A DFT study of free radicals formed from artemisinin and related compounds

Drew, M.G.B., Metcalfe, J. and Ismail, F.M.D. (2004) A DFT study of free radicals formed from artemisinin and related compounds. Journal of Molecular Structure-Theochem, 711 (1-3). pp. 95-105. ISSN 0166-1280 doi: 10.1016/j.theochem.2004.08.028

Abstract/Summary

Ab initio calculations using density functional theory have shown that the reactions that occur between artemisinin, 1, a cyclic trioxane active against malaria, and some metal ions and complexes lead to a series of radicals which are probably responsible for its therapeutic activity. In particular it has been shown that the interaction of Fe(H) with artemisinin causes the O-O bond to be broken as indeed does Fe(III) and Cu(I), while Zn(II) does not. Calculations were carried out with Fe(II) in several different forms including the bare ion, [Fe(H2O)(5)](2+) and [FeP(Im)] (P, porphyrin; Im, imadazole) and similar results were obtained. The resulting oxygen-based radicals are readily converted to more stable carbon-based radicals and/or. stable products. Similar radicals and products are also formed from two simple model trioxanes 2 and 3 that show little or no therapeutic action against malaria although some subtle differences were obtained. This suggests that the scaffold surrounding the pharmacophore may be involved in molecular recognition events allowing efficient uptake of this trioxane warhead into the parasite. (C) 2004 Elsevier B.V. All rights reserved.