was formulated in mouse plasma to facilitate solubilization and to avoid precipitation upon administration via the tail vein. The oral dose was 0.3 mg/kg and was administered via gavage (0.1 mL) as a solution in undiluted PEG400. Following intravenous administration (Panel A), both of the drugs exhibited low clearance and a low volume of distribution, with a long half-life of about 15 to 18 h. The low clearance is consistent with in vitro data showing their high metabolic stability in the presence of hepatic microsomes (see supplemental materials). Following oral administration, the terminal half-life of each compound was similar to that after intravenous dosing, and absorption appeared to be slow with Tmax values of approximately 7.5 h. The oral bioavailability of both ELQ-300 and P4Q-391 at 0.3 mg/kg was approximately 100%.

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