| Titre : |
Role of metals in the mechanism of action of antimalarial peroxides |
| Type de document : |
texte imprimé |
| Auteurs : |
Bousejra-El Garah, Fatima, Auteur ; Robert, Anne, Directeur de thèse |
| Année de publication : |
2010 |
| Langues : |
Anglais (eng) |
| Tags : |
MALARIA TREATMENT ANTIMALARIAL PEROXIDES ARTEMISININ TRIOXAQUINES TETRAOXANES HEME ALKYLATION PFATP6 MODELING |
| Résumé : |
"The 1,2,4-trioxane core structure of artemisinin is essential for its activity. It was shown that iron(II) catalyses the reductive cleavage of the peroxide bond of the drug, leading to the formation of C-centered radicals. These radicals are able to alkylate heme resulting from host cell hemoglobin digestion, and parasitic proteins. These alkylation processes are believed to induce parasite death. In the present work, we studied the two main mechanisms proposed in the literature for artemisinin, namely heme alkylation and PfATP6 inhibition. In addition, we also explored the possible bio-activation of artemisinin by copper enzymes. We report our investigation into the reactivity of metal salts and complexes, such as heme, toward highly active antimalarial peroxide-containing drugs, namely artemisone, trioxaquines, trioxolanes, and tetraoxanes. Overall, our results with heme confirmed that the alkylating properties of artemisinin, in particular in malaria-infected mice, are not limited to this natural compound, but are shared with other potent peroxide-containing drugs. It is likely that heme alkylation plays a very important role in their anti-plasmodial mechanism of action. In this work, we also considered an alternative mechanism of action for artemisinin, based on the inhibition of PfATP6. The main result is that the predicted binding affinity of the tested compounds does not correlate with their in vitro antimalarial activity."
|
| Document : |
Thèse de Doctorat |
| Etablissement_delivrance : |
Université de Toulouse 3 |
| Date_soutenance : |
18/03/2010 |
| Ecole_doctorale : |
Sciences de la matière (SdM) |
| Domaine : |
Chimie. Biologie. Santé |
| Localisation : |
LCC |
| En ligne : |
http://thesesups.ups-tlse.fr/824/ |
Role of metals in the mechanism of action of antimalarial peroxides [texte imprimé] / Bousejra-El Garah, Fatima, Auteur ; Robert, Anne, Directeur de thèse . - 2010. Langues : Anglais ( eng)
| Tags : |
MALARIA TREATMENT ANTIMALARIAL PEROXIDES ARTEMISININ TRIOXAQUINES TETRAOXANES HEME ALKYLATION PFATP6 MODELING |
| Résumé : |
"The 1,2,4-trioxane core structure of artemisinin is essential for its activity. It was shown that iron(II) catalyses the reductive cleavage of the peroxide bond of the drug, leading to the formation of C-centered radicals. These radicals are able to alkylate heme resulting from host cell hemoglobin digestion, and parasitic proteins. These alkylation processes are believed to induce parasite death. In the present work, we studied the two main mechanisms proposed in the literature for artemisinin, namely heme alkylation and PfATP6 inhibition. In addition, we also explored the possible bio-activation of artemisinin by copper enzymes. We report our investigation into the reactivity of metal salts and complexes, such as heme, toward highly active antimalarial peroxide-containing drugs, namely artemisone, trioxaquines, trioxolanes, and tetraoxanes. Overall, our results with heme confirmed that the alkylating properties of artemisinin, in particular in malaria-infected mice, are not limited to this natural compound, but are shared with other potent peroxide-containing drugs. It is likely that heme alkylation plays a very important role in their anti-plasmodial mechanism of action. In this work, we also considered an alternative mechanism of action for artemisinin, based on the inhibition of PfATP6. The main result is that the predicted binding affinity of the tested compounds does not correlate with their in vitro antimalarial activity."
|
| Document : |
Thèse de Doctorat |
| Etablissement_delivrance : |
Université de Toulouse 3 |
| Date_soutenance : |
18/03/2010 |
| Ecole_doctorale : |
Sciences de la matière (SdM) |
| Domaine : |
Chimie. Biologie. Santé |
| Localisation : |
LCC |
| En ligne : |
http://thesesups.ups-tlse.fr/824/ |
|  |
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