Artemisinin can be seen above. The most prominent characteristic is the peroxide and the lactone function groups.
Mechanism of actionCurrent research is still being done to find the specific mechanism of action of artemisinin. One idea involves the parasite infecting red blood cells which causes the release of heme groups that contain iron complexes. The iron than reduces the peroxide in artemisinin, which produces free radicals that can damage and kill the parasite.1
SynthesisThe cost to extract artemisinin is costly which is not viable for impoverish countries. The average cost to extract artemisinin from wormwood trees and turn them into a drug cost $2.40 per dose.
Biosynthesis from MicrobesHowever, in 2006 a team from Berkely have published an article claiming that they have engineered saccharomyces cerevisiae microbes that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid. 2
The synthesis of artemisinin is shown below in three parts: The formation of IPP and DMAPP, the formation of E,Z-FPP and finally the formation of Artemisinin.
Total SynthesisIn 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (13). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.3
Clinical UseNumerous drug derivatives of Artemisinin are availabe to treat malaria. The uptake of these drugs can range from oral, rectal, intramuscular, or intravenous. Also, these derivatives can be made water soluble or lipid soluble.
A notable water soluble derivative is Artesunate. Since the drug is water soluble it can be injected intravenously in amounts of: 2.4 mg/kg loading dose over 5 minutes 1.2 mg/kg dose 12 hours later 1.2 mg/kg once daily after that
Artesunate is normally taken with another antimalaria drug to avoid the possibility of resistance. The drug works by destroying the egg production in Schistosoma haematobium infection.4
A notable lipid soluble derivative is Artemether. Since this form is lipid soluble it cannot be used intravenously but can be taken up orally, rectally and intramuscularly. A normal oral dosage of co-artemether consist of taking 4 tables at 0, 8, 24, 36,48 and 60 hours.5
References
1C J Woodrow, R K Haynes and S Krishna. "Artemisinins" Postgraduate Medical Journal 2005; 81:71-78
2 Richmond Sarpong, Jay D. Keasling. "Production of the antimalarial drug precursor artemisinic acid in engineered yeast" Nature 440, 940-943 (13 April 2006)
3 G. Schmid, W. Hofheinz. "Total Synthesis of qinghaosu" J. Am. Chem. Soc.; 1983; 105 (3); 624-625
4Boulangier D, Dieng Y, Cisse B, et al. (2007). "Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks.". Trans R Soc Trop Med Hyg 101 (2): 113–16.
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