Metalloantimalarials:  Targeting of P. falciparum Strains with Novel Iron(III) and Gallium(III) Complexes of an Amine Phenol Ligand

Emergence of chloroquine (CQ)-resistant Plasmodium falciparum strains necessitates discovery of potent and inexpensive antimalarial drugs. The high cost of new drugs negatively impacts their access and distribution in the regions of the world with scarce economic resources. While exploring structure−activity relationships, using gallium(III) as a surrogate marker for iron(III), we found cationic, and moderately hydrophobic, compounds, [{1,12-bis(2-hydroxy-3-ethyl-benzyl)-1,5,8,12-tetraazadodecane}metal(III)]⁺ (metal = Fe(III) and Ga(III); [Fe-3-Eadd]⁺, 3; [Ga-3-Eadd]⁺, 4), that possessed antimalarial activity. Crystal structure analyses revealed octahedral geometry for these complexes. The RP-HPLC analysis, after incubation in PBS or HEPES buffer (pH 7.4) at 37 °C for 3 days, detected only parental compounds thereby providing evidence for stability under physiological conditions. Both 3 and 4 demonstrated promising half-maximum inhibitory concentration (IC₅₀) values of ∼80 and 86 nM in the CQ-sensitive HB-3 line, respectively. However, both 3 and 4 were found to possess elevated IC₅₀ values of 2.5 and 0.8 μM, respectively, in the CQ-resistant Dd2 line, thus displaying preferential cytotoxicity toward the CQ-sensitive HB3 line. In cultured parasites, 3 and 4 targeted hemozoin formation. Thus, these compounds acted similarly to chloroquine with regard to action and resistance, despite the lack of structural similarity to quinolines. Finally, similarity in coordination chemistry, stability, and antimalarial cytotoxicity profiles indicated that gallium(III) ion can serve as a template for iron(III) in structure elucidation of active molecules in solution.