Synthesis and Antiplasmodial Activity of EG-Artemisinin Ethers and Artemisinin–Quinoline Hybrids

Abstract

The aim of this study was to synthesize a series of ethylene glycol (EG) ethers and quinoline hybrids of the antimalarial drug artemisinin and to evaluate their antimalarial activity in vitro against Plasmodium falciparum strains. The ethers were synthesized in a one-step process by coupling ethylene glycol (EG) moieties of various chain lengths to carbon 10 of dihydroartemisinin, while the artemisinin-quinoline hybrids were obtained by condensation of dihydroartemisinin with different amine-functionalized quinoline moieties. For solubility reasons, part of the hybrids were converted to oxalate salts upon reaction of the free bases with oxalic acid. All the synthesized compounds were tested against chloroquine (CQ) susceptible (CQS) D10 and chloroquine resistant (CQR) Dd2 Plasmodium falciparum strains. The IC₅₀ values revealed that all the ethers were active against both strains but less potent than artemether irrespective of the strain. However, they were more active than CQ against the resistant strain. Ether 8 featuring three EO units was the most active of all ethers. It showed activity similar to that of CQ against D10 and much more potency than CQ against Dd2 strain (IC₅₀, 0.023 vs. 0.473 nM). The hybrids and their salts were also all active against both strains. Hybrid 19 which possessed an isopropyl linker and its oxalate salt 19a were the most active against the Dd2 strain. They
were more potent than CQ (IC₅₀, 0.009 and 0.011 vs. 0.255 nM, respectively).

Keywords: Artemisinin (ART), dihydroartemisinin (DHA), artemether (ARM), chloroquine (CQ), malaria, Plasmodium falciparum, ethylene
glycol) (EG), ethylene oxide (EO), hybrid