Metabolism studies on selected antimalarial sesquiterpene endoperoxides

Using microbial models of mammalian drug metabolism, the metabolic profile of the antimalarial agents, anhydrodihydroartemisinin (enol ether) and deoxoartemisinin were evaluated. Screening studies on the enol ether indicated that of the 60 microorganisms used, Streptomyces lavendulae L-105 and Rhizopogon species ATCC 36060 were appropriate candidates for large scale fermentation. Streptomyces lavendulae produced a 14 carbon degradation product (EEM-1) and 9{dollar}beta{dollar}-hydroxyanhydrodihydroartemisinin (EEM-2). Rhizopogon species produced C-(11)-epi-deoxydihydroartemisinin (EEM3) and 3{dollar}alpha{dollar}-hydroxydeoxyanhydrodihydroartemisinin (EEM-4). In the process of the structure elucidation of EEM-1, the enol ether epoxide was prepared chemically and fully identified. Mammalian metabolism studies indicated that of the four microbial metabolites, EEM-2 was the only microbial metabolite produced by the mammalian system.; Screening studies on deoxoartemisinin indicated that of the 50 microorganisms used, Aspergillus ochraceus ATCC 18500, and Mucor ramannianus 1839 (Sih), were appropriate candidates for large scale fermentation. Aspergillus ochraceus produced an unusual rearrangement product (DOM-1) and a 13 carbon degradation product (DOM-2). Mucor ramannianus produced 3{dollar}alpha{dollar}-hydroxydeoxoartemisinin (DOM-3) and 9{dollar}beta{dollar}-hydroxydeoxoartemisinin (DOM-4). In the process of the structure elucidation of (DOM-2), the DOM-2 acetate was prepared chemically and was fully identified. Mammalian metabolism studies on deoxoartemisinin revealed that it is metabolized to two major metabolites one of which is DOM-4 and the second is an isomer of DOM-4. The presence of an isomer of DOM-4 as a major mammalian metabolite led to the synthesis 9{dollar}alpha{dollar}-hydroxydeoxoartemisinin (DOM-4 isomer) which turned out not to be a mammalian metabolite of deoxoartemisinin. In this process, the ketone of DOM-4 (DOM-4k) and DOM-4 isomer were prepared chemically and fully identified.; The structures of these compounds were established by spectroscopic methods and by comparison of the spectral data with those of the starting material and with similar compounds in the literature. The structures of EEM-1 and the enol ether epoxide were confirmed by X-ray. DOM-1 is yet to be fully characterized.; In vitro antimalarial testing was limited to selected metabolites and revealed that EEM-2 and DOM-4 possess significant antimalarial activity.