Mechanism-Based Design of Parasite-Targeted Artemisinin Derivatives:  Synthesis and Antimalarial Activity of Benzylamino and Alkylamino Ether Analogues of Artemisinin

Bishop, Laurence P. D.; Storr, R. C.; Hawley, S R; Maggs, James L.; Ward, Stephen A.; Park, B K

doi:10.1021/jm9604944

Cited by 27 publications

(5 citation statements)

References 17 publications

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“…In conclusion, effective inhibition of heme polymerization can be achieved by simply modifying the oxidative status of porphyrin iron. Small amounts of Fe(II)PPIX are necessary for the activation of the peroxide bridge of artemisinin-type molecules (33,34). Fe(II) is also involved in the lipid peroxidation process via interaction with vinyl groups to form epoxides (35).…”

Section: Discussionmentioning

confidence: 99%

A Novel Endogenous Antimalarial: Fe(II)-Protoporphyrin IXα (Heme) Inhibits Hematin Polymerization to β-Hematin (Malaria Pigment) and Kills Malaria Parasites

Monti¹,

Vodopivec²,

Basilico³

et al. 1999

Biochemistry

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The polymerization of hemoglobin-derived ferric-protoporphyrin IX [Fe(III)PPIX] to inert hemozoin (malaria pigment) is a crucial and unique process for intraerythrocytic plasmodia to prevent heme toxicity and thus a good target for new antimalarials. Quinoline drugs, i.e., chloroquine, and non-iron porphyrins have been shown to block polymerization by forming electronic pi-pi interactions with heme monomers. Here, we report the identification of ferrous-protoporphyrin IX [Fe(II)PPIX] as a novel endogenous anti-malarial. Fe(II)PPIX molecules, released from the proteolysis of hemoglobin, are first oxidized and then polymerized to hemozoin. We obtained Fe(II)PPIX on preparative scale by electrochemical reduction of Fe(III)PPIX, and the reaction was monitored by cyclic voltammetry. Polymerization assays at acidic pH were conducted with the resulting Fe(II)PPIX using a spectrophotometric microassay of heme polymerization adapted to anaerobic conditions and the products characterized by infrared spectroscopy. Fe(II)PPIX (a) did not polymerize and (b) produced a dose-dependent inhibition of Fe(III)PPIX polymerization (IC(50) = 0.4 molar equiv). Moreover, Fe(II)PPIX produced by chemical reduction with thiol-containing compounds gave similar results: a dose-dependent inhibition of heme polymerization was observed using either L-cysteine, N-acetylcysteine, or DL-homocysteine, but not with L-cystine. Cyclic voltammetry confirmed that the inhibition of heme polymerization was due to the Fe(II)PPIX molecules generated by the thiol-mediated reduction of Fe(III)PPIX. These results point to Fe(II)PPIX as a potential endogenous antimalarial and to Fe(III)PPIX reduction as a potential new pharmacological target.

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Section: Discussionmentioning

confidence: 99%

A Novel Endogenous Antimalarial: Fe(II)-Protoporphyrin IXα (Heme) Inhibits Hematin Polymerization to β-Hematin (Malaria Pigment) and Kills Malaria Parasites

Monti¹,

Vodopivec²,

Basilico³

et al. 1999

Biochemistry

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“…These were quantitatively deprotected to 13a–f with TFA. Finally, compounds 13 were converted in reasonable to good yields into the target compounds, 6a–f , by reaction with 15 (artelinic acid, synthesized from dihydroartemisinin, 14 20) and TBTU 21. The hybrid molecules 6a–f were isolated as single isomers as shown by the 1 H-NMR spectra 21, which presented (i) only one singlet at δ ca.…”

mentioning

confidence: 99%

Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: Design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition

