ANTIMALARIAL ACTIVITY OF NEW DIHYDROARTEMISININ DERIVATIVES .6. ALPHA-ALKYLBENZYLIC ETHERS

A series of diastereomeric dihydroartemisinin alpha-alkylbenzylic ethe rs was synthesized in search for analogs with higher antimalarial effi cacy and longer plasma half-life than the existing artemisinin derivat ives. Artelinic acid was used as the model molecule for the design of new analogs. Two approaches were taken in an attempt to (a) increase t he lipophilicity of the molecule and (b) decrease the rate of oxidativ e dealkylation of the target compounds. All compounds in this study sh owed at least equal or better in vitro antimalarial activity against P lasmodium falciparum than artelinic acid. The most active compounds of this series showed 10-, 20-, and 40-fold better inhibitory activity t han artemether, artemisinin, and artelinic acid, respectively. Compoun ds which have a small methyl group substituted at the alpha-methylene group showed weaker activity than compounds with a larger carbethoxyal kyl substituent, indicating that the lipophilicity and the steric effe ct of the molecules play important roles in their antimalarial activit y. This fact is further substantiated by the significantly weaker anti malarial activity of the carboxylic acids than their corresponding est ers. Compounds with electron-withdrawing function (NO2) substantially increase the antimalarial activity. The S-diastereomers, in general, a re severalfold more potent than the corresponding R-isomer.