Synthesis and antiplasmodial activity of 6H,13H-pyrazino[1,2-a;4,5-a′]diindole analogues substituted with basic side chains

Abstract

The synthesis of pentacyclic 6H,13H-pyrazino[1,2-a;4,5-a′]diindole analogues and their evaluation for antiplasmodial activity against 3D7 Plasmodium falciparum strains using [³H]hypoxanthine incorporation and SYBR® Green assays are reported. While the unsubstituted analogues are characterized by only weak antimalarial activity, introduction of one or two basic side-chains led to substantially increased antiplasmodial activity and reduced cytotoxicity against macrophage J774.1 cells. Screening data on chloroquine-sensitive 3D7 and chloroquine-resistant Dd2 strains using the Malstat assay showed that compounds 18, 21 and 23 are characterized by nanomolar activity against both strains, making them promising leads for the development of new antimalarial agents against chloroquine-resistant Plasmodium.