title: Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.
abstract: 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 (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) 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 PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) 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 PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.
authors.affiliation: Department of Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Hrycyna
authors.forename: Robert L
authors.initials: RL
authors.lastname: Summers
authors.forename: Adele M
authors.initials: AM
authors.lastname: Lehane
authors.forename: Marcos M
authors.initials: MM
authors.lastname: Pires
authors.forename: Hilda
authors.initials: H
authors.lastname: Namanja
authors.forename: Kelsey
authors.initials: K
authors.lastname: Bohn
authors.forename: Jerrin
authors.initials: J
authors.lastname: Kuriakose
authors.forename: Michael
authors.initials: M
authors.lastname: Ferdig
authors.forename: Philipp P
authors.initials: PP
authors.lastname: Henrich
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Kiaran
authors.initials: K
authors.lastname: Kirk
authors.forename: Jean
authors.initials: J
authors.lastname: Chmielewski
authors.forename: Rowena E
authors.initials: RE
authors.lastname: Martin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects*; D004355:Drug Stability; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D015394:Molecular Structure; D009865:Oocytes / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011803:Quinine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology*; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D011804:Quinolines; D011803:Quinine; C037219:quinoline