Probing the Chloroquine Resistance Locus of Plasmodium falciparum with a Novel Class of Multidentate Metal(III) Coordination Complexes

• Published in: The Journal of biological chemistry Vol. 272; no. 10; pp. 6567 - 6572
• Main Authors: Goldberg, Daniel E., Sharma, Vijay, Oksman, Anna, Gluzman, Ilya Y., Wellems, Thomas E., Piwnica-Worms, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-03-1997; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antimalarials - pharmacology; ATP-Binding Cassette Transporters - antagonists & inhibitors; Cations; Chloroquine - pharmacology; Drug Resistance; Ferric Compounds - pharmacology; Heme - chemistry; Hemeproteins - chemistry; Metals - chemistry; Metals - pharmacology; Plasmodium falciparum; Plasmodium falciparum - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.10.6567

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∼1 μM). 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.