The Deoxygenation and Isomerization of Artemisinin and Artemether and Their Relevance to Antimalarial Action

Jefford, Charles W.; Vicente, M. Graça H.; Jacquier, Yvan Daniel Michel; Mareda, Jiri; Millasson‐Schmidt, Patricia; Brunner, Gerhard; Bürger, Ulrich

doi:10.1002/hlca.19960790520

Cited by 106 publications

(87 citation statements)

References 52 publications

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“…[2][3][4][6][7][8][9][10][11][12] In contrast, our study found that the major reaction product under an aqueous buffer condition was dihydroartemisinin which exhibited more potent antimalarial activity than artemisinin. This suggested that under physiological conditions, iron could react with artemisinin, giving active metabolites, the main product should be dihydroartemisinin, and probably oxygen free radicals during redox reaction of artemisinin.…”

Section: Discussionmentioning

confidence: 83%

“…14,15) It should be noted that in aqueous buffer, the products of iron-artemisinin reaction were different from those obtained from the reaction performed in organic solvents. It was suggested elsewhere that the mode of action of artemisinin involved the cleavage of the endoperoxide bridge by iron, yielding a carbon centred free radical [2][3][4]13) which, in turn, alkylated the parasite-specific proteins.…”

Section: Discussionmentioning

confidence: 99%

“…It was demonstrated that artemisinin can kill parasites in the ring and late stage, both in vitro and in vivo. 1) It is believed that the mode of action of artemisinin is its iron-dependent mechanism, involving cleavage of the peroxide bridge by heme iron, yielding carbon centred free radicals [2][3][4] which in turn alkylates some parasite-specific proteins. 5) Although the chemical reaction of artemisinin with free iron or heme has been extensively studied, and the end-products have been characterized in many laboratories, [6][7][8][9][10][11][12][13] the nature of the biological active intermediates is still unclear.…”

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confidence: 99%

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Redox Reaction of Artemisinin with Ferrous and Ferric Ions in Aqueous Buffer.

Sibmooh

Udomsangpetch

Kijjoa

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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Artemisinin, a sesquiterpene with endoperoxide bond, possesses potent antimalarial activity against the ring and late stage of chloroqine-resistant Plasmodium falciparum malaria both in vitro and in vivo. The mode of antimalarial activity of artemisinin is iron-dependent. The aim of this study was to investigate the reactions of artemisinin with ferrous and ferric ions in aqueous buffer. Artemisinin generated a cycle of iron oxidation and reduction. It oxidized ferrous and reduced ferric ions with similar rate of reaction (k‫5.0؎01؍‬ M ؊1 · s ؊1 for ferrous and k‫0.2؎5.8؍‬ M ؊1 · s ؊1 for ferric ion). The major active product was dihydroartemisinin which exhibited antimalarial activity at least 3 times more potent than artemisinin. Dihydroartemisinin preferably binds to ferric ion, forming ferric-dihydroartemisinin complex. The re-oxidation of the complex gives artemisinin and ferric ion. This suggests that in aqueous buffer, the reaction of artemisinin with iron may give rise to the active reaction products, one of them being dihydroartemisinin, which is responsible for antimalarial activity.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Redox Reaction of Artemisinin with Ferrous and Ferric Ions in Aqueous Buffer.

Sibmooh

Udomsangpetch

Kijjoa

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Dihydroartemisinin, deoxyartemisinin, 3-hydroxy-deoxyartemisinin, and the furano-acetate metabolite of artemisinin were derived from artemisinin using published procedures. 12,13 Enzyme-linked immunosorbent assay procedure. Polystyrene microtiter plates (Costar radioimmunoassay; Corning Costar Europe, Badhoevedorp, The Netherlands) were coated with 100 l of a 1:10,000 dilution of monoclonal antibody F170-10 in PBS for 3 hr at room temperature.…”

Section: Methodsmentioning

confidence: 99%

The development of an immunoassay for the detection of artemisinin compounds in urine.

Eggelte

Agtmael

Vuong

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. We have produced monoclonal antibodies against artelinic acid and investigated the reactivity with artemisinin drugs and metabolites. Antibody F170-10 is fairly specific for artelinic acid but does bind artemisinin and artemether (3-5% cross-reactivity). Dihydroartemisinin, artesunate, and metabolites of artemisinin showed less reactivity. With this antibody, an inhibition ELISA has been set up to detect artemisinin compounds in urine. In healthy subjects who received a single oral dose of artemisinin, artemether, artesunate or dihydroartemisinin, ELISA reactivity in urine was found. This reactivity in urine paralleled the plasma concentrations of artemether and dihydroartemisinin. The results show that this immunoassay for artelinic acid can be used to detect artemisinin compounds in urine for about 8 hr after intake. With a more sensitive test, this simple method as a urine dipstick may be become useful for drug use and compliance studies in malaria-endemic areas where the artemisinin derivatives are increasingly used.Drug-resistant Plasmodium falciparum is a still increasing problem in malaria control. In Southeast Asia, it has reached such proportions that use of the latest antimalarial drugs, e.g., artemisinin-derived drugs, is required to treat severe malaria. Fortunately the situation in Africa, which has the bulk of the world malaria cases, is less problematic with regard to the number of antimalarial drugs that still can be used. However, the impact of the still-increasing chloroquine resistance will be substantial as replacement of chloroquine by more expensive drugs will impose severe constraints on the health budgets of those countries with low economic wealth.1 Early treatment is important to decrease malaria mortality, since even the most effective drugs cannot prevent an unacceptable high mortality of 20% in severe malaria. 2,3 Self-treatment is common in malaria-endemic areas where the amount of antimalarial drugs sold in shops and in the markets exceeds that used through the official health channels. 4,5 People often have already taken antimalarial drugs before presenting themselves at a health center. Uncontrolled use of antimalarial drugs will favor the emergence of drugresistant strains through selection of less susceptible parasites. There are indications that due to the increasing chloroquine resistance, malaria morbidity and hospitalizations are increasing. 6Although only recently introduced, artemisinin compounds can already be freely purchased in many malariaendemic areas, despite the fact that many of these drugs are still in the process of official registration. The artemisininderived agents have to be taken for at least 5 days to limit the recrudescence rate when they are not combined with other antimalarials. 7,8 Since these drugs act quickly, it is likely that often the full course may not be taken.No simple methods are available for detection of intake of artemisinin derivatives, which can be used to monitor compliance and to investigate self-treatment. Various methods ha...

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“…With respect to its mechanism of action, it is probable 19 that antimalarial tetraoxanes such as WR 148999 undergo an iron-mediated reductive activation to form presumed parasiticidal carbon free radicals as is postulated for artemisinin and related synthetic trioxanes. 4,5,21,22 Experiments to test this hypothesis are in progress.…”

Section: Duration Of Actionmentioning

confidence: 99%