Artemether Artemisinins

Both artemisinin and artemether undergo deoxygenation on treatment with zinc in AcOH <96HCA1475>, but Fe(II) salts rupture the peroxy linkage and lead to rearranged products... 

Li GQ. (1989) Clinical studies on artemisinin suppository and on artesunate and artemether. In S. Jiaxiang (ed.), Antimalarial drug development in China. National Institute of Pharmaceutical Research and Development, Beijing, People s Republic of China, pp. 69-73. 

Haynes RK, Vonwiller SC. (1994) Extraction of artemisinin and artemisinic acid Preparation of artemether and new analognes. Trans R Soc Trap Med Hyg 88 23-26. 

Artemisinin (18) is a natural product for which many semisynthetic derivatives have been generated. The major rationale to produce these derivatives was to deal with the low aqueous solubility of artemisinin and its short half-life in plasma. The lipid-soluble arteether (22) and artemether (23), and the water-soluble sodium artesunate (24), were designed for... 

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

The analogous adducts of artemether Ic and fenozan 4 were also obtained and characterized in each case porphyrin adducts were isolated in 20-30% yield. When artemisinin was treated with manganese(II) TPP in the presence of cyclohexene, Robert and Meu-nier also failed to observe any of the corresponding epoxide. The authors suggest that the Dewar benzene rearrangement and the oxidation reactions observed by Posner... 

Perhaps more significantly they were also able to isolate a polar, water-soluble compound that they believed was 55 in which the cysteine residue had been incorporated into the artemisinin backbone. The broadness of the signals in the proton NMR spectrum made characterization problematic, but treatment of 55 with acetic anhydride afforded 56, which was fully characterized (Scheme 16A). More recently, the same group has isolated and characterized another product from artemether. Adduct 57 was derived from the C4 secondary radical and cysteine (Scheme 16B). 

Woerdenbag and coworkers reported on the cytotoxicity of artemisinin endoperoxides to Ehrlich ascites tumour cells . Artemisinin had an IC50 of 29.8 p.M, whereas arteether, artemether, artelininc acid and sodium artesunate all had more potent activities, ranging from 12.2 to 19.9 p.M. It was found that opening of the lactone ring of artemisinin dramatically reduced the cytotoxicity. An ether dimer of dihydroartemisinin 106, prepared by... 

Artemisinin is very poorly soluble in water or oil and can thus only be administered orally. Active derivatives have been synthesized such as artemether, arteether and beta-arteether (Artemotil), artelinic acid and artesunate, which are used for oral, intramuscular, rectal and intravenous administration. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself (see Fig. 2). 

Oral formulations of artemisinin and its derivatives are absorbed rapidly but incompletely. Peak plasma concentrations are reached in 1-2 h. A relative bioavailability of 43% was found for oral artemether compared to intramuscular administration. The absolute bioavailability of artesunate, the only derivative for which an intravenous formulation exists, was about 15%. Artesunate is extensively hydrolyzed to dihydroartemisinin in the gastro-intestinal lumen before first-pass metabolism in the gut wall and liver takes place. Artesunate acts like a prodrug with fast transformation into... 

Artemisinin DihydroartemIsinIn Artemether Arteether Artelinic acid Artesunic acid... 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

Three currently-used artemisinin based combination therapies (ACT) artesunate-mefloquine, artemether-lumefantrine and dihydroartemisinin-piperaquine, have been proven highly simple, safe and effective in the treatment of multidrug resistant P. falciparum malaria. 

Artemisinin is a natural endoperoxide-containing sesquiterpene, isolated from a plant used in traditional Chinese medicine. Acetalic artemisinin derivatives (artemether, artesunate) are very active against chemoresistant forms of Plasmodium falciparum, and are clinically used for treatment (Figure 4.14)." However, they suffer from an unfavorable pharmacological profile. They are quickly metabolized by fast oxidative metabolism, hydrolytic cleavage, and glucuronidation. 

