Synthesis, characterization, inhibition of β-hematin formation, lipophilicity, and antimalarial activity of metal-amodiaquine complexes

Abstract

Malaria kills more people than any other infectious disease. It claims over 600,000 lives each year. Despite ongoing efforts, an effective scientific endeavor to eradicate it has yet to be realized. In line with our strategy of searching for a rational alternative treatment, we have developed five new coordination compounds containing amodiaquine (AQ): [Zn(AQ)Cl₂]₂ (1); [Zn(AQ)(OH)₂(H₂O)] (2); [Zn(AQ)(Ac)₂] (3); [Cu(AQ)(Ac)₂] (4) and [Ag(AQ)(PPh₃)₂(H₂O)]NO₃ (5) which were synthesized under mild conditions. The M-AQ complexes were characterized using a combination of conductivity measurements, elemental and thermal analyses, electronic, infrared, and NMR spectroscopies, ESI-MS spectrometry and EPR. AQ is coordinated to the metal by the nitrogen atom of the quinoline ring. Overall, compounds 1, 2, and 3 demonstrated greater inhibitory efficacy compared to amodiaquine alone. Based on these IC₅₀ values, we can infer that these metal-AQ complexes are as potent in inhibiting β-hematin formation as AQ, consistent with their strong binding affinity to Fe(III)PPIX (protoporphyrin IX). All metal-AQ complexes exhibited negative log D values at pH 5 indicating a more hydrophilic character. All the Metal-AQ complexes exhibited in vitro activity against CQ-resistant strains of P. falciparum. The Zn-AQ complexes were the most active in the series, comparable to AQ and more active than chloroquine diphosphate against the CQ-resistant strain PfW2. At a dose of 30 mg/kg, treatment with complex 1 increased the median survival time of the mice by 75 %. This may be due to the presence of two amodiaquine molecules in its composition.

Keywords: Amodiaquine; Antiplasmodial; Copper; Heme detoxification; Metal complexes; Silver; Zinc.