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

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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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“Although total chemical synthesis of artemisinin derivatives has been achieved, the specific endoperoxide bridge in artemisinin is too complex to make such process costeffective (Haynes 2006).”
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“To Artemisinin and its derivatives are mostly used as antimalarial drugs (20).”
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Ali, A., Ahmad, M. M., Khan, M. A., Ganai, A. A., Kiran, U., Prakash, A., Hassan, M. I., Saxena, P., Khan, S., Ahlawat, S., et al. (2016) · South African Journal of Botany · doi:10.1016/j.sajb.2016.03.009 · Cited by 5
Antiplasmodial activity of alkyl-substituted 1,2-dioxetanes against Plasmodium falciparum
da Silva, A. F., Oliveira, V. X., Silva, L. S., et al. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.08.096 · Cited by 5
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“The identification of the active pharmaceutical ingredient artemisinin eventually resulted in the preparation of the semi-synthetic derivative artesunate that has a longer half-life and better bioavailability when compared to artemisinin (2).”
Background
Synthesis and validation of ultrasensitive stripping voltammetric sensor based on polypyrrole@ZnO/Fe 3 O 4 core–shell nanostructure for picomolar detection of artesunate and dopamine drugs
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Malaria-Infected Mice Are Cured by a Single Low Dose of a New Silylamide Trioxane Plus Mefloquine
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“Trioxanes derived from artemisinin (1), such as artemether (2c) and sodium artesunate (2d), are now being used clinically to cure malaria-infected people [10-16].”
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Biologically active compounds from natural and marine natural organisms with antituberculosis, antimalarial, leishmaniasis, trypanosomiasis, anthelmintic, antibacterial, antifungal, antiprotozoal, and antiviral activities
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“The latter drugs are formed by a semi-synthetic process which transforms the artemisinin molecule, first into dihydroartemisinin and then into artemether or artesunate (WHO, 1986; Haynes, 2006).”
Background
Retracted : Tetraoxanes: Synthetic and medicinal chemistry perspective
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“19 T R 15 Unfortunately, this compound has shown poor pharmacokinetic properties 16,17 and further derivatization of this molecule leads to the discovery of many other semi-synthetic derivatives such as artemether ( 5 ), arteether ( 6 ), artesunate ( 7 ), etc., which are equally potent and are…”
Background
Retracted
New orally active artemisinin dimer antimalarials
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Self-citation
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Transfer Of Rol Genes And Evaluation Of Artemisinin Synthesis In Transgenic Artemisia Annua L. And Artemisia Dubia Wall
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Alternative Properties of Artemisia (Asteraceae) Phyto-Extracts to Anti-Malarian Ones: Preliminary Bibliografic Review on Nemato-Toxic EffectsPreprint
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“Second generation artemisinin includes artemisone which has shown improved pharmacokinetic properties such as longer half-life and lower toxicity (Haynes 2006 ).”
Background
Degradation of Artesunate in Aqueous Solution
Hayder, M. A. (2011) · eSpace (Curtin University) · Cited by 2
Therapeutic Effect of Artemether in an Experimental Model of Nephrosis
Mirshafiey, A., Nouri, H. R., Sedaghat, R., et al. (2008) · Pharmaceutical Biology · doi:10.1080/13880200802182364 · Cited by 1
“The attractiveness of the artemisinin class of antimalarials is due to their activity against multidrugresistant Plasmodium falciparum and Plasmodium vivax strains (Price et al., 1998; Guthmann et al., 2006; Haynes, 2006).”
Background

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

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