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The role of C-centered radicals on the mechanism of action of artemisinin |
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| Authors: | A G Taranto J W de M Carneiro F G de Oliveira M T de Araujo C R Correa |
| Institution: | a Programa de Pós-Graduação em Química Orgânica, Universidade Federal Fluminense, 24210-150, Niterói, RJ, Brazil b Departamento de Química Geral e Inorgânica, Universidade Federal Fluminense, 24210-150, Niterói, RJ, Brazil c Departamento de Físico-Química, Universidade Federal Fluminense, 24210-150, Niterói, RJ, Brazil |
| Abstract: | Artemisinin is a sesquiterpene lactone with an endoperoxide function that is essential for its antimalarial activity. Endoperoxides are supposed to act on heme leading to the reduction of the peroxide bond and production of radicals, which can be responsible for killing the parasite. The geometries of artemisinin, radical anions and neutral species generated by rearrangement after reduction of the peroxide bond were fully optimized with the AM1 and PM3 semi-empirical methods, in order to characterize the intermediates formed during the process. Among the radicals calculated along the pathway for reductive decomposition of artemisinin, the secondary radical centered on carbon C4 has the highest stability when compared to other radicals that can be achieved either by hydrogen migration to the original O-centered radical or by homolytic break of C–C bond. This suggests that the C4-centered radical may be the species responsible for killing the parasite, as has been indicated previously in experimental studies. |
| Keywords: | Artemisinin Mechanism of action Radicals Semi-empirical calculations AM1 PM3 |
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