PROBING THE CHLOROQUINE RESISTANCE LOCUS OF PLASMODIUM-FALCIPARUM WITH A NOVEL CLASS OF MULTIDENTATE METAL(III) COORDINATION-COMPLEXES

The malaria organism Plasmodium falciparum detoxifies heme released du ring degradation of host erythrocyte hemoglobin by sequestering it wit hin the parasite digestive vacuole as a polymer called hemozoin, Antim alarial agents such as chloroquine appear to work by interrupting the heme polymerization process, but their efficacy has been impaired by t he emergence of drug-resistant organisms, We report here the identific ation of a new class of antimalarial compounds, hexadentate ethylene - bis[propyl(2-hydroxy-(R)-benzylimino)]-metal(III) complexes [(R)-ENBPI -M(III)] and a corresponding ((R)-benzylamino)] analog [(R)-ENBPA-M(II I)], a group of lipophilic monocationic leads amenable to metallopharm aceutical 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-s ubstituted ENBPI Fe(III) complex being most potent (IC50 similar to 1 mu M), Inhibiting both chloroquine sensitive and -resistant parasites, potency of these imino complexes correlated in a free metal-independe nt manner with their ability to inhibit heme polymerization in vitro, In contrast, the reduced (amino) 3-MeO-ENBPA Ga(III) complex (MR045) w as 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 li nkage with the chloroquine resistance phenotype suggesting that a locu s for 3-MeO-ENBPA Ga(III) susceptibility was located on the same 36-ki lobase segment of chromosome 7 as the chloroquine resistance determina nt, These compounds may be useful as novel probes of chloroquine resis tance mechanisms and for antimalarial drug development.