The Propionate of Heme Binds N₄O₂ Schiff Base Antimalarial Drug Complexes

Abstract

Schiff base N4O2 complexes offer a flexible template on which to develop novel antimalarial drug complexes that inhibit the aggregation of hemozoin, a detoxification product of the malaria parasite Plasmodium falciparum. The efficacies of these complexes are dependent on the charges of the complexes. Further evidence suggests that these complexes inhibit hemozoin formation via a specific drug/heme propionate salt that prevents the formation of the requisite axial propionato linkage in the repeating dimeric unit of the hemozoin aggregate.

Detoxification Biominerals

“…The power of these concepts has recently been demonstrated by Marletta and coworkers, who employed HRP II-mediated formation of hemozoin as a screen against which to test new libraries of compounds for antimalarial activity [99]. Similarly, Wright and coworkers have used their bionucleating templates as a proxy for HRP II to examine the mode of efficacy of a number of different classes of inhibitors, including other metalloporphyrins [100] and Scheme 2 Potential inhibition pathways to hemozoin aggregation unique Schiff-base metallodrugs [101]. In each of these cases, inhibitors that act in all of the imagined functions have been discovered that may one day result in new treatments for malaria.…”

Heme Detoxification in Malaria: A Target Rich Environment

“…Considering the minimal hemozoin aggregation assay system employed, a readily envisioned mechanism for these complexes is that they interact with either the propionate moieties of the porphyrin ligand or the aspartic acid side chains of the BNT II template. Fluorescence quenching experiments revealed that under assay conditions, the drugs did not appreciable interact with the template (36). In contrast, Fe(III)PPIX quenched the weak fluorescence of the Fe(III) and Ga(ill) ENBPI analogues, suggesting interaction between heme substrate and the inhibitor.…”

“…When the acetate buffer concentration increased from 25 mM to 500 mM, the IC 50 of the complexes increased until they no longer inhibited hemozoin aggregation. A control series of experiments performed at 25 mM acetate buffer concentration with increasing concentrations of NaCl revealed no effect on die IC 50 values of the complexes (36). This suggested that the interactions between the drug complexes and heme propionate are not simple salt interactions, but specific to the carboxylate moiety.…”

“…The IC 50 was 4.5 uM for the iron complex, 50 uM for the gallium complex, and nonexistent for the neutral magnesium complex in an HRP II mediated assay. The IC 50 for the BNT II mediated assay were found to be 9.0 and 58 uM for the iron and gallium complex respectively and again no activity was found for the magnesium complex (36). Considering the minimal hemozoin aggregation assay system employed, a readily envisioned mechanism for these complexes is that they interact with either the propionate moieties of the porphyrin ligand or the aspartic acid side chains of the BNT II template.…”

Novel lanthanide salicylaldimine complexes with unusual coordination mode

“…Transition metal salicylaldimines (salen-type) have been studied broadly due to their significance as biomimetic models for metaloproteins, effective catalysts for oxygenation processes and utilization in asymmetric catalysis, as building blocks for the self-assembly of helicates, and as antimalarial drugs [1][2][3][4][5][6][7][8][9]. X-ray structure data reveal that in the d-block metal complexes of this type, the Schiff bases generally act as deprotonated tetradentate ligands with the N 2 O 2 set of donor atoms capable of effective coordination in the planar fashion.…”