From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements
Abstract
The artemisinin derivatives, dihydroartemisinin (DHA), artesunate, atemether and arteether, are currently used for treatment of malaria in artemisinin combination therapies (ACT) with longer half-life drugs. The demand is enormous--in 2005, the estimated global demand for one such ACT alone, artemether-lumifantrine, which constitutes about 70% of all current clinically-used ACTs, is for 120 million adult treatment courses. At 0.5 gm of artemether per total dose regimen, the amount of artemisinin required is approximately 114 tons. This has placed substantial stress on total artemisinin supplies world-wide, and considerable attention is being focussed on enhancing availability of artemisinin by improvement in horticultural practice and extraction of artemisinin from Artemisia annua. Artemisinic acid, which also occurs in A. annua, can be converted into artemisinin and is the ultimate target of a biotechnological approach, which if successful, will augment artemisinin supply in the future. The conversion of artemisinin into the known artemisinin derivatives, and problems with the methods are critically reviewed. Some attention is paid to mechanistic aspects which clarify stereochemistry. The current artemisinins are by no means ideal drugs. Artesunate in particular is incompatible with basic quinolines by virtue of proton transfer, and has intrinsic chemical instability. At pH 1.2, conversion to DHA is rapid, with t(1/2) 26 min, and at pH 7.4, t(1/2) is about 10 hours. With a pK(a) of 4.6, over 99% of artesunate will be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract will be minimal. Although a considerable effort has been vested in the search for new artemisinins, largely through functionalization of artemisinin at C-10, O-11 or at C-15 via artemisitene, or of DHA at C-10, deliberate enhancement of the 'druggability' of artemisinins by reducing lipophilicity, which at the same time will attenuate the neurotoxicity characteristic of the current derivatives, and enhance absorption, by and large has not been considered. A review of the various types of newer derivatives is given together with a consideration of medicinal chemistry aspects.
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Terpene biosynthesis and its regulation in A. annua have been well reviewed, including the central role of amorpha-4,11-diene (451) in artemisinin biosynthesis and the likelihood that glandular trichomes are the location of artemisinin biosynthesis.
“Terpene biosynthesis [271,272,273,274,275,276] and its regulation [277,278] in A. annua have been well reviewed, including the central role of amorpha-4,11-diene (451) in the biosynthesis of artemisinin (495) [279] and the likelihood that glandular trichomes are the location wherein artemisinin biosynthesis actually occurs [244,280]”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [271]
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“Artemether is a semi-synthetic derivative of artemisinin and the most widely used antimalarial drug ( Haynes, 2006 ).”
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- Authors
- Haynes, R.
- Affiliations
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Haynes, Richard
- ORCID
- Haynes, Richard
- Venue
- Current Topics in Medicinal Chemistry
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2006-03-01
- Volume
- 6
- Issue
- 5
- Pages
- 509-537
- ISSN
- 1568-0266 (ISSN-L)
- OpenAlex
- W2071695336
- Cited by
- 224
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 8 · 2020: 9 · 2019: 4 · 2018: 9 · 2017: 12 · 2016: 14 · 2015: 10 · 2014: 14 · 2013: 17 · 2012: 14
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Topics in Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
- 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
- Keywords
- artemisinin, artemisinin derivatives, dihydroartemisinin, artesunate, arteether, artemisinin-based combination therapy, Artemisia annua, artemisinic acid, artemisinin biosynthesis, stereochemistry, drug stability, drug-drug interactions, lipophilicity, neurotoxicity
- MeSH terms
- Animals, Antimalarials, Humans, Molecular Conformation, Sesquiterpenes, Stereoisomerism, Drug Design, Artemisia annua, Artemisinins
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