Syntheses and antimalarial activities of N-substituted 11-azaartemisinins

被引:64
作者
Torok, DS
Ziffer, H
Meshnick, SR
Pan, XQ
Ager, A
机构
[1] NIH,BETHESDA,MD 20892
[2] UNIV MICHIGAN,SCH PUBL HLTH,DEPT EPIDEMIOL,ANN ARBOR,MI 48109
[3] UNIV MIAMI,SCH MED,CTR TROP PARASIT DIS,DEPT MICROBIOL & IMMUNOL,MIAMI,FL 33177
关键词
D O I
10.1021/jm00026a012
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.
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收藏
页码:5045 / 5050
页数:6
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