Arteether, a new antimalarial drug: synthesis and antimalarial properties

Abstract

Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

“…The IC 50 values for artesunate and dihydroartemisinin were 1.66 nM and 1.79 nM in the W2/Indochina clone and 2.18 nM and 1.83 nM in the D6/Sierra Leone clone, respectively. 19 In the study of Wongsrichanalai and others, the geometric mean IC 50 values of artesunate (3.22 nM) and dihydroartemisinin (3.24 nM) were also similar in 10 culture-adapted Vietnamese strains. 40 Artesunate is relatively unstable in aqueous solutions, 18 which may imply that the hydrolysis of artesunate to dihydroartemisinin during the 48-hr incubation at 37ЊC may explain why the mean IC 50 values of these two derivatives are within a similar range.…”

“…19,35,37,38 Artesunate is even more active in vitro than artemether and arteether; its activity is about four times greater than that of artemisinin. 19,38,39 Artesunate was almost as active as dihydroartemisinin in our studies. The IC 50 values for artesunate and dihydroartemisinin were 1.66 nM and 1.79 nM in the W2/Indochina clone and 2.18 nM and 1.83 nM in the D6/Sierra Leone clone, respectively.…”

“…18 Initial in vitro studies on laboratory-adapted clones of P. falciparum have shown that dihydroartemisinin is more active than the other artemisinin derivatives. 19 Based on the observation that dihydroartemisinin is a highly active metabolite of artemisinin derivatives and that it is well absorbed by oral administration, Chinese investigators have developed oral dihydroartemisinin for clinical use. Dihydroartemisinin is not commercially available outside China.…”

In Vitro Gametocytocidal Activity of Artemisinin and Its Derivatives on Plasmodium Falciparum

“…This bioassay offers an additional advantage of simultaneously assessing the susceptibilities of different stages of gametocytes to a drug. QHS and NIHO2 were found to be equally toxic to the asexual stages of the chloroquine-resistant FCD-3 isolate employed in this study whereas in other strains dihydroartemisinin has been reported to be a more potent schizontocidal drug (7). Both these compounds exhibited high in vitro gametocytocidal activity at a concentration of 25 ng/ml.…”

Genotoxic evaluation of the antimalarial drugs artemisinin and artesunate in human HepG2 cells and effects on CASP3 and SOD1 gene expressions

“…dure (Brossi et al, 1988). The chloride acid RCOCl was prepared from the corresponding carboxylic acids by heating with thionyl chloride at 55°C for 3 h and reacting with DHA in the presence of triethylamine in dry dichloromethane at 0°C for 2 h to furnish ester derivatives in 49-58% yields.…”