Metal(triphenylphosphine)-atovaquone Complexes: Synthesis, Antimalarial Activity, and Suppression of Heme Detoxification.

To ascertain the bioinorganic chemistry of metals conjugated with quinones, the complexes [Ag(ATV)(PPh ₃ ) ₂ ] ( 1 ), [Au(ATV)(PPh ₃ )]·2H ₂ O ( 2 ), and [Cu(ATV)(PPh ₃ ) ₂ ] ( 3 ) were synthesized by the coordination of the antimalarial naphthoquinone atovaquone (ATV) to the starting materials [Ag(PPh ₃₎₂ ]NO ₃ , [Au(PPh ₃ )Cl], and [Cu(PPh ₃ ) ₂ NO ₃ ], respectively. These complexes were characterized by analytical and spectroscopical techniques. X-ray diffraction of single crystals precisely confirmed the coordination mode of ATV to the metals, which was monodentate or bidentate, depending on the metal center. Both coordination modes showed high stability in the solid state and in solution. All three complexes showed negative log D values at pH 5, but at pH 7.4, while complex 2 continued to have a negative log D value, complexes 1 and 3 displayed positive values, indicating a more hydrophilic character. ATV and complexes 1 - 3 could bind to ferriprotoporphyrin IX (FePPIX); however, only complexes 1 - 3 could inhibit β-hematin crystal formation. Phenotype-based activity revealed that all three metal complexes are able to inhibit the growth of P. falciparum with potency and selectivity comparable to those of ATV, while the starting materials lack this activity. The outcomes of this chemical design may provide significant insights into structure-activity relationships for the development of new antimalarial agents.