Ethers, of dihydroartemisinin

Another type of (9-glycosides (127), 12-(3 aryl ethers of dihydroartemisinin, was synthesized by a reaction of acetyl dihydroartemisinin or trifluoroacetyl dihydroartemisinin with various substituted phenols in the presence of trifluoroacetic acid. Most of these compounds were proved to have better antimalarial activity against P. berghei in mice than qinghaosu, but less activity than artemether. Unexpectedly,... 

Trioxane ethers (46 1-4) were as effective as the lower alkyl ethers of dihydroartemisinin except (46 1, R = CH3) [52]. From the size of the substituents of the trioxane ethers the benzyl ether was the most active. Trioxane carboxylate esters (47 1-6) and carbamate esters (47 7-9) were tested against W-2 and D-2 clones. The trioxane monomethyl... 

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... 

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 ethers and esters of dihydroartemisinin noted above may be considered as its (9-glycosides (126) (Structure 5-10). 

Venugopalan et al. also prepared some ethers and thioethers of dihydroartemisinin.Haynes et al. synthesized many new C-12 esters and ethers of dihydro- artemisinin. Compared with similar work performed 20 years ago, they successfully prepared some (3-aromatic esters of dihydroartemisinin by means of Schmit and Mitsunobu procedures. 

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... 

Haynes, R. K., Chan, H-W., Cheung, M-K., et al. (2002) C-10 ester and ether derivatives of dihydroartemisinin - 10-cx artesunate, preparation of authentic 10-P artesunate, and of other ester and ether derivatives bearing potential aromatic intercalating groups at C-10. Eur. J. Org. Chem., 113-132. 

Ethers, esters and carbonates of dihydroartemisinin have been prepared to obtain novel and more active derivatives [45]. After examination of the ethers, including the epimers at position 10, artemether (31 2, R = CH3) and arteether (31 3, R = CH2CH3), they were found to be about twice as active as artemisinin, but less active than dihydroartemisinin. Artemether has been isolated as a natural constituent of A. annua. Arteether was found to be 34 times more active than chloroquine against the W-2 (Indochina) clone of P. falciparum (normally resistant to chloroquine) and three times less active against the D-6 (Sierra Leone) clone (normally resistant to mefloquine). Artemether was two times more active and eight times more active than mefloquine against the W-2 and D-6 clones, respectively. Both artemether and arteether are more oil soluble than artemisinin and are currently in clinical trials. 

Esters (32 4, R = C(=0)-alkyl or -aryl), of which a-epimers were mainly obtained, were more active than the ethers. Sodium artesunate (32 5, R = C(=0)-CH2CH2C00Na), the half succinic acid half-ester of dihydroartemisinin is water-soluble and shows potent antimalarial activity. Therefore, this can be administered intravenously. However it is uncertain whether this derivative is pharmacologically effective because of its sensitivity to hydrolysis. In considering this result new ether derivatives of dihydroartemisinin, which are stable and water soluble derivatives have been prepared [46]. Dihydroartemisinin was condensed with esters of aliphatic or aromatic carboxylic acids with hydroxy groups to produce mainly ethers with the P-configuration. Ethyl 2-( 10-dihydroartemisininoxy) acetate (31 4, R = CH2COOCH2CH3) and methyl... 

Dihydroartemisinin ethers. A water-soluble derivative of artemisinin, the sodium salt of artesunic acid (the succinic half-ester derivative of dihydroartemisinin Fig. 35.2), can be administered by intravenous injection, a property that makes it especially useful in the treatment of advanced and potentially lethal cases of Plasmodium falciparum. Sodium artesunate is capable of rapidly reversing parasitaemia and causing the restoration to consciousness of the comatose cerebral malaria patient. The utility of sodium artesunate, however, is impaired by its poor stability due to the facile hydrolysis of the ester linkage. To overcome the ease of hydrolysis of the ester function in sodium artesunate, Lin et aO prepared a series of analogues in which the solubilizing moiety is joined to dihydroartemisinin by an... 

In total, we prepared six new dihydroartemisinin analogues as shown in Figure 5 from the corresponding lactones and three new analogues from artemisinin itself. 9-Desmethylartemisinin 42 was transformed into the lactol 147, which was then converted to the P-ether 148. Treatment of DHQHS under anhydrous conditions with acid and terf-butylhydroperoxide gave perether 150 in 62% yield, which contains two peroxide moieties. 

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. ... 

The corresponding fluoroalkyl ethers 119 (cf. Scheme 27) have been prepared by the reaction of fluoroalkyl alcohols with dihydroartemisinin 115 using various methods (with BF3-Et20 or TMSCl as catalysts) in moderate to good yields <1998JME4101>. 

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