Search

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.

Qinghaosu(artemisinin) is the antimalarial principle of the Chinese traditional herb qinghao (Artemisia annua L.). Now qinghaosu and its derivatives have distinguished themselaves as a new generation of antimalarial drugs, especially in the treatment of multidrug-resistant cases. Qinghaosu has a unique carbon framework containing a special endoperoxy dridge, which is entirely different from that of all previous antimalarial agents and hence makes a novel antimalarial mechanism possible. Up to now there is still no clear picture about this mechanism at the molecular lever. However, the ferric/ferrous ions that are abundant in the red cell in which the parasite lives, is likely the most important co-factor for the antimalarial process of qinghaosu (scheme 1).

A convenient methodology for attaching an acid-stable UV chromophore onto the qinghaosu (artemisinin) framework with readily available dihydroqinghaosu acetate as the starting material is presented. The resulting derivatives of deoxoqinghaosu may be used as a sensitive probe in the mechanistic and biological/pharmacological investigations. As the first application of the present methodology, naphth-2-ol is attached to qinghaosu nucleus through a carbon–carbon single bond by a boron trifluoride-catalyzed Friedel–Crafts alkylation. A previously undetected racemization at C-9 mediated by an enol ether under the reaction conditions (BF3·OEt2, CH2Cl2) that have been widely used for preparing C-10 derivatives of dihydroqinghaosu is observed. The knowledge gained from the present work may assist the rational design of new trioxane-type antimalarial agents.

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.

Antimalarial compound qinghaosu (1) and its phenyl derivative 2 were reacted with reduced glutathione (GSH) and Fe(II/III) to give, besides other known degradation products, an interesting adduct from a primary C-centered free radical and GSH. Because GSH plays a very important role in the cell cycle, this finding may eventually lead to a new understanding of its mode of action.

Antimalarial compound qinghaosu (1) and its phenyl derivative 2 were reacted with reduced glutathione (GSH) and Fe(II/III) to give, besides other known degradation products, an interesting adduct from a primary C-centered free radical and GSH. Because GSH plays a very important role in the cell cycle, this finding may eventually lead to a new understanding of its mode of action.