Linker-Based Hemisuccinate Derivatives of Artemisinin: Synthesis and Antimalarial Assessment against Multidrug-Resistant Plasmodium yoelii nigeriensis in Mice

Artesunic acid 5, the hemisuccinate derivative of dihydroartemisinin 2, is the only clinically useful water-soluble derivative of artemisinin 1. However, being a lactol ester, it is rapidly hydrolyzed back to dihydroartemisinin in aqueous alkaline solution, a reaction that seriously limits its utility. A new series of potentially more stable linker-based hemisuccinate derivatives 12a-i and 14a-c have been prepared. The process involved acid-catalyzed reaction of dihydroartemisinin with various diols and polyethylene glycols to give hydroxy-functionalized ethers 7a-i and 10a-c and their further derivatization to hemisuccinate esters 12a-i and 14a-c. Both the hydroxy-functionalized ethers 7a-i and 10a-c and their hemisuccinate derivatives 12a-i and 14a-c have been assessed for antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. Several of these hemisuccinate derivatives have shown very promising activity. Hemisuccinate derivatives 12f and 12i, the two most active compounds of the series, provided 100% protection to malaria-infected mice at 24 mg/kg x 4 days and therefore are twice as potent as artesunic acid, which provides a similar level of protection at 48 mg/kg x 4 days.