Capela

Oliveira

Gonçalves

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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A series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range. Keywordsantimalarial; artemisinin; FP-2; Vinylsulfone Artemisinin, 1, a sesquiterpene lactone isolated from the Artemisia annua Chinese herb, and its analogues (e.g. artemether, 2, arteether, 3, and artesunate, 4) were a major breakthrough in malaria chemotherapy because they produce a very rapid therapeutic response, particularly against multidrug-resistant Plasmodium falciparum malaria. 1,2 Despite the rapid clearance of parasites, the short half-lives of these compounds lead to many late recrudescences after monotherapy. 3 Thus, artemisinin-based combination therapy (ACT) has now been recommended by the World Health Organisation as standard therapy for falciparum malaria. 4 Cysteine proteases from malaria parasites are of particular interest as therapeutic targets due to their role in parasite development. 5 P. falciparum expresses four cysteine proteases from the papain family known as falcipains, of which falcipain-2 (FP-2) 6,7 and falcipain-3 (FP-3) 7,8 are the most relevant as therapeutic targets. Peptidyl vinyl sulfones, e.g. 5, are potent irreversible inhibitors of falcipains, acting as Michael acceptors of the catalytic cysteine residue. 9 Falcipain inhibitors have been shown to inhibit the development of cultured erythrocytic parasites by blocking the hydrolysis of host hemoglobin and to cure mice infected with lethal malaria infections. 10 *Corresponding authors: Phone: +351217946476; Fax: +35 1217946470; fclopes@ff.ul.pt. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptA concern regarding the use of protease inhibitors as antimalarials is that selection of drugresistant mutants will eventually occur. Indeed, parasites resistant to a dipeptidyl vinyl sulfone have been selected in the laboratory, although this resistance was somewhat unstable. 11 Thus, dipeptidyl vinyl sulfones are obvious candidates for combination antimalarial therapy as a strategy to retard the development of resistance. This information prompted us to design artemisinin-vinyl sulfone hybrid molecules with the potential to help prevent multi-drug resistance in P. falci...

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“…Indeed, the emergence of malaria as a worldwide epidemic can largely be attributed to the indiscriminate use of conventional drugs, due to which there has been a rapid development of resistant varieties of the malaria parasite. In that regard, the discovery of artemisinin 1 , a sesquiterpene lactone endoperoxide, isolated from the Chinese traditional medicinal herb Artemisia annua, has proven to be a milestone in malaria chemotherapy. − It was found to be active against both chloroquine-sensitive and chloroquine-resistant strains of malaria, and its semisynthetic derivatives artemether 2 , arteether 3 , and artesunic acid 4 (Figure ) have shown tremendous potential and are presently the drugs of choice for the treatment of multidrug-resistant malaria caused by Plasmodium falciparum. − Several analogues of artemisinin have been synthesized so far that have shown potential antimalarial activity. − The very fact that it is the endoperoxide linkage of artemisinin and its semisynthetic analogues in the form of a 1,2,4-trioxane ring system, which is responsible for its antimalarial activity, has led to the development of several synthetic trioxanes and various other related peroxides that have shown potent antimalarial activity both in vivo and in vitro. − …”

Section: Introductionmentioning

confidence: 99%

Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii nigeriensis in a Swiss Mice Model

et al. 2021

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Novel 6-arylethyl-1,2,4-trioxanes6a−i and 7a−i are easily accessible in one step from the diimide reduction of 6arylvinyl-1,2,4-trioxanes 5a−i. All of these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in a Swiss mice model. Most of the saturated trioxanes 6c, 6f, 6g, 6h, and 6i, the active compounds of the series, provided 100% protection to the malaria-infected mice at a dose of 24 mg/kg × 4 days. Further, trioxane 6i, the most active compound of the series, also showed 100% protection even at a dose of 12 mg/kg × 4 days and 20% protection at a dose of 6 mg/kg × 4 days. In this model, β-arteether provided 100% protection at a dose of 48 mg/kg × 4 days and only 20% protection at a dose of 24 mg/kg × 4 days via the oral route, which was found to exhibit 4-fold antimalarial activity compared with the currently used drug β-arteether.

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Mechanism-Based Design of Parasite-Targeted Artemisinin Derivatives: Synthesis and Antimalarial Activity of Benzylamino and Alkylamino Ether Analogues of Artemisinin

Cited by 27 publications

References 17 publications

A Novel Endogenous Antimalarial: Fe(II)-Protoporphyrin IXα (Heme) Inhibits Hematin Polymerization to β-Hematin (Malaria Pigment) and Kills Malaria Parasites

A Novel Endogenous Antimalarial: Fe(II)-Protoporphyrin IXα (Heme) Inhibits Hematin Polymerization to β-Hematin (Malaria Pigment) and Kills Malaria Parasites

Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: Design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition

Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii nigeriensis in a Swiss Mice Model

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