Further evidence for the participation of primary carbon-centered free radicals in the antimalarial action of the qinghaosu (artemisinin) series of compounds

Abstract

Friedel–Crafts alkylation of 1,3-dimethoxybenzene with O-acetyldihydroqinghaosu gave a pair of 11-epimers of 12-(2,4-dimethoxyphenyl)deoxoqinghaosu 2 and 2′. The antimalarial activity of 11β-epimer 2 was comparable with that of artemether. Compound 2 reacted smoothly with ferrous ions or L-cysteine and catalytic amounts of ferrous ions to give a series of products derived from the previously postulated C-centered free radical, in particular the primary C-centered free radical. However, 11α-epimer 2′ was almost inert to ferrous ions and also showed low antimalarial activity. The identification of free radical mediated products and the correlation between chemical reactivity and bio-activity once again provided evidence for the key role of primary carbon-centered free radicals in the antimalarial activity of the qinghaosu series of compounds.