The antimalarial ferroquine: from bench to clinic

Biot, Christophe; Nosten, François; Fraisse, Laurent; Ter-Minassian, Daniel; Khalife, Jamal; Dive, Daniel

doi:10.1051/parasite/2011183207

Cited by 155 publications

(111 citation statements)

References 43 publications

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“…Indeed, in HIV-infected individ- uals, CQ was repeatedly reported to be effective in counteracting the deleterious immune activation associated with the disease (61). However, in clinical trials against influenza virus and chikungunya virus, CQ was rather disappointing (62,63). This could be due to high viral loads in vivo, poor penetration in specific tissues, and narrow therapeutic indexes.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we reported that FQ, a ferrocenic analog of CQ, is a promising inhibitor of HCV (15). This bio-organometallic compound is currently one of the most promising new candidate drugs in the antimalarial pipeline, and it is also in phase II clinical trials as a treatment for uncomplicated malaria (62). With IC 50 s of 0.91 M (this work) and 0.80 M (15) for B5 and FQ, respectively, these two compounds indeed show similar potency.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Vausselin

Séron

Lavie

et al. 2016

J Virol

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Aminoquinolines and piperazines, linked or not, have been used successfully to treat malaria, and some molecules of this family also exhibit antiviral properties. Here we tested several derivatives of 4-aminoquinolines and piperazines for their activity against hepatitis C virus (HCV). We screened 11 molecules from three different families of compounds, and we identified anti-HCV activity in cell culture for six of them. Of these, we selected a compound (B5) that is currently ending clinical phase I evaluation for neurodegenerative diseases. In hepatoma cells, B5 inhibited HCV infection in a pangenotypic and dose-dependent manner, and its antiviral activity was confirmed in primary hepatocytes. B5 also inhibited infection by pseudoparticles expressing HCV envelope glycoproteins E1 and E2, and we demonstrated that it affects a postattachment stage of the entry step. Virus with resistance to B5 was selected by sequential passage in the presence of the drug, and reverse genetics experiments indicated that resistance was conferred mainly by a single mutation in the putative fusion peptide of E1 envelope glycoprotein (F291I). Furthermore, analyses of the effects of other closely related compounds on the B5-resistant mutant suggest that B5 shares a mode of action with other 4-aminoquinoline-based molecules. Finally, mice with humanized liver that were treated with B5 showed a delay in the kinetics of the viral infection. In conclusion, B5 is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle. IMPORTANCEIn the last 4 years, HCV therapy has been profoundly improved with the approval of direct-acting antivirals in clinical practice. Nevertheless, the high costs of these drugs limit access to therapy in most countries. The present study reports the identification and characterization of a compound (B5) that inhibits HCV propagation in cell culture and is currently ending clinical phase I evaluation for neurodegenerative diseases. This molecule inhibits the HCV life cycle by blocking virus entry. Interestingly, after selection of drug-resistant virus, a resistance mutation in the putative fusion peptide of E1 envelope glycoprotein was identified, indicating that B5 could be used to further investigate the fusion mechanism. Furthermore, mice with humanized liver treated with B5 showed a delay in the kinetics of the viral infection. In conclusion, B5 is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Vausselin

Séron

Lavie

et al. 2016

J Virol

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“…This has stimulated the interest in other compounds with more acceptable toxicity, such as ruthenium complexes (32)(33)(34)(35)(36). Effects of ruthenium compounds on some bacteria and parasites have been studied (37)(38)(39)(40)(41)(42)(43)(44)(45)(46). "Classical ruthenium complexes" contain heteroatom ligands (e.g., azole derivatives), and NAMI-A and KP-1019 have been evaluated in phase I clinical trials for cancer treatment (47)(48)(49).…”

mentioning

confidence: 99%

In VitroEffects of Novel Ruthenium Complexes in Neospora caninum and Toxoplasma gondii Tachyzoites

