SYNTHESES AND ANTIMALARIAL ACTIVITIES OF N-SUBSTITUTED 11-AZAARTEMISININS

A two-step reaction sequence between artemisinin and methanolic ammoni a followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromati c amines for ammonia in the reaction sequence yields N-substituted 11- azaartemisinins in similar or greater yield. When Amberlyst 15 is repl aced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45 % and 15% yields, respectively. In vitro and in vivo test data for a n umber of novel N-substituted 11-azaartemisinins, against drug-resistan t strains of Plasmodium falciparum, show they possess antimalarial act ivities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times mo re active in vitro and 4 times more active in vivo than artemisinin.