Diamidine Compounds: Selective Uptake and Targeting in<i>Plasmodium falciparum</i>

Stead, Andrew M W; Bray, Patrick G.; Edwards, I. Geoffrey; Koning, Harry P. de; Elford, B C; Stocks, Paul A.; Ward, Stephen A.

doi:10.1124/mol.59.5.1298

Cited by 96 publications

(127 citation statements)

References 33 publications

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“…Based on kinetic and pharmacological inhibitor profiles of isosmotic hemolysis and radiolabel flux experiments, several quaternary ammonium compounds have been demonstrated to permeate P. falciparum-infected erythrocytes via the parasite-induced new permeation pathway (NPP [11,22]). Similarly, diamidine compounds, which-being highly charged and hydrophilic-are structurally comparable to the bis-quaternary ammonium compounds, have also been demonstrated to enter the host erythrocyte via the NPP (23). In this study, we have investigated the mechanism of entry and antimalarial activity of a newly synthesized bis-quaternary ammonium compound, T16 (1,12-dodecanemethylene bis[4-methyl-5-ethylthiazolium] diodide; Fig.…”

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confidence: 99%

Heme Binding Contributes to Antimalarial Activity of Bis-Quaternary Ammoniums

Biagini

Richier

Bray

et al. 2003

Antimicrob Agents Chemother

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Quaternary ammonium compounds have received recent attention due to their potent in vivo antimalarial activity based on their ability to inhibit de novo phosphatidylcholine synthesis. Here we show that in addition to this, heme binding significantly contributes to the antimalarial activity of these compounds. For the study, we used a recently synthesized bis-quaternary ammonium compound, T16 (1,12-dodecanemethylene bis[4-methyl-5-ethylthiazolium] diodide), which exhibits potent antimalarial activity (50% inhibitory concentration, ϳ25 nM). Accumulation assays reveal that this compound is readily concentrated several hundredfold (cellular accumulation ratio, ϳ500) into parasitized erythrocytes. Approximately 80% of the drug was shown to be distributed within the parasite, ϳ50% of which was located in the parasite food vacuoles. T16 uptake was affected by anion substitution (permeation increasing in the order Cl ؊ < Br ؊ ‫؍‬ NO 3 ؊ < I ؊ < SCN ؊ ) and was sensitive to furosemide-properties similar to substrates of the induced new permeability pathway in infected erythrocytes. Scatchard plot analysis of in situ T16 binding revealed high-affinity and low-affinity binding sites. The high-affinity binding site K d was similar to that measured in vitro for T16 and ferriprotoporphyrin IX (FPIX) binding. Significantly, the capacity but not the K d of the high-affinity binding site was decreased by reducing the concentration of parasite FPIX. Decreasing the parasite FPIX pool also caused a marked antagonism of T16 antimalarial activity. In addition, T16 was also observed to associate with parasite hemozoin. Binding of T16 to FPIX in the digestive food vacuole is shown to be critical for drug accumulation and antimalarial activity. These data provide additional new mechanisms of antimalarial activity for this promising new class of antimalarial compounds.Worldwide resistance to traditional antimalarial drugs such as chloroquine and pyrimethamine sulfadoxine raises the urgency for the development of new drugs aimed at new drug targets (18). Inhibition of phosphatidylcholine synthesiswhich leads to the inhibition of membrane biogenesis during the asexual intraerythrocytic stage of the human malaria parasite Plasmodium falciparum-has recently attracted attention as a potentially new chemotherapeutic target (18,26). Over recent years, numerous (Ͼ600) compounds have been rationally synthesized to mimic choline structure. The resulting compounds from these structure-activity studies are quaternary and bis-quaternary ammoniums with lead compounds that exert potent (i.e., low nM) in vitro activity against P. falciparum and P. vivax (2, 5, 6, 26) as well as good in vivo activity against P. falciparum and P. cynomolgi in aotus and rhesus monkeys, respectively (26).Biochemical investigations show that in P. knowlesi, the protein-mediated transport of choline into the infected erythrocyte is a rate-limiting step for phosphatidylcholine synthesis (1). In this malaria parasite, the in vitro and in vivo activity exerted by the quaternary ...

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Heme Binding Contributes to Antimalarial Activity of Bis-Quaternary Ammoniums

Biagini

Richier

Bray

et al. 2003

Antimicrob Agents Chemother

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“…Another potential explanation for our results with ester borrelidin derivatives is that these compounds may offer increased selectivity due to better permeability in infected erythrocytes. Malaria parasites have been shown to increase erythrocyte permeability to ions, organic solutes, and antimalarial drugs through new permeation pathways that are associated to P. falciparum infection (54)(55)(56)(57). Further work is needed to determine the role of permeability differences in the selectivity of borrelidin analogs.…”

Section: Discussionmentioning

confidence: 99%

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo.aminoacyl-tRNA synthetase | malaria | drug design | borrelidin | plasmodium

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“…In addition, DB289 has been shown to possess good in vivo activity against malaria in the mouse and in vitro activity against various Plasmodium strains, such that it is currently undergoing clinical trials for all these disease conditions. Normal human erythrocytes are impermeable to diamidine drugs, but those infected with P. falciparum are not, by virtue of a new porous pathway induced in the host cell membrane by the parasite itself (Ginsburg et al, 1983;Stead et al, 2001). …”

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Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)

Midgley¹,

Fitzpatrick²,

Taylor³

et al. 2007

Drug Metab Dispos

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ABSTRACT:DB289 (pafuramidine maleate; 2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) is a prodrug of DB75 (furamidine dihydrochloride; 2,5-bis(4-guanylphenyl)furan dihydrochloride), an aromatic dication related to pentamidine that has demonstrated good efficacy against African trypanosomiasis, Pneumocystis carinii pneumonia, and malaria, but lacks adequate oral availability. The pharmacokinetics and metabolism of 14 C-DB289 have been investigated in rat and monkey after oral and intravenous administration. Oral doses were well absorbed (ϳ50-70%) and effectively converted to DB75 in both species but subject to first-pass metabolism and hepatic retention, limiting its systemic bioavailability to 10 to 20%. Clearance of DB289 approximated the liver plasma flow and its large volume of distribution was consistent with extensive tissue binding. Plasma protein binding of DB289 was 97 to 99% in four animal species and humans, but that of DB75 was noticeably less and more species-and concentration-dependent. Together, prodrug and active metabolite accounted for less than 20% of the plasma radioactivity after an oral dose, but DB75 was the major radiochemical component in key organs such as brain and liver and was largely responsible for the persistence of 14 C in the body. The predominant route of excretion of radioactivity was via the feces, although biliary secretion was not particularly extensive. High-performance liquid chromatography and liquid chromatography-mass spectrometry investigations showed that the formation of DB75 from the prodrug involved the sequential loss of the two N-methoxy groups, either directly or by O-demethylation followed by reduction of the resulting oxime to the amidine. It was estimated that almost half of an oral dose of DB289 to rats and about one-third of that to monkeys was metabolized to DB75.

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Diamidine Compounds: Selective Uptake and Targeting inPlasmodium falciparum

Cited by 96 publications

References 33 publications

Heme Binding Contributes to Antimalarial Activity of Bis-Quaternary Ammoniums

Heme Binding Contributes to Antimalarial Activity of Bis-Quaternary Ammoniums

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)

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