title: Probing the chloroquine resistance locus of Plasmodium falciparum with a novel class of multidentate metal(III) coordination complexes.
abstract: The malaria organism Plasmodium falciparum detoxifies heme released during degradation of host erythrocyte hemoglobin by sequestering it within the parasite digestive vacuole as a polymer called hemozoin. Antimalarial agents such as chloroquine appear to work by interrupting the heme polymerization process, but their efficacy has been impaired by the emergence of drug-resistant organisms. We report here the identification of a new class of antimalarial compounds, hexadentate ethylenediamine-N, N'-bis[propyl(2-hydroxy-(R)-benzylimino)]metal(III) complexes [(R)-ENBPI-M(III)] and a corresponding ((R)-benzylamino)] analog [(R)-ENBPA-M(III)], a group of lipophilic monocationic leads amenable to metallopharmaceutical development. Racemic mixtures of Al(III), Fe(III), or Ga(III) but not In(III) (R)-ENBPI metallo-complexes killed intraerythrocytic malaria parasites in a stage-specific manner, the R = 4,6-dimethoxy-substituted ENBPI Fe(III) complex being most potent (IC50 approximately 1 microM). Inhibiting both chloroquine-sensitive and -resistant parasites, potency of these imino complexes correlated in a free metal-independent manner with their ability to inhibit heme polymerization in vitro. In contrast, the reduced (amino) 3-MeO-ENBPA Ga(III) complex (MR045) was found to be selectively toxic to chloroquine-resistant parasites in a verapamil-insensitive manner. In 21 independent recombinant progeny of a genetic cross, susceptibility to this agent mapped in perfect linkage with the chloroquine resistance phenotype suggesting that a locus for 3-MeO-ENBPA Ga(III) susceptibility was located on the same 36-kilobase segment of chromosome 7 as the chloroquine resistance determinant. These compounds may be useful as novel probes of chloroquine resistance mechanisms and for antimalarial drug development.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Goldberg
authors.forename: V
authors.initials: V
authors.lastname: Sharma
authors.forename: A
authors.initials: A
authors.lastname: Oksman
authors.forename: I Y
authors.initials: IY
authors.lastname: Gluzman
authors.forename: T E
authors.initials: TE
authors.lastname: Wellems
authors.forename: D
authors.initials: D
authors.lastname: Piwnica-Worms
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002412:Cations; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance; D005290:Ferric Compounds / Q000494:pharmacology; D006418:Heme / Q000737:chemistry; D006420:Hemeproteins / Q000737:chemistry; D008670:Metals / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D002412:Cations; D005290:Ferric Compounds; D006420:Hemeproteins; D008670:Metals; C020753:hemozoin; D006418:Heme; D002738:Chloroquine