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 drugresistant organisms. We report here the identification of a new class of antimalarial compounds, hexadentate ethyl- enediamine-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 met-allo-complexes killed intraerythrocytic malaria parasites in a stage-specific manner, the R ‫؍‬ 4,6-dimethoxy-substituted ENBPI Fe(III) complex being most potent (IC 50 ϳ1 M). 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.

New pentacoordinated Schiff-base diorganotin(IV) complexes derived from nonpolar side chain α-amino acids

“…A huge interest on metal complexes of Schiff-bases derived from amino acids and salicylaldehyde has emerged due to their structural, magnetic and electrochemical properties, as well as their potential use as models for a number of important biological systems [2][3][4] and for the research of pyridoxal reaction pathways [5][6][7]. Among their several biological functions, they show antimicrobial [8], antimalarial [9], antiproliferative [10], chemotherapeutic [11], radiopharmaceutical [12], insulin-mimetic [13] and fungicidal [14] properties. One of the most important bioinorganic chemistry research areas in organotin compounds is the investigation of their cytotoxic and antineoplastic (antiproliferative) activities [15].…”

Synthesis and Spectroscopic Study of Metal Complexes with New Schiff Base Derived from 2-acetylpyridine and Methionine Amino Acid

“…As well as the acidic -COOH proton of amino acid moiety was observed in the region 11.55 ppm which support remarkably the structure of the formed Schiff base HL [10,11]. Moreover, the 13 C NMR spectrum of HL, figure(2), in DMSO-d 6 displays variable peaks at (41,48-49), (121-122) and (170) ppm [10,12] which are characteristic of two methyl groups, -C=N and -COOH carbon atoms,. The data correlated from NMR spectra indicates the proper suggested of free ligand.…”

“…Schiff base complexes of amino acids have gained importance not only from the inorganic point of view but also because of their physiological and pharmacological activities [7,8]. Metal complexes of Schiff base phenolates with favorable cell membrane permeability have been exploited in cancer multidrug resistance [9] and tested as antimalarial agents [10].…”

Synthesis, characterization and antiprotozoal studies of some metal complexes of antimalarial drugs

“…In the search for novel drugs against resistant parasites, the modification of existing drugs by coordination to metal centres has attracted considerable attention [18][19][20]. However, the potential of metal complexes as antiparasitic agents has so far been very little explored [21][22][23].…”