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Cited by 224Sesquiterpenes and Asteraceae StudiesMalaria Research and ControlPhytochemical compounds biological activities

The DOI matches its Crossref record.

From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements

Haynes, Richard·2006·Current Topics in Medicinal Chemistry
DOI 10.2174/156802606776743129
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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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Metadata

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)
DOI
10.2174/156802606776743129
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
  • Physical Sciences › Chemistry › Organic Chemistry › Sesquiterpenes and Asteraceae Studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › 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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