Synthesis and Antimalarial Activities of Base-catalyzed Adducts of 11-azaartemisinin

A series of N-substituted 11-azaartemisinins were prepared in high yield employing base-catalyzed additions to an amide nitrogen of olefins and terminal acetylenes conjugated with electron withdrawing groups (EWGs). When the terminal acetylene was conjugated with carbomethoxy, N,N-dimethyl amide or carbonyl groups, the E-adducts resulted. A mixture of E- and Z-adducts were obtained when the EWG was a nitrile. In vitro antimalarial activities of each compound were determined against two drug-resistant strains of Plasmodium falciparum. Many of the compounds prepared were several times more active than artemisinin.