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Quinine Dimers Are Potent Inhibitors of the Plasmodium falciparum Chloroquine Resistance Transporter and Are Active against Quinoline-Resistant P. falciparum

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Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia
§ Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, United States
Department of Microbiology and Immunology, Columbia University, New York, New York 10027, United States
Division of Infectious Diseases, Department of Medicine, Columbia University, New York, New York 10027, United States
Cite this: ACS Chem. Biol. 2014, 9, 3, 722–730
Publication Date (Web):December 26, 2013
Copyright © 2013 American Chemical Society

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    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the “chloroquine resistance transporter” (PfCRT). The resistance-conferring form of PfCRT (PfCRTCQR) mediates CQ resistance by effluxing the drug from the parasite’s digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRTCQR can also decrease the parasite’s susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRTCQR and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H+ ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRTCQR reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRTCQR from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRTCQR. This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

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    17. . Bibliography. 2019, 385-525.
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    31. Przemysław J. Boratyński. Dimeric Cinchona alkaloids. Molecular Diversity 2015, 19 (2) , 385-422.
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