Efeito antileishmanial de derivados esteroidais em Leishmania sp

Abstract

Leishmaniasis is a group of infectious diseases caused by protozoa of the genus Leishmania sp, responsible for a great socioeconomic impact worldwide. The available treatments for leishmaniasis are limited because they present high toxicity, parenteral administration, high cost and side effects. Steroids are a diversified group of compounds with varied applicability in pharmacology. However, the antileishmanial activity of this class is still little explored. In the present work, we investigated the antileishmanial effects of groups of steroidal derivatives: cholesterol; colic and deoxycholic acid. In addition, we determined, in vitro, possible important cellular targets/alterations in the biological activity of the most promising compound and in silico analysis of its oral bioavailability and pharmacokinetics. The antipromastigote activity in Leishmania sp and cytotoxicity in peritoneal macrophages were determined by the colorimetric method MTT. The antiamastigote activity was evaluated in with L. amazonensis-infected macrophages after 72 hours of treatment. The effects of the best compound on promastigote targets were performed using fluorescent labeling on treated promastigotes, and in silico analyzes were performed using computational tools. In a general analysis of the results obtained by the in vitro tests, it is observed that among the steroid derivatives tested in this work, the derivatives of deoxycholic acid presented the best antileishmanial effect for the promastigote and amastigote forms in vitro. Among this series of compounds, compound 11d (IC50 = 15.34 μM) is the most selective for L. amazonensis (SI>9.78) and the most specific for the intracellular form of this species. This compound has as probable cellular target the mitochondria, increasing the ROS production and decreasing the ΔΨm. Moreover, the compound has been shown to cause damage to the DNA content of the parasite. In silico studies of the physicochemical and pharmacokinetic properties of compound 11d showed that it has the ability to permeate through biological membranes and oral administration is possible.