Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 5. Analogs of 10-Deoxoartemisinin Substituted at C-3 and C-9

Novel 3- and 9-substituted analogs (4−19) of 10-deoxoartemisinin, 3, were prepared from the corresponding known lactones by one-pot reduction with sodium borohydride and boron trifluoride etherate. Reproducibility problems associated with this heterogeneous reaction were encountered on small reactio...

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Published in:Journal of medicinal chemistry 1996-10, Vol.39 (21), p.4149-4155
Main Authors: Avery, Mitchell A, Mehrotra, Sanjiv, Johnson, Theresa L, Bonk, Jason D, Vroman, Jeffrey A, Miller, Robert
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Artemisinins
Biological and medical sciences
Boranes
Borohydrides
Humans
In Vitro Techniques
Medical sciences
Molecular Weight
Pharmacology. Drug treatments
Plasmodium falciparum
Plasmodium falciparum - drug effects
Sesquiterpenes - chemistry
Sesquiterpenes - pharmacology
Structure-Activity Relationship
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Summary:Novel 3- and 9-substituted analogs (4−19) of 10-deoxoartemisinin, 3, were prepared from the corresponding known lactones by one-pot reduction with sodium borohydride and boron trifluoride etherate. Reproducibility problems associated with this heterogeneous reaction were encountered on small reaction scales, and thus alternative methodology was sought for this reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate lactols was made more reproducible using a two-step sequence involving low-temperature reduction with diisobutylaluminum hydride followed by deoxygenation with boron trifluoride etherate in the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were much more active than the natural product (+)-artemisinin (1) or 10-deoxoartemisinin (3). Conventional structure−activity relationships are discussed in relation to the bioassay data.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9603577