Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum

Pradines, Bruno; Fusaı̈, Thierry; Daries, William; Laloge, V.; Rogier, Christophe; Millet, Pascal; Panconi, E.; Kombila, Maryvonne; Parzy, Daniel

doi:10.1093/jac/48.2.179

Cited by 65 publications

(38 citation statements)

References 33 publications

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“…We observed FQ IC 50 s in the low nM range for both CQR and CQS P. falciparum isolates, in line with previous reports from Africa and Southeast Asia (4,9,18,21,22). The ex vivo activity of FQ against multidrug-resistant P. vivax isolates from Papua, Indonesia (median IC 50 ϭ 18 nM), was comparable to the IC 50 (median ϭ 15 nM) recently observed against P. vivax isolates from the Thai-Burmese border where most isolates are chloroquine sensitive (19).…”

supporting

confidence: 92%

“…Ferroquine is a promising, novel ferrocene 4-aminoquinoline with potent in vitro activity against CQ-sensitive (CQS) and -resistant (CQR) P. falciparum strains from various geographical areas (4,9,18,21,22) as well as good in vivo efficacy in rodent malaria (6,11). A recent report of ex vivo drug susceptibility of P. vivax on the Thai-Burmese border supports the further development of this lead antimalarial compound (19).…”

mentioning

confidence: 97%

“…In vivo experiments performed on rodent Plasmodium species demonstrated powerful activity of the drug and a high oral bioavailability, two major qualities for selecting lead compounds for further development (6,11). In vitro susceptibility of FQ has been tested in different culture-adapted P. falciparum strains (5,11,12) and field isolates from Gabon, Africa, Senegal, Cambodia, and Thailand (1,4,9,21,22) and has proven to be effective against CQ-sensitive (CQS) and CQR strains. More recently, the ex vivo activity of FQ against chloroquine-sensitive strains of P. vivax has been demonstrated in Thailand (19).…”

mentioning

confidence: 99%

“…In several studies, weak cross-reactivity with CQ has been described in P. falciparum isolates (1,4,9,21,22). However, other studies have not observed significant correlation of in vitro drug responses between FQ and other standard drugs (16,19).…”

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confidence: 99%

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Ex Vivo Drug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax

Marfurt

Chalfein

Prayoga

et al. 2011

Antimicrob Agents Chemother

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Ferroquine (FQ; SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potent in vitro efficacy against chloroquine (CQ)-resistant Plasmodium falciparum and CQ-sensitive P. vivax. In the current study, ex vivo FQ activity was tested in multidrug-resistant P. falciparum and P. vivax field isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistant P. falciparum and P. vivax (median 50% inhibitory concentrations [IC 50 s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (for P. falciparum, r ‫؍‬ 0.546 to 0.700, P < 0.001; for P. vivax, r ‫؍‬ 0.677 to 0.821, P < 0.001). The observed ex vivo cross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of both P. falciparum and P. vivax highlights a promising role for FQ as a lead antimalarial against CQ-resistant Plasmodium and a useful partner drug for artemisinin-based combination therapy.

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confidence: 92%

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confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Ex Vivo Drug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax

Marfurt

Chalfein

Prayoga

et al. 2011

Antimicrob Agents Chemother

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“…1). FQ is currently under phase II clinical trial investigations.Only six previous studies investigated the activity of ferroquine against P. falciparum strains isolated from infected patients (1,2,10,21,28,30). The drug susceptibilities of P. falciparum strains vary among different locations, where isolates have different antimalarial resistance backgrounds.…”

mentioning

confidence: 99%

In Vitro Activity of Ferroquine Is Independent of Polymorphisms in Transport Protein Genes Implicated in Quinoline Resistance in Plasmodium falciparum

