Metal–atovaquone complexes with antiplasmodial activity: chemical reactivity and structure–activity relationships

Abstract

Five novel metal-based complexes of Ag(I) [Ag(ATV)] (1), Zn(II) [Zn(ATV)₂(H₂O)₂]·2H₂O (2), [Zn(ATV)₂(CH₃OH)₂]·H₂O (3), {Zn(ATV)₂}_n (4), and Cu(II) [Cu(ATV)₂] (5), with the antimalarial naphthoquinone atovaquone (ATV) were synthesized and characterized. Ag(I) and Cu(II) complexes were thoroughly analyzed using IR, NMR, EPR, and conductivity measurements, whereas the crystal structures of the three Zn(II) complexes were determined by single-crystal X-ray diffraction, supported by complementary analytical techniques. Depending on the metal center, ATV coordinates in either a monodentate or bidentate coordination mode, producing highly stable metal complexes both in the solid state and in DMSO solution. These metal–ATV complexes retain the potent antiplasmodial activity of ATV against chloroquine-sensitive and -resistant Plasmodium falciparum strains and introduce additional mechanisms of action. According to FT IR results, Zn(II) complexes inhibit β-hematin formation, complex 3 accelerates ring-stage parasite killing, and complex 5 promotes intracellular copper accumulation, which correlate with enhanced antiplasmodial potency. These results demonstrate that metal coordination can fine-tune the ATV biological profile, positioning these compounds as promising leads for the design of new antimalarial drugs.