STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE ANTIMALARIAL AGENT ARTEMISININ .5. ANALOGS OF 10-DEOXOARTEMISININ SUBSTITUTED AT C-3 AND C-9

Novel 3- and 9-substituted analogs (4-19) of 10-deoxoartemisinin, 3, w ere prepared from the corresponding known lactones by one-pot reductio n with sodium borohydride and boron trifluoride etherate. Reproducibil ity problems associated with this heterogeneous reaction were encounte red on small reaction scales, and thus alternative methodology was sou ght for this reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate lactols was made more reproducible using a two-step sequence involving low-temperature reduction with di isobutylaluminum hydride followed by deoxygenation with boron trifluor ide etherate in the presence of triethylsilane. In this manner, 10-deo xoartemisinin (3) could be obtained from artemisinin (1) in greater th an 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were muc h more active than the natural product (+)-artemisinin (1) or 10-deoxo artemisinin (3). Conventional structure-activity relationships are dis cussed in relation to the bioassay data.