Design, synthesis, derivatization, and structure-activity relationships of simplified, tricyclic, 1,2,4-trioxane alcohol analogues of the antimalarial artemisinin
Abstract
Novel C4-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natural product artemisinin (1). In vitro efficacies of these two new pairs of C4-diastereomers against chloroquine-sensitive Plasmodium falciparum support conclusions about the importance to antimalarial activity of formation of a C4 radical by a 1,5-hydrogen atom abstraction. Derivatives 6, 7, and 21 of C4 beta-substituted trioxane alcohols 4a, 5d, and 5e were prepared, each in a single-step, high-yielding transformation. Four of these new analogues, 6a-c and 7, are potent in vitro antimalarials, having 140 to 50% of the efficacy of the natural trioxane artemisinin (1).
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The step iii reaction most probably proceeds via an ene-type mechanism similar to the conversion of 480 to 481, apparently without requirement for light, with 3O2 rather than 1O2 as the active species.
“This reaction most probably proceeds via an “ene-type” mechanism similar to that for the conversion of 480 to 481, although apparently without the requirement for light (i.e. 3O2 rather than 1O2 is perhaps the active species) [193,236,304,305].”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [305]
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- Authors
- Cumming, J. N., Wang, D., Park, S. B., Shapiro, T. A., & Posner, G. H.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1998-02-12
- Volume
- 41
- Issue
- 6
- Pages
- 952-964
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2079456758
- Cited by
- 69
- References
- 79
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 1 · 2021: 5 · 2020: 1 · 2017: 1 · 2016: 3 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI 34885)
- National Center for Research Resources (M01RR000722, RR00722)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phytochemical compounds biological activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
- Keywords
- artemisinin analogues, 1,2,4-trioxanes, antimalarial drugs, Plasmodium falciparum, structure-activity relationship, chloroquine-sensitive malaria
- MeSH terms
- Animals, Antimalarials, Chloroquine, Drug Evaluation, Preclinical, Heterocyclic Compounds, Plasmodium falciparum, Sesquiterpenes, Stereoisomerism, Structure-Activity Relationship, Drug Design, Artemisinins
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