Malaria is a pervasive and deadly threat to the global population, and the resources available to treat this disease are limited. There is widespread clinical resistance to the most commonly prescribed antimalarial drugs. To address this issue, we synthesized a range of 4'-pyrrolidinodiazenyl chalcones using a covalent bitherapy approach to study their potential antimalarial properties. We examined the structure-activity relationships of these compounds, which could explain their antimalarial activities. The in vitro blood stage antimalarial activity of the compounds was evaluated against the mixed-blood stage culture (ring, trophozoites and schizonts) of Plasmodium falciparum 3D7, and the 50% inhibitory concentrations (IC