Síntese, avaliação da atividade antimalárica e do mecanismo de ação de complexos metálicos híbridos

Abstract

Malaria is still one of the most severe public health problems; it kills about 435,000 people around the world every year. Then, it is necessary to search for new antimalarial strategies. In view of that, in this work is reported the synthesis of new compounds, capable of being active against resistant strains, therefore, they can be used in malaria monotherapy. In this sense, two classes of new gold(I) complexes have been described: the gold(I) hybrids and the gold(I) phosphinic complexes. The gold(I) hybrids ([AuCQPQ]PF6 (1), [AuCQPQ]NO3 (2), [AuAQPQ]PF6 (3) and [AuAQPQ]NO3 (4)) were achieved using the precursors AuPQCl and [AuAQ2]Cl with the respective aminoquinoline, while the phosphinic gold(I) compounds ([AuPQPPh3]NO3 (8), [AuPQPPh3]PF6 (9), [AuAQPPh3]NO3 (10) and [AuAQPPh3]PF6 (11)) were obtained from the reaction between the AuPPh3 with the antimalarial drugs primaquine and amodiaquine. All of these compounds were characterized by analytical and spectroscopic techniques, such as vibrational absorption spectroscopy in the infrared region, electron absorption spectroscopy in the UV-vis region, elemental analysis, 1H, 13C, 31P NMR, COSY, DEPT 135, HMBC, HSQC, molar conductivity and ESI-MS. The metal hybrid 1-4 belong to a new class of compounds, in which two drugs that acts in different phases of the parasite cycle (erythrocytic, blood and gametocytes) were coordinated to gold(I), which makes possible that this single molecule acts as multi-phase drug. Additionally, each component of this gold(I) hybrid is able to interact or inhibit essential malaria parasite targets, which also makes that compounds 1-4 being promising multi-targets compounds. In fact, the results obtained showing that gold(I) hybrids exhibited a moderate reversible interaction with DNA, that can be by intercalation or interaction with minor groove, and they were capable inhibit the β-haematin formation and the TrxR enzyme, proving the multi-target action of hybrids 1 and 3. The antimalarial activity of hybrid 1 and 3 were determined on in vitro studies (against chloroquine sensitive (3D7) and resistant (W2) strains of P. falciparum) and on in vivo studies. Hybrid 3 stood out as the most active compound the series studied, it was about 100 times more active than chloroquine in resistant (W2) strains of P. falciparum. In vivo studies were observed that the use of gold(I) hybrid complexes may be better than combination therapy. Furthermore, the gold(I) hybrids had their multi-phase potential evaluated against the three stages of the parasite cycle (blood, liver and gametocytes). Finally, the gold(I) phosphinic compounds had their mechanism of action evaluated against the inhibition of β-hematin formation and it was observed that compound 11 showed the best inhibition capacity.