Arteether, a new antimalarial drug: Synthesis and antimalarial properties

Article abstract of DOI:10.1021/jm00398a026

Arteether (6) has been prepared from dihydroqinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving α-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by ¹H NMR data (J_11,12, 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 qinghaosu (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.