Artemether structure

Initially, we sought a practical total synthesis of the natural enantiomer (+)-artemisinin (1) to support clinical therapeutic studies with artemisinin and derived prodrug congeners, such as artemether and artesunate, and by providing a radiolabeled version of artemisinin for metabolism and mode of action studies (Eq. 1). Associated model studies from our total synthesis resulted in numerous additional analogues for our fledgling SAR study and the conception of other structural... 

Posner et al. reported that some new types of qinghaosu dimers (Structure 5-22) had antimalarial, antiproliferative, and antitumor activities. Compound 149 was 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. Dimers 145-150 were especially... 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

The antimalarial activity of (9) involves its interaction with heme or hemin in the parasitized erythrocyte. Molecular modeling techniques have been used to investigate how the two molecules dock, the one on the other <95MI 620-0l>. The x-ray structures of artemether (23) and hemin have been taken and modeled with the SYBYL software. It is found that, in the optimum interaction, the peroxide bridge lies close to the central iron atom of heme or hemin. It will be seen in Section... 

Fig. (14) Chemical structures of artemisinin (44) and of its semisynthetic derivatives artemether (45) and artesunate (46)...

The followingybwr chemical structures, namely (/) artemisinin (//) dihydroartemisinin (Hi) artemether (oil-soluble) (iv) artemotil (oil soluble) and (v) artesunate (water soluble) are found to be active against the entire Plasmodium genera that cause malaria predominantly across the tropical regions of the globe, such as Africa, Indian sub-continent. South East Asia and the like. 

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