Antimalarial Activity of New Water-Soluble Dihydroartemisinin Derivatives

Article abstract of DOI:10.1021/jm00394a037

The usefulness of sodium artesunate (3), a water-soluble derivative of artemisinin (1), is impaired by its poor stability in aqueous solution.To overcome the ease of hydrolysis of the ester group in 3, a new series of derivatives of dihydroartemisinin (2) was prepared in which the solubilizing moiety, which contains a carboxylate group, is joined to dihydroartemisinin by an ether rather than an ester linkage.The new derivatives were prepared in good yield by treatment of dihydroartemisinin with an appropriate alcohol under boron trifluoride etherate catalysis at room temperature.All major condensation products are the β isomer.Hydrolysis of the esters with 2.5percent KOH/MeOH gave the corresponding pottassium salts, which were converted to free acids (8b-d) by acidification.The derivatives were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone).No cross-resistance to the antimalarian agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was observed.In general, the new compounds are more effective against the W-2 than the D-6 strain.Esters (5a-d) possess activity comparable to that of the parent compounds 1 and 2; however, conversion of the esters to their corresponding carboxylates (7a-d) or acids (8a-d), with the exception of artelinic acid (8d), drastically decreases the antimalarial activities in both cell lines.Artelinic acid, which is both soluble and stable in 2.5percent K2CO3 solution, possesses superior in vivo activity against Plasmodium berghei than artemisinin or artesunic acid.