Abstract
Quinoline-based scaffolds have been the mainstay of antimalarial drugs, including many artemisinin combination therapies (ACTs), over the history of modern drug development. Although much progress has been made in the search for novel antimalarial scaffolds, it may be that quinolines will remain useful, especially if very potent compounds from this class are discovered. We report here the results of a structure-activity relationship (SAR) study assessing potential unsymmetrical bisquinoline antiplasmodial drug candidates using in vitro activity against intact parasites in cell culture. Many unsymmetrical bisquinolines were found to be highly potent against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. Further work to develop such compounds could focus on minimizing toxicities in order to find suitable candidates for clinical evaluation.
Highlights
Malaria remains a challenge for worldwide public health
Piperaquine is a long-acting component of dihydroartemisinin-piperaquine, one of the artemisinin combination therapies recommended by the World Health Organization to treat P. falciparum malaria [7]
The in vitro antiplasmodial activities obtained for the bisquinolines reported here are given in
Summary
Malaria remains a challenge for worldwide public health. While there has been considerable progress and optimism about malaria elimination, eradication may not be rapid. As not to squander the progress that has been made, every possible new tool is needed, especially in light of the development of drug resistance to nearly every current therapeutic for P. falciparum malaria [3,4,5]. Bisquinolines have been explored for malaria for a long time, and the most successful of these, piperaquine (PPQ; Table 1), has been used as both mono- and combination therapy [6]. Piperaquine is a long-acting component of dihydroartemisinin-piperaquine, one of the artemisinin combination therapies recommended by the World Health Organization to treat P. falciparum malaria [7]. Clinical trials performed in China during the early 1970s led to piperaquine’s wide use in China, both as treatment and as prophylaxis for P. falciparum and P. vivax malaria [12,13,14,15,16]
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