Dihydroartemisinin derivatives

Furstoss R,Archelas A,WaegeU B (1980) Tetrahedron Lett 21 451 Fourneron J-D, Archelas A,Vigne B, Furstoss R (1987) Tetrahedron 43 2273 HuYL, Highet RJ, Marion D,Ziffer H (1991) J Chem Soc Chem Commun 1176 Ziffer H, Hu Y, Pu Y (1992) Beauveria sulfurescens mediated oxidation of dihydroartemisinin derivatives. In Servi S (ed) Microbial reagents in organic synthesis. Kluwer Academic Publ, Dordrecht, p 361... 

When dihydroartemisinin was found to be more active than qinghaosu and the introduction of the hydroxy group into the molecular nucleus could not improve its solubility in water, three types of dihydroartemisinin derivatives were synthesized and evaluated in China (Scheme... 

To search for stable, water-soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunate and artelinic acid, deoxoarteli-nic acid 134 was prepared (Scheme 5-18) and tested in vitro and in vivo. It was reported that 134 showed superior antimalarial activity and was more stable in simulated stomach acid than arteether. In 1992, Haynes et al. already reported on the synthesis of 5-carba-4-deoxoartesunic acid (135) from artemisinic acid (20) in a similar way, but they did not mention its activity at that time. ... 

Nguyen-Cong, V., Vandang, G. and Rode, B.M. (1996b). Using Multivariate Adaptive Regression Splines to QSAR Studies of Dihydroartemisinin Derivatives. Eur.J.Med.Chem., 31, 797-803. 

Pinheiro, J.C., Ferreira, M.M.C. and Romero, O.A.S. (2001) Antimalarial activity of dihydroartemisinin derivatives against P. falciparum resistant to mefloquine a quantum chemical and multivariate study. J. Mol. Struct. (Theochem), 572, 35—44. 

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... 

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. 

N. Truong Thi Thanh, C. Menage, J.P. Begue, D. Bonnet-Delpon, J.C. Gantier, B. Pradines, J.C. Doury, T. Truong Dinh, Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin, J. Med. Chem. 41 (1998) 4101-4108. 

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). 

With hemin in MeCN-H20 at pH 7.8, artemisinin 9a was converted into acid 72 in 23% yield. Dihydroartemisinin 29a reacted in a different way giving a 1 1 mixture of the 3-deoxo-derivative 71 and the diketoaldehyde 73a < 1996TL253>. 

A popular approach to improving the metabolic stability of O-glycoside derivatives of dihydroartemisinin is to replace the C-O linkage at C-10 with a C-C linkage. These derivatives generally showed better bioavailability, as well as lower toxicity, when compared to the corresponding C-O derivatives <1998BML1003>. 

It is an ethyl ether derivative of dihydroartemisinin in sterile arachis oil. A racemic mixture of a, P-artether (30 70 ratio) has greater solubility and stability than artemisinin and is more cost-effective. 

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. 

The 10-sulfones derived from the reaction of dihydroartemisinin with thiophenol and subsequent oxidation react with organozinc reagents to give 10P-substituted... 

The first 25 compounds (in oil solution) were tested in the mice-infected chloroquine-resistant P. berghei by administration of intramuscular injection. Most of these derivatives showed more activity than qinghaosu and dihydroartemisinin. 

O Neill et al. also synthesized this kind of derivative by the reaction of dihydroartemisinin and phenols under the TMSOTf and AgC104 promotion at —78 °C. The p-trifluoromethyl derivative was selected for in vivo biological evaluation, preliminary metabolism and mechanism of action studies (Scheme 5-11). ... 

O Neill et al. synthesized 12-C ethanol of deoxoartemisinin and its ethers and esters (Scheme 5-14). The selected derivatives were generally less potent than the dihydroartemisinin in vivo test. ... 

A variety of 10-aryl <03EJ02098> and IO-CF3 <03JOC9763> derivatives of dihydroartemisinin and 9-substituted derivatives of artemisinin <03JMC4244> have been synthesised and their reactions and stereochemistry studied. 

Artemether (N2) and arteether (N3) are the most well-studied analogs among many synthetic derivatives and are used in malaria-prone regions, particularly India (131). Artemether and sodium artesunate (a hemisuccinate derivative of dihydroartemisinin) (N4) have been added by the World Health Organization to its Model List of Essential Medicines (132). 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

Artemether is a methyl ether derivative of dihydroartemisinin. It is dispensed in ampoules for intramuscular injection suspended in groundnut oil and in capsules for oral use. Like artesunate and artemisinin it has been used for both severe and uncomphcated malaria. Artesunate is probably faster-acting than the other two. 

Artemotil is the ethyl ether derivative of dihydroartemisinin. It was the choice of the WHO for development and was considered less toxic, because one would expect it to be metabolized to ethanol rather than methanol. It is also... 

All three Artemisia derivatives are quickly hydrolysed to the active substance dihydroartemisinin. They produce a more rapid clinical and parasitological response than other antimalarial drugs. There are no reports of significant toxicity, and as late as 1994 there was no convincing evidence of specific resistance, but chloroquine-resistant Plasmodium berghei is resistant to artemisinin as well. The recrudescence rate is fairly high (1). 

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