STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE ANTIMALARIAL AGENT ARTEMISININ .4. EFFECT OF SUBSTITUTION AT C-3

Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via th e synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by al kylation provided initially alkylated hydrazones that upon chromatogra phy gave ketones 6-13 and 25-30. Direct ozonolysis of the ketones foll owed by in situ acidification lead directly to the formation of title compounds 14-21 and 31-36. The analogs were tested in vitro against W- 2 and D-6 strains of Plasmodium falciparum and found to be in some cas es much more active than the natural product (+)-artemisinin. The resu lts were included in structure-activity relationship (CoMFA) studies f or further analog design.