Reactions of artemisinin and arteether with acid: Implications for stability and mode of antimalarial action

Drew, M.G.B., Metcalfe, J., Dascombe, M.J. and Ismail, F.M.D. (2006) Reactions of artemisinin and arteether with acid: Implications for stability and mode of antimalarial action. Journal of Medicinal Chemistry, 49 (20). pp. 6065-6073. ISSN 0022-2623 doi: 10.1021/jm060673d

Abstract/Summary

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/6-31+G* level) and established the preferred Lewis acid protonation sites (artemisinin O5a >> O4a approximate to 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.