Henry

Briolant

Fontaine

et al. 2008

Antimicrob Agents Chemother

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The in vitro activity of ferroquine (FQ) (SR97193), a 4-aminoquinoline antimalarial compound that contains a ferrocenic nucleus, against 15 Plasmodium falciparum strains was assessed and compared with those of chloroquine (CQ), quinine (QN), monodesethylamodiaquine (MDAQ), and mefloquine (MQ). These 15 strains were genotyped for polymorphisms in quinoline resistance-associated genes such as Pfcrt, Pfmdr1, Pfmrp, and Pfnhe-1. FQ was highly active against CQ-resistant parasites or in parasites with reduced susceptibility to QN, MDAQ, or MQ. Encouragingly, we did not find a correlation between responses to FQ and those to other quinoline drugs. These results suggest that no cross-resistance exits between FQ and CQ or quinoline Two of the current options to reduce the morbidity and mortality of malaria are chemoprophylaxis and chemotherapy. During the past 20 years, many strains of Plasmodium falciparum have become resistant to chloroquine and other antimalarial drugs (24). This has prompted a search for an effective alternative antimalarial drug with minimal side effects. The emergence and spread of parasites that are resistant to antimalarial drugs has caused an urgent need for novel compounds to be discovered and developed.An approach to remove aminoquinoline resistance in parasites is to modify the position and the chemical nature of the substituents or the length of the side chain on the quinoline nucleus of the aminoquinoline (12, 34). Recently, many different metals have been incorporated into antimalarial agents (29). Indeed, several organometallic compounds based on chloroquine with a ferrocene nucleus localized at different sites have been synthesized (5-8). This approach is currently being developed by J. Brocard and colleagues (URA-CNRS 402, Lille, France), who have synthesized ferroquine (FQ) {i.e., 7-chloro-4-[(2-N,NЈ-dimethylaminomethyl)ferrocenylmethylamino]quinoline} (Fig. 1). FQ is currently under phase II clinical trial investigations.Only six previous studies investigated the activity of ferroquine against P. falciparum strains isolated from infected patients (1,2,10,21,28,30). The drug susceptibilities of P. falciparum strains vary among different locations, where isolates have different antimalarial resistance backgrounds. It seems that ferroquine activity is independent of chloroquine resistance in P. falciparum (21), and ferroquine antimalarial activity is not influenced by polymorphisms in the Pfcrt gene (Plasmodium falciparum chloroquine resistance transporter), which encodes a protein located in the parasite digestive vacuole and is involved in drug transport and chloroquine resistance (10, 11). The objective of this study was to determine whether genetic polymorphisms in genes associated with quinoline resistance modulate in vitro responses to ferroquine. We assessed polymorphisms in genes that are potentially associated with quinoline resistance: Pfcrt, Pfmdr1 (P. falciparum multidrug resistance gene 1), Pfnhe-1 (P. falciparum sodium/hydrogen exchanger), and Pfmrp (P. falciparum multidru...

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Antimalarial Agents

Casteel¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Malaria continues to be a major global health problem and seems to be increasing in some parts of the world. By way of an introduction, relevant aspects of the disease, including incidence and resistance, and of the parasite and its biochemistry and genetics are presented. The chemotherapeutic agents now available to prevent and treat malaria are discussed individually. Some of these drugs have been in use for decades or even centuries, such as quinine, chloroquine, and primaquine. Other agents are of more recent origin including mefloquine, halofantrine, atovaquone, and the artemisinins. Chloroquine had been the drug of first resort for many years. It is inexpensive, well‐tolerated, and extremely effective where parasites remain sensitive. But the development of resistance to chloroquine has emphasized the need for new agents and strategies to treat malaria. New information on the genetic basis of chloroquine resistance and on the overall mechanism of action of chloroquine holds promise for advances in therapy. Another important tactic in dealing with infection by resistant parasites is the use of drug combinations. The combination of pyrimethamine and sulfadoxine has been very successful, but resistance is developing. Newer, highly effective combinations include atovaquone with proguanil, lumefantrine with artemether, and chlorproguanil with dapsone. The artemisinin group of compounds has made a powerful positive impact on malaria chemotherapy although their use in monotherapy is not recommended. Details of the mechanism of action of these drugs are becoming clearer. Knowledge about action should assist in addressing issues of possible toxicity. Great progress has been made in sequencing the genome of Plasmodium falciparum . New molecular targets have been identified as a result and efforts are underway to develop antimalarial agents based on these targets. Researchers around the world are also exploring natural products for yet another lead in antimalarial chemotherapy. “If we take as our standard of importance the greatest harm to the greatest number, then there is no question that malaria is the most important of all infectious diseases 1 .” “Ah, poor heart! he is so shaked of a burning quotidian tertian, that it is most lamentable to behold [2].”

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Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum

Cited by 65 publications

References 33 publications

Ex Vivo Drug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax

Ex Vivo Drug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax

In Vitro Activity of Ferroquine Is Independent of Polymorphisms in Transport Protein Genes Implicated in Quinoline Resistance in Plasmodium falciparum

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