4,9-Diaminoacridines and 4-aminoacridines as antiplasmodial dual-stage hits

Malaria is one of the deadliest infectious diseases in the world. The eradication of malaria has not yet been achieved, mainly due to the emergence of resistant parasites. Therefore, multi-target drugs have being prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. In this sense, and keeping in mind that the one cost-effective strategy is to repurpose existing drugs for malaria, or to rescue antimalarial pharmacophores, we report the synthesis and in vitro evaluation of two novels acridines families (4,9-diaminoacridines and 4-aminoacridines) through the combination of primaquine (PQ) and chloroquine (CQ), two well-known antimalarial drugs with activities in different stages of the parasite life cycle. All the synthesized compounds retained the activity of the parent drugs against erythrocytic stages of P. falciparum (CQ-sensitive 3D7, and CQ-resistant W2 strains), and liver-stages of P. berghei, hence acting as dual-stage antiplasmodial hits.