Síntese e caracterização de compostos de coordenação baseados em Atovaquona. Estudo de seus possíveis mecanismos de ação e avaliação biológica

Abstract

Malaria is a parasitic disease caused by microorganisms belonging to the genus Plasmodium. The total incidence of cases of this ailment reached 247 million in 2021, compared to 245 million in 2020 and 229 million in 2019, highlighting the extent of the challenge it poses. Therefore, it is necessary to explore new alternatives for antimalarial therapies. Currently, due to the development of drug resistance in clinical treatments, the therapeutic approach to combat malaria relies on the combined use of two or more drugs, also known as combination therapy. However, the employment of combination therapies presents some drawbacks, prompting the pursuit of promising research. Among these, the synthesis of metal complexes stands out. In this context, throughout this work, eight metal complexes containing the antimalarial drug Atovaquone were synthesized, representing a novel class with potential antimalarial activity. The compounds were obtained with good yields (46-85%) through the reaction of the ligand Atovaquone (ATV) with the respective metal complexes [Au(PPh3)Cl], [Ag(PPh3)2NO3], [Cu(PPh3)2NO3], Ag(OAc), Cu(OAc)2, Zn(OAc)2·2H2O, and ZnCl2·2H2O, using a 1:1 stoichiometric ratio. All compounds were carefully characterized by elemental analysis, infrared spectroscopy, Raman spectroscopy, nuclear magnetic resonance (NMR), ultravioletvisible (UV-VIS) absorption spectroscopy, and single-crystal X-ray diffraction analysis. These studies confirmed the formation of the eight complexes of gold(I), silver(I), copper(I/II), and zinc(II) with Atovaquone. Stability tests conducted by NMR, molar conductivity, and UV-VIS indicated that the complexes are stable in dimethyl sulfoxide (DMSO) for over 72 hours. The interaction of the compounds with ferriprotoporphyrin, a crucial component in the formation of β-hematin, was investigated, revealing their interaction with this compound, as evidenced by the obtained association constant values. However, they did not inhibit the formation of βhematin, suggesting that this is not their primary target of action. The lipophilicity of the compounds was evaluated, demonstrating their tendency to dissolve and interact with lipid substances, with values comparable to the drugs CQ, CQDF, and AQ, which could be relevant to their pharmacological activity. Additionally, spectroscopic titrations of the complexes with DNA were performed to estimate interaction constants between the metal complexes and this macromolecule, finding association constants within the range of previously reported metal complexes in the literature with reversible interactions. Furthermore, the interaction between the gold metal complex and reduced glutathione was observed, suggesting a strong interaction between this compound and glutathione. The compounds showed promising antimalarial activity, with nanomolar activity, demonstrating that all compounds were more active than chloroquine, especially against chloroquine-resistant strains of the Plasmodium falciparum parasite. Moreover, they exhibited anticancer activity in tumor cells, with the gold(I) compound showing activity and selectivity comparable to cisplatin in tumor cells.