Barna

Debache

Vock

et al. 2013

Antimicrob Agents Chemother

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bUpon the screening of 16 antiproliferative compounds against Toxoplasma gondii and Neospora caninum, two hydrolytically stable ruthenium complexes (compounds 16 and 18) exhibited 50% inhibitory concentrations of 18.7 and 41.1 nM (T. gondii) and 6.7 and 11.3 nM (N. caninum). To achieve parasiticidal activity with compound 16, long-term treatment (22 to 27 days at 80 to 160 nM) was required. Transmission electron microscopy demonstrated the rapid impact on and ultrastructural alterations in both parasites. These preliminary findings suggest that the potential of ruthenium-based compounds should thus be further exploited.T oxoplasma gondii and Neospora caninum are cyst-forming apicomplexan parasites that infect a wide range of hosts. In an immunocompetent host, infection with either parasite does not cause disease (1-3). N. caninum has emerged as one of the most important infectious causes of bovine abortion (4-6). In contrast, T. gondii causes toxoplasmosis in humans and many animal species, either in chronically infected individuals during a decrease in immunoreactivity or if a seronegative mother acquires a primary infection during pregnancy, leading to abortion or serious fetal abnormalities (7-9). Toxoplasmosis treatment is based on only a few chemotherapeutics with considerable adverse effects (10, 11). In Neospora-seropositive cattle, pregnancy and the associated immunomodulation are already sufficient to cause recrudescence, fetal damage, and abortion (2-6). Chemotherapy has been considered a promising option if effective drugs can be identified (12, 13). Several compounds were investigated in vitro (14-16), but only a few were evaluated in small-animal models (14,(17)(18)(19)(20)(21)(22)(23)(24).We have evaluated compounds originally synthesized as anticancer drugs. Currently used metal complexes (25-31) exhibit considerable toxicity. This has stimulated the interest in other compounds with more acceptable toxicity, such as ruthenium complexes (32-36). Effects of ruthenium compounds on some bacteria and parasites have been studied (37-46). "Classical ruthenium complexes" contain heteroatom ligands (e.g., azole derivatives), and NAMI-A and KP-1019 have been evaluated in phase I clinical trials for cancer treatment (47-49). Organometallic complexes are defined by at least one metal-carbon bond. The 6 -arene ruthenium(II) phosphite complexes 5, 6, 12, and 15 to 18 were characterized earlier (50), while [Ru( 6 -p-cymene)(bipyridine)Cl][Cl] 11 was synthesized as shown previously (51). Based on our experiences in the design of selective inhibitors of CYP11B2 (53) and CYP11B1 (54), the pyridine-based compounds 4, 7 to 10, and 14 were from a small in-house library of CYP enzyme inhibitors. 2,2=-Bipyridine 3 was obtained from Joachim W. Heinicke, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany. The cytotoxic lipophilic imidazolium salt 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride 3 was synthesized as described previously (54-56). The arylimidamide DB745 2 (23) was kindly provided by David Bo...

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“…FQ was more active compared to CQ against all of the 19 CQ-R and CQ-S clones of P. falciparum examined in 11 different studies conducted by different laboratories. Importantly, no resistance to FQ was found among the CQ-R strains examined (Biot et al, 2011). At 8.3 mg/kg/d for four days, FQ was much more effective than CQ on rodent infected with malaria (Plasmodium berghei and Plasmodium vinckei).…”

Section: Learning From the Cq Hybrid Approach For Antimalarial Drug Dmentioning

confidence: 94%

Chloroquine-based hybrid molecules as promising novel chemotherapeutic agents

Srivastava

Lee

2015

European Journal of Pharmacology

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The antimalarial ferroquine: from bench to clinic

Cited by 155 publications

References 43 publications

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

In VitroEffects of Novel Ruthenium Complexes in Neospora caninum and Toxoplasma gondii Tachyzoites

Chloroquine-based hybrid molecules as promising novel chemotherapeutic agents

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