title: Quinoline antimalarials containing a dibemethin group are active against chloroquinone-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine-resistance transporter (PfCRT).
abstract: A series of 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains were shown to inhibit synthetic hemozoin formation. These compounds were equally active against cultures of chloroquine-sensitive (D10) and chloroquine-resistant (K1) Plasmodium falciparum. The most active compound had an IC(50) value comparable to that of chloroquine, and its potency was undiminished when tested in three additional chloroquine-resistant strains. The three most active compounds exhibited little or no cytotoxicity in a mammalian cell line. When tested in vivo against mouse malaria via oral administration, two of the dibemethin derivatives reduced parasitemia by over 99%, with mice treated at 100 mg/kg surviving the full length of the experiment. Three of the compounds were also shown to inhibit chloroquine transport via the parasite's chloroquine-resistance transporter (PfCRT) in a Xenopus oocyte expression system. This constitutes the first example of a dual-function antimalarial for which the ability to inhibit both hemozoin formation and PfCRT has been demonstrated directly.
authors.affiliation: Department of Chemistry,  University of Cape Town , Private Bag, Rondebosch 7701, South Africa.
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Zishiri
authors.forename: Mukesh C
authors.initials: MC
authors.lastname: Joshi
authors.forename: Roger
authors.initials: R
authors.lastname: Hunter
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Robert L
authors.initials: RL
authors.lastname: Summers
authors.forename: Rowena E
authors.initials: RE
authors.lastname: Martin
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D005260:Female; D008288:Malaria / Q000188:drug therapy; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009865:Oocytes / Q000378:metabolism; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine