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The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum . Since the parasite enzymes should trigger the production of the active drug in the parasite's food vacuoles, our approach is summarized as "to dig its grave with its fork". However, despite promising sub-micromolar IC 50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.

The in vivo alkylation of heme by the antimalarial trioxaquine DU1301 afforded covalent heme-drug adducts that were detected in the spleens of Plasmodium sp.-infected mice. This result indicates that the alkylation capacities of trioxaquines in mammals infected with Plasmodium strains are similar to that of artemisinin, a natural antimalarial trioxane-containing drug.

Heme alkylation by the antimalarial drug artemisinin is reported in vivo, within infected mice that have been treated at pharmacologically relevant doses. Adducts resulting from the alkylation of heme by the drug were characterized in the spleen of treated mice, and their glucuroconjugated derivatives were present in the urine. Because these heme-artemisinin adducts were not observed in noninfected mice, this report confirms that the alkylating activity of this antimalarial drug is related to the presence of the parasite in infected animals. The identification of heme-artemisinin adducts in mice should be considered as the signature of the alkylation capacity of artemisinin in vivo.

The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin‐based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin‐resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8‐amino‐ or 8‐hydroxyquinoline entity covalently bound to a 1,4‐naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC50=622 nm on an artemisinin‐resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action. [ABSTRACT FROM AUTHOR]

Background: Owing to the emergence of multiresistant Plasmodium falciparum parasites in Southeast Asia, along with the impressive decrease in the efficacy of the endoperoxide compound artemisinin and of artemisinin-based combination therapies, the development of novel antimalarial drugs or combinations is required. Although several antiplasmodial molecules, such as endoperoxide-based compounds, are in advanced research or development, we do not know whether resistance to artemisinin derivatives might impact the efficacy of these new compounds.Objectives: To address this issue, the antiplasmodial efficacy of trioxaquines, hybrid endoperoxide-based molecules, was explored, along with their ability to select in vitro resistant parasites under discontinuous and dose-escalating drug pressure.Methods: The in vitro susceptibilities of artemisinin- and trioxaquine-resistant laboratory strains and recent Cambodian field isolates were evaluated by different phenotypic and genotypic assays.Results: Trioxaquines tested presented strong cross-resistance with artemisinin both in the artemisinin-resistant laboratory F32-ART5 line and in Cambodian field isolates. Trioxaquine drug pressure over 4 years led to the in vitro selection of the F32-DU line, which is resistant to trioxaquine and artemisinin, similar to the F32-ART lineage. F32-DU whole genome sequencing (WGS) revealed that resistance to trioxaquine was associated with the same non-synonymous mutation in the propeller domain of the K13 protein (M476I) that was found in the F32-ART lineage.Conclusions: These worrisome results indicate the risk of cross-resistance between artemisinins and endoperoxide-based antiplasmodial drugs in the development of the K13 mutant parasites and question the usefulness of these molecules in the future therapeutic arsenal. [ABSTRACT FROM AUTHOR]