Dihydroartemisinin (DHA) is the active metabolite of acetalic derivatives of artemisinin (artemether, artesunate). Oxidation by cytochrome P450 enzymes or/and hydrolysis provides DHA, which is itself poorly stable in vivo. Indeed, the corresponding oxonium ion, a precursor of inactive metabolites by ring opening or by glucuronidation, can easily be formed (Figure 4.15). 

An LC-MS pre-column method with selected ion monitoring (SIM) was recently developed and validated for the analysis and standardization of artemisinin 9a in Artemisia annua L. <2005MI7010>, and the densitometric thin layer chromatographic determination of artemisinin 9a and artemether 28a and arteether 28b has also been described <2003MI359>. 

A new gas chromatography (GC) method was developed to characterize artemether 28a and its metabolites in body fluids. The extracts were derivatized and then separated on an optimized capillary GC system and identified by chemical ionization MS using ammonia as the reagent gas <1998JCH(B)101>. A sensitive, selective, and reproducible GC-MS-SIM method has also been developed for the determination of artemether 28a and dihydroartemisinin 29a in plasma, using artemisinin 9a as an internal standard <1999JCH(B)251>. 

An FIPLC method using electrochemical detection in the reductive mode for the determination of artemether 28a and its metabolite dihydroartemisinin 29a <1997JCFI(B)145> and for the simultaneous quantification of artesunate 31 and dihydroartemisinin 29a in plasma has been developed <1997JCFI(B)259, 1998JCFI(B)201>. An effective reversed-phase FIPLC method using electrochemical and UV detection has been developed for the simultaneous determination in plant extracts of artemisinin and its bioprecursors such as arteannuin B 32a, and artemisitene 27 <1995JNP798, 2001JIC489>. 

A one-pot preparation of artemether 28a, arteether 28b, and related O-alkylated compounds from artemisinin 9a and the appropriate hydroxy compound, using NaBH4/Amberlyst-15 as reagent, has been described <2002TL7235, 2002IJC2185>. 

Since this chapter was prepared, the only chemical developments in compounds belonging to this class have involved artemisinin and its derivatives, and some of these will be summarized here. Using combustion calorimetry, Liu and co-workers have determined the standard molar enthalpies of formation of artemisinin 9a, artemether 28a and artesunate 31 as —1493, —2420 and —3320kJmoP respectively, and the thermal stabilities of these compounds were also investigated by thermal analysis in combination with FT-IR <2007MI1045>. 

Artemisinins (artesunate, artemether,1 dihydroartemisinin1) Sesquiterpene lactone endoperoxides Treatment of P falciparum infections oral combination therapies for uncomplicated disease intravenous artesunate for severe disease... 

Artemisinins are also proving to have outstanding efficacy for the treatment of complicated falciparum malaria. Large randomized trials and meta-analyses have shown that intramuscular artemether has an efficacy equivalent to that of quinine and that intravenous artesunate is superior to intravenous quinine in terms of parasite clearance time and—most important—patient survival. Intravenous artesunate also has a superior side-effect profile compared with that of intravenous quinine or quinidine. Thus, intravenous artesunate will likely replace quinine as the standard of care for the treatment of severe falciparum malaria, although it is not yet widely available in most areas. Artesunate and artemether have also been effective in the treatment of severe malaria when administered rectally, offering a valuable treatment modality when parenteral therapy is not available. 

The pharmaceutical properties of artemisinin are far from optimal it is insoluble in water and only marginally soluble in oil. It has poor oral bioavailability and has been administered for the treatment of Plasmodium falciparum malaria in humans at total doses of about 1 g (over 3 days). Early studies by Chinese scientists in 1979 led to the discovery of dihydroartemisinin 3, artemether 4 (Artenam), and sodium artesunate 5, oil and water soluble derivatives, respectively (Figure 9.1 ).6-7 These drugs are currently in clinical use in Asia in a number of preparations such as suppositories, i.v. injectables, oil depos, to name only a few.8 Capsules containing 0.5 g of artemisinin for oral administration are available in Vietnam. 

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