| Autor: |
G. B. Drew, Michael, Metcalfe, John, J. Dascombe, Michael, M. D. Ismail, Fyaz |
| Zdroj: |
Journal of Medicinal Chemistry; October 2006, Vol. 49 Issue: 20 p6065-6073, 9p |
| Abstrakt: |
The currently accepted mechanism of trioxane antimalarial action involves generation of free radicals within or near susceptible sites probably arising from the production of distonic radical anions. An alternative mechanistic proposal involving the ionic scission of the peroxide group and consequent generation of a carbocation at C-4 has been suggested to account for antimalarial activity. We have investigated this latter mechanism using DFT (B3LYP/6-31G level) and established the preferred Lewis acid protonation sites (artemisinin O5a O4a O3a > O2a > O1a; arteether O4a ≥ O3a > O5b O2a >O1a; Figure 3) and the consequent decomposition pathways and hydrolysis sites. In neither molecule is protonation likely to occur on the peroxide bond O1−O2 and therefore lead to scission. Therefore, the alternative radical pathway remains the likeliest explanation for antimalarial action. |
| Databáze: |
Supplemental Index |
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