IN VITRO METABOLISM OF FERROQUINE (SSR97193) IN ANIMAL AND HUMAN HEPATIC MODELS AND ANTIMALARIAL ACTIVITY OF MAJOR METABOLITES ON <i>PLASMODIUM FALCIPARUM</i>

Daher, Wassim; Pélinski, Lydie; Klieber, Sylvie; Sadoun, Freddy; Meunier, Viviane; Bourrié, Martine; Biot, Christophe; Guillou, F.; Fabre, Gérard; Brocard, Jacques; Fraisse, Laurent; Maffrand, J.P.; Khalife, Jamal; Dive, Daniel

doi:10.1124/dmd.104.003202

Cited by 33 publications

(40 citation statements)

References 23 publications

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“…The biotransformation of FQ has been recently studied in vitro in animal and human models. 11 Even if mono-N-desmethyl-and di-N,N-desmethyl-FQ showed a decreased in vitro activity compared to the parent molecule, they remained more active than CQ on P. falciparum CQ-resistant strains. 11,28 It is notably that the metabolites of CQ showed no activity against CQ-resistant strains.…”

Section: Resultsmentioning

confidence: 99%

“…11 Even if mono-N-desmethyl-and di-N,N-desmethyl-FQ showed a decreased in vitro activity compared to the parent molecule, they remained more active than CQ on P. falciparum CQ-resistant strains. 11,28 It is notably that the metabolites of CQ showed no activity against CQ-resistant strains. The dramatic activity of FQ metabolites against CQ-resistant P. falciparum parasites growth enables us to expect a long-acting antimalarial activity during chemotherapy of malaria.…”

Section: Resultsmentioning

confidence: 99%

“…The other C-N cleavage generates the active mono-N-desmethyl-(dMFQ) 11 and mono-N-desethyl-FQ (dEFQ) 28 , respectively. By comparison with HCQ and FQ, it is tempting to suggest that during a clinical use of metallocenes 3 and 4, formation of these active metabolites may occur and participate in the global activity of the parent products.…”

Section: Resultsmentioning

confidence: 99%

“…10 A recent study of FQ metabolism in animal and human hepatic models revealed similarities to that of CQ. 11 One notable difference is that while the two main CQ metabolites are not active against CQ-resistant P. falciparum, FQ metabolites still exhibited a significant activity. Also, it is important to note that the close parent of CQ, hydroxychloroquine (HCQ) was reported to be less toxic than CQ, but was found inactive on CQ-resistant P. falciparum.…”

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of Hydroxyferroquine Derivatives with Antimalarial and Antiviral Activities

et al. 2006

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Three ferroquine (FQ) derivatives, closely mimicking the antimalarial drug hydroxychloroquine (HCQ) have been prepared. Whereas these organometallic compounds provide the expected reduced cytotoxic effects compared to FQ, they inhibit in vitro growth of Plasmodium falciparum far better than chloroquine (CQ). Moreover, this new class of bioorganometallic compounds exert antiviral effects with some selectivity towards SARS-CoV infection. These new drugs may offer an interesting alternative for Asia where SARS originated and malaria has remained endemic.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of Hydroxyferroquine Derivatives with Antimalarial and Antiviral Activities

et al. 2006

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“…In vitro drug susceptibility testing has demonstrated that several hydroxamate-based HDAC inhibitors are potent inhibitors (IC 50 s in low nanomolar concentrations) of laboratory strains of P. falciparum and, importantly, display promising selectivity for malaria parasites versus mammalian cell lines (Ͼ100 fold), depending on the inhibitor and cell lines used (2,12). H͔hypoxanthine incorporation) as previously published for chloroquine (8,9), amodiaquine (1,19), piperaquine (1, 30), mefloquine (1, 10), artesunate (1, 10) (the chloroquine-sensitive and -resistant lines were 3D7 and K1, respectively), SAHA (12), 2-ASA-9 (2), and 2-ASA-14 (2) (the chloroquine-sensitive and -resistant laboratory lines, respectively, were D6 and W2 for SAHA and 3D7 and Dd2 for 2-ASA-9 and 2-ASA-14 In the present study, we compared the ex vivo activities of three hydroxamate-based HDAC inhibitors against multidrugresistant clinical isolates of P. falciparum and P. vivax. This is the first report of antimalarial activity of this class of compounds directly against clinical isolates and against P. vivax parasites.…”

Section: Discussionmentioning

confidence: 99%

Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

Marfurt

Chalfein

Prayoga

et al. 2011

Antimicrob Agents Chemother

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Histone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum (n ‫؍‬ 24) and P. vivax (n ‫؍‬ 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC 50 s] of 310, 533, and 266 nM) and P. vivax (median IC 50 s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P. vivax schizont maturation, comparable to that in P. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.

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On the Molecular Mechanisms of the Antimalarial Action of Ferroquine

Dubar

Biot

2014

Bioorganometallic Chemistry

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IN VITRO METABOLISM OF FERROQUINE (SSR97193) IN ANIMAL AND HUMAN HEPATIC MODELS AND ANTIMALARIAL ACTIVITY OF MAJOR METABOLITES ON PLASMODIUM FALCIPARUM

Cited by 33 publications

References 23 publications

Design and Synthesis of Hydroxyferroquine Derivatives with Antimalarial and Antiviral Activities

Design and Synthesis of Hydroxyferroquine Derivatives with Antimalarial and Antiviral Activities

Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

On the Molecular Mechanisms of the Antimalarial Action of Ferroquine

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