Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity.

Leandro Da Costa Clementino,Marcia A S Graminha,Wilquer Castro Laurindo,Guilherme Felipe Santos Fernandes,Bruno Pereira Motta,Amanda Martins Baviera,Igor Muccilo Prokopczyk,Jean Leandro Dos Santos,Danyelle Toyama,Flávio Henrique-Silva,Bhaskar Saha

doi:10.1371/journal.pone.0259008

Abstract

Leishmaniasis is a neglected disease that affects 12 million people living mainly in developing countries. Herein, 24 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antileishmanial activity. Compound 4f, a furoxan derivative, was particularly remarkable in this regard, with EC50 value of 3.6 μM against L. infantum amastigote forms and CC50 value superior to 500 μM against murine peritoneal macrophages. In vitro studies suggested that 4f may act by a dual effect, by releasing nitric oxide after biotransformation and by inhibiting cysteