Avaliação in vitro e in vivo da atividade antiplasmodial e citotoxicidade de novos compostos derivados de 4- aminoquinolinas

Abstract

With the emergence of resistant strains of Plasmodium the new therapeutic strategies are necessary for malaria control. The use of the hybridized 4- aminoquinoline ring with different chemical groups has been shown to be a promising technique to obtain benefits from activity, even in the presence of resistant strains. The objective this study was to evaluate new candidates for antimalarial drugs by the analysis of physicochemical, pharmacokinetic and molecular docking in silico, cytotoxicity, mechanism of action in vitro and antiplasmodial activity (in vitro and in vivo). Two groups of molecules were synthesized from the 4-aminoquinoline ring and conjugated to different aromatic groups. The first group, designated H, has a hydrazone attached to the 4-aminoquinoline ring, and the second group, designated I, it has an imine group as the substituent, both having biological properties. Physical- chemical properties and docking were analyzed using computational tools. Cytotoxicity parameters were evaluated in human erythrocytes, VERO - kidney epithelial cells and WI26VA4 human fibroblasts. The antiplasmodial activity against P. falciparum W2 was performed by the HRPII-ELISA technique. Possible alterations in the digestive vacuole of the parasite were observed by confocal microscopy. Finally, in vivo antimalarial activity was determined by the Peters suppressive test, performed on P. berghei NK65 infected mice and treated with the derivatives. Most of all, in silico data showed that the molecules had good physicochemical and pharmacokinetic prediction, they are non-carcinogenic and no classified in category III acute oral toxicity. In the hemolysis test, it was found that no derivative promoted more than 10% cell lysis. In addition, the derivatives showed low cytotoxicity, and were selective to the parasites. The in vitro evaluation of the molecules influence on the vacuole pH showed that I6 and I7 promoted an increase in the internal pH of the organelle that coincided with the pharmacological effects of artesunate, which is standard drug. In relation to the in vivo activity, I6 and I7 obtained important values of IMP on the 5th day after infection (I6 15 mg/kg = 72.64% and I7 15 mg/kg = 71.15% and 25 mg/kg = 93,7%). In the 9th d.p.i there was reduction in the activity of both derivatives, but I7 maintained its activity. It was observed that the synthesis process of the series of 4-aminoquinoline derivatives of this study was promising, especially in group I, producing molecules with antiplasmodial activity.