Hybrid Molecules as Efficient Drugs against Multidrug-Resistant Malaria Parasites

This review is focused on hybrid molecules defined as chemical entities with two or more structural domains, as antimalarial drug-candidates, over the past 25 years. Due to their different pharmacophores, such hybrids can interact with a single biological target by different and complementary mechanisms; they can also act simultaneously on several targets having complementary biological functions (dual mode of action), and can theoretically reduce the selection of parasite drug-resistance. This review is not an exhaustive report of all hybrid drugs tested on malaria parasites but a selection of hybrids with pharmacologically relevant antiplasmodial properties and original chemical structures. The choice of pharmacophore synthons and junction arms is obviously decisive. Among the large varieties of hybrid drugs published, emoquine-1 appears at the moment as a promising antimalarial drug candidate, considering 1) its high activities on several multidrug-resistant Plasmodium lab strains and field isolates, 2) its capacity to eliminate the quiescent forms of the artemisinin-resistant parasites, and 3) its curative properties in a malaria mouse model. Such molecules confirm the synergistic effect of hybrid compounds compared to the combination of the pharmacophores leading to novel chemical structures that meet the critical parameters for new antimalarial drugs.