Atividade antiplamódica de metalodroga associada à Cinchonina

Abstract

Currently, the chemotherapic tretment is the only way for malária control and the development of new drugs with antimalrial activity that provides low cost, low toxicity and efficiency is essential. This search provided the metals association, that may increase the antimalarial activity of drugs and decrease toxicity. Therefore, the antiplasmodial activity of cinchonine bounded with copper and cinchonine metal-free was evalueted. For in vitro assays, 7 drugs serial concentrations (1:2) ranging from 0,78 to 50 µg/ml was performed in Plasmodium falciparum 3D7 and K1 strains. For parasitemia supression analysis, female swiss mice weighing 27 ± 2 g and 6 to 8 weeks of age was used, inoculating 1x106 of Plasmodium berghei ANKA parazited erythrocytes, separating them into 4 animals per group and treating “per gavage” for 4 consecutive days: Negative control with placebo and Tween 20; Negative control with placebo; Mice-treated with bounded copper cinchonine; Mice-treated with cinchonine; Positive control treated with chloroquine. Doses of 5 mg/kg to 90 mg/kg were used. In vitro and in vivo antimalarial activity was evalueted by inhibition of parasite growth treated with drug test divided for the control group, further on the evaluation of cumulative mortality, citotoxicity in RAW cells, acute toxicity, histopathological analyzes and selectivity index, all performed in triplicate. The antiplasmodials in vitro assays of IC50 range 0,06 to 0,04 µg/ml for cin+Cu and 0,23 to 0,06 µg/ml for cinchonine and selectivity index was 32 and 122, respectively in chloroquine sensitive and resistente strains. All tested drugs exhibited in vivo antiplasmodial activity, reducing parasitemia in 93%, with lower mortality in cinchonine-bounded with copper groups. The histopathological analyzes shows mild hepatic steatosis in groups treated with cinchonine and cin+Cu and inflammatory infiltrate in the first drug. Despite these promising results, further tests about the mechnism of action of these drugs in the body and transmission blocking tests in gametocytes forms are important.