Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids

Dihydroartemisinin (DHA) was coupled to different aminoquinoline moieties forming hybrids 9–14, which were then treated with oxalic acid to form oxalate salts (9a–14a). Compounds 9a, 10a, 12, 12a, and 14a showed comparable potency in vitro to that of chloroquine (CQ) against the chloroquine sensitive (CQS) strain, and were found to be more potent against the chloroquine resistant CQR strain. Hybrids 12 and its oxalate salt 12a were the most active against CQR strain, being 9- and 7-fold more active than CQ, respectively (17.12 nM; 20.76 nM vs 157.9 nM). An optimum chain length was identified having 2 or 3 Cs with or without an extra methylene substituent.

Graphical abstractNovel artemisinin-quinoline hybrids were synthesized by connecting dihydroartemisinin via ether and amine bonds to different 4-aminoquinoline entities, and it resulted in compounds with good in vitro antimalarial activity.Figure optionsDownload full-size imageDownload as PowerPoint slide