A two-step reaction sequence between artemisinin and methanolic ammonia, followed by treatment with Amberlyst 15 yielded 11-aza-artemisinin in 65% yield. When a variety of primary alkyl and heteroaromatic amines were substituted for ammonia in the reaction sequence, a series of N- substituted 11-azaartemisinins were obtained in good yield. By substituting a mixture of sulfuric acid/silica gel for Amberlyst 15 in the reaction sequence, both N-substituted 11-azaartemisinin and N-substituted 10-azadesoxyartemisinin, the expected metabolite, were obtained. In vitro test data for the N-substituted 11-azaartemisinins show several are 10 to 25 times more potent antimalarial drugs than artemisinin. The most active derivative, N-(2'-acetaldehydo) 11-azaartemisinin was 4 times more active than artemisinin in vivo.
