Synthesis, characterization, inhibition of β-hematin formation and antimalarial activity of zinc-chloroquine complexes

Malaria remains a major public health challenge due to drug-resistant Plasmodium strains. To overcome this, coordinating antimalarials like chloroquine (CQ) to transition metals has emerged as a promising synergistic approach. This work reports the synthesis and characterization of three zinc(II)-chloroquine complexes: [Zn(CQ)Cl₂]·2H₂O (1), [Zn(CQ)₂(OAc)₂]·1.5H₂O (2), and [Zn(CQ)(Tg)₂Cl]Cl (3). The compounds were obtained in good yields and characterized by elemental analysis, TGA, UV-Vis, IR, and NMR. Mechanistic studies via UV-Vis titrations showed that all complexes interact with hemin (heme group). However, in the quantitative β-hematin inhibition assay (IC₅₀), complex 2 outperformed free chloroquine, complex 1 showed moderate activity, and 3 was inactive. Consistently, complex 2 was the most effective compound against the chloroquine-resistant PfW2 strain. These findings suggest that β-hematin inhibition is a primary mechanism for complexes 1 and 2, making these Zn-CQ metallodrugs affordable and promising candidates for malaria treatment.