ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

全世界约有2.7亿人感染疟疾

Some 270 million people worldwide are infected with malaria which causes between 1 and 2 million deaths per year. The formidable problems encountered in developing a malaria vaccine, and the ability of Plasmodium falciparum to become resistant to new drugs, has stimulated the World Health Organization and others to search for new drigs to treat this disease. Artemisinin has served as a lead compound to develop new drugs to treat the resistant strains of P. falciparum that have spread ouver southeast Asia and threaten India and Aftica. Since no strains P. falciparum resistant to artemisinin derivatives have appeared, many derivatives (esters and ethers of dihydtoartemisinin) have been prepared in China and the United States. Metabolic studies of arteether, a dihydroartemisinin derivative scheduled for clinical tests, found that it is rapidly dealkylated to dihydroartemisinin. It is very likely that esters of dihydroartemisinin are rapidly hydrolyzed to the same compound. In order to prepare compounds that can not be degraded to dihydroartemisinin, we introduced additional functional groups into artemisinin by a microbially mediated oxidation using Beauveria sulfurescens. Derivatives of these hydroxylated materials hiave been prepared and tested. IN a second approach we replaced by hydroxy group of dihydroartemisinin with an allyl group. The double bond of the allyl substitutent enabled us to introduce polar groups into the molecule so as to adjust its lipo- or hydro-philicity. The polarity is important in deciding the mode of administration. Most of the compounds were found to be as or more effective than artemisinin and arteether against P. falciparum in vitro. The best compound, the n-propyl derivative, is undergoing in vivo testing in mice infected with P. berghei.