Discussion

Malaria is caused by parasite infection of the genus Plasmodium. Human infection is caused by one of five Plasmodium species including falciparum, malaria, knowlesi, vivax and ovale. P. falciparum is associated with the most severe form of malaria and responsible for approximately 400 000 deaths per year. A number of antimalarial drugs are currently used to treat malaria. However, P. falciparum, which is responsible for mortality especially in Eastern and Southern Africa, has developed resistance to all currently used drugs. Hence, there is a great need for the development of new drugs for malaria. Here, we report non-symmetrical furan-amidines as novel antimalarial leads. The non-symmetrical furan-amidines were originally designed and shown to be inhibitors of NRH:quinone oxidoreductase 2 (NQO2), a potential therapeutic target in cancer chemotherapy. The malaria parasite P. falciparum contains an enzyme that has similar activity to NQO2, called PfNDH2, therefore the non-symmetrical furan-amidines were tested against Plasmodium. The most active furan-amidines showed IC₅₀ values in the nanomolar range for the inhibition of P. falciparum erythrocyte development. Interestingly, upon screening, the non-symmetrical furan-amidines showed very low binding affinities towards DNA in comparison to the known symmetrical furan-amidine (DB75), which is a known DNA intercalator. This confirmed that the non-symmetrical furan-amidines are not DNA intercalators. Synthesis of further novel non-symmetrical furan-amidines and their target identification is ongoing.