Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 4. Effect of Substitution at C-3
- 1 January 1996
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 39 (15) , 2900-2906
- https://doi.org/10.1021/jm960200e
Abstract
Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via the synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by alkylation provided initially alkylated hydrazones that upon chromatography gave ketones 6−13 and 25−30. Direct ozonolysis of the ketones followed by in situ acidification lead directly to the formation of title compounds 14−21 and 31−36. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found to be in some cases much more active than the natural product (+)-artemisinin. The results were included in structure−activity relationship (CoMFA) studies for further analog design.Keywords
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