Artemisinin is an efficient antimalarial drug containing a 1,2,4-trioxane which is able to alkylate heme both in vitro and in vivo, giving rise to covalent heme-artemisinin coupling products. The low valent iron(II) protoporphyrin-IX, which is the prosthetic group of hemoglobin, induces the homolysis of the peroxide bond of artemisinin by an electron transfer. The generated alkoxy radical is quickly rearranged to a C-centered radical that efficiently alkylates the heme macrocycle at meso positions. Heme is therefore both the activating agent and the target of artemisinin. Additionally, the iron(II) heme cofactor of carboxyhemoglobin was found to react as efficiently with artemisinin as oxyhemoglobin does, providing a heme-drug covalent adduct in up to 60% yield. This result indicates that the presence of a CO ligand bound to iron does not preclude the reductive activation of the peroxide, thereby confirming the high affinity of artemisinin for iron(II) heme. On the basis of this mechanism of action, a variety of new peroxide-based antimalarials named trioxaquines® have been synthesized. Trioxaquines are made by the covalent attachment of a trioxane, having alkylating ability, to a quinoline, known to readily penetrate infected erythrocytes. Several trioxaquines are active in vitro on chloroquine resistant malaria parasite at nanomolar concentrations, and are efficient to cure infected mice by oral route at 20–50 mg/kg. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Artemisinin is an efficient antimalarial drug containing a 1,2,4-trioxane, which is able to alkylate heme both in vitro and in vivo, giving rise to covalent heme–artemisinin coupling products. The low valent iron(II) protoporphyrin-IX, which is the prosthetic group of hemoglobin, induces the homolysis of the peroxide bond of artemisinin by an inner-sphere electron transfer. The generated alkoxy radical is quickly rearranged to a C-centered radical, which efficiently alkylates the heme macrocycle at meso positions. Heme is therefore both the activating agent and the target of artemisinin. On the basis of this mechanism of action, a new family of peroxide-based antimalarials named trioxaquines® has been synthesized. Trioxaquines are made by the covalent attachment of a trioxane, having alkylating ability, to a quinoline, known to easily penetrate within infected erythrocytes. Several trioxaquines are active in vitro on chloroquine resistant malaria parasite at nanomolar concentration, and are efficient by oral route to cure infected mice at 20–50mg/kg. [Copyright &y& Elsevier]

In vitro, the heme cofactor of human iron(II) hemoglobin was efficiently and quickly alkylated at meso positions by the peroxide-based antimalarial drug artemisinin, leading to heme–artemisinin-derived covalent adducts. This reaction occurred in the absence of any added protease or in the presence of an excess of an extra non-heme protein, or even when artemisinin was added to hemolysed human blood. This activation of artemisinin by the heme moiety of non-digested hemoglobin clearly indicates the high affinity of this drug for heme, and its efficient alkylating ability under very mild conditions. [Copyright &y& Elsevier]

The peroxide function of artemisinin has been activated by iron(II)–heme generated in situ from iron(III)–protoporphyrin–IX or iron(III)–protoporphyrin–IX dimethylester and a reducing agent. In mild conditions, this reaction produced high yield (85%) of heme derivatives alkylated at meso positions by a C4-centered radical derived from artemisinin. The adducts at α-, β-, and δ-meso positions were obtained as major products, and alkylation at γ-meso position was minor (7–13% of the total amount of adducts). These adducts were not separable, but the mixture has been characterized after demetallation by a detailed NMR study. [Copyright &y& Elsevier]

Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties on DNA methyltransferases and HDAC's for epigenetics, and on cytochrome bc1 and dihydroorotate dehydrogenase for mitochondrion. [ABSTRACT FROM AUTHOR]

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs. [ABSTRACT FROM AUTHOR]

The preparation and the biological evaluation of a new antimalarial modular drug, named trioxaquine are reported. The trioxane moiety of this trioxaquine is prepared through the halogenocyclisation of a hemiperoxyacetal derived from the allylic hydroperoxide of 2,3-dimethyl-2-butene. [Copyright &y& Elsevier]

Abstract: The interaction of heme or heme-artemisinin adducts (heme-art) with different peptides mimicking repeat sequences of the Histidine-Rich-Protein-II of Plasmodium falciparum (PfHRP-II) was investigated. The pseudo-first order rate constants of the coordination of heme or heme-art onto a histidine rich peptide, used as a mimic of PfHRP-II putative heme binding sequence, are of the same order of magnitude, namely 42 and 14s−1, respectively. Despite the intrinsic reactivity of the carbonyl at C10 of heme-art toward a hydroxyl function, a peptide containing a serine or threonine residue does not readily react with heme-art adducts. Therefore, a much higher affinity of heme-art compared to heme toward PfHRP-II, if so, must be induced by a specific interaction or a chemical reaction, these phenomena being both due to the tertiary structure of the parasite protein itself. [Copyright &y& Elsevier]