Avaliação in vitro de derivados triazólicos quanto atividade leishmanicida em Leishmania (L) amazonensis e Leishmania (L) infantum chagasi

Abstract

Leishmaniasis is considered a neglected disease caused by the genet protozoan Leishmania sp. transmitted by a bite of a genet insect sandflies gender Lutzomyia. The therapy against leishmaniasis are imitated, with a few drugs been used. In this way, the new drug discovery could be a good strategy. Triazole are safe drugs and also good tolerated presenting low toxicity showing a broad spectrum of action. Thus, the present study had the objective test and evaluate in vitro nineteen compounds triazole derivates for the leishmanicidal activity with the forms amastigote and promastigote of Leishmania (L) amazonensis and L. (L) infantum chagasi. And the toxicity of the compounds against mammalian cells were tested. Comparing all experiments with Amphotericin (AMB) values. They also were evaluated as the pharmacokinetics and the Lipinski’s ‘rule of five’. The best compounds that showed activity against the promastigote forms were FS33 and FS41 showing effective concentration 50 with 2,71 and 4,71 µg/mL respectively for L. amazonensis and FS71 and FS54 with 1,24 and 0,8 µg/mL of EC 50 respectively for L. chagasi comparing with the control drug ANB (p<0,05). They also have better cytotoxicity concentration 50 comparing with ANB (p<0,05). The antiamastigote assay against L. amazonensis showed FS35 and FS28 as the most active with 1,1 and 0,9 µg/mL with selective index 18,4 and 128,9 respectively, and in L. chagasi infection the compound most active was FS44 with 3,1 µg/mL with 20,1 of SI. The assay of Hydrogen peroxide showed that the compound analyzed decrease the liberation (FS17, FS44, FS54). The molecular docking indicated that three compounds may inhibit Glicose-6-fosfate desidrogenase. The ADME forecast, showed that the compound may has goods interactions with the

human organism because they inhibit less cytochrome P450 proteins in general has high gastrointestinal absorption and Lipinski's 'rule of five' evaluation also showed that these compounds can be orally administered in future in vivo assays. Than that derivate used may be promising in Leishmaniasis treatment.