Discovery of amodiachins, a novel class of 4-aminoquinoline antimalarials active against multi-drug resistant Plasmodium falciparum.

The emergence and spread of drug-resistant strains of Plasmodium falciparum, the parasite responsible for the most severe, and often fatal form of malaria, have hampered worldwide prevention, treatment, and eradication efforts. This study aims to discover and develop novel antimalarial compounds to combat multidrug-resistant strains of P. falciparum. The research described herein builds upon optimizing the stability and activity of amodiaquine analogs, a 4-aminoquinoline antimalarial. Series of compounds were synthesized, and their efficacy was assessed against cultured P. falciparum and against a murine malaria model. The results indicate that the addition of a piperidine heterocycle greatly improves antiparasitic activity and varying the length and branching of a terminal alkyl attenuates metabolic stability and in vivo efficacy. This study highlights potential candidates for further evaluation and identifies the importance of discovering novel compounds to overcome drug resistance for treatment of malaria.