ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

在发展疟疾的过程中遇到的棘手问题

TheThe formidable problems encountered in developing a malaria vaccine, and the ability of Plasmodium falciparum to develop resistance to new drugs, have stimulated interest in using combinations of drugs for treating this disease, which claims more than a million lives a year. Although strains of P. falciparum have become resistant to many drugs, no strains have thus far become resistant to derivatives of artemisinin. Artemisinin derivatives are thought to damage the parasite's membranes, while quinine or mefloquine inhibit dihydrofolate reductase. Thus, the parasite has to mutate at a different locus to become resistant to artemisinin. A large number of derivatives (esters and ethers of dihydroartemisinin) have been prepared in China and the United States and shown to be active against P. falciparum. For additional structure- activity studies, we wanted to introduce a new functional group into the molecule, without destroying the peroxide necessary for its antimalarial activity. We have investigated the ability of the fungus Beauveria sulfurescens to introduce hydroxy groups on unactivated methyl, methylene and methine groups in artemisinin derivatives. In an earlier study we found that B. sulfurescens introduced a hydroxy in low yield on the C-14 methyl of the N-phenylurethan of the dihydroartemisinin. When arteether, the ethyl ether of dihydroartemisinin, was employed as a substrate with the same fungus two hydroxylated derivatives were isolated, 14-hydroxyarteether and 9~-hydroxyarteether. The yields were greater than that obtained from the N-phenylurethane of dihydroartemisinin. In vitro studies of several derivatives prepared to date show them to be approximately as active as arteether. Work is in progress on scaling up these reactions, so as to prepare larger quantities of the compounds for testing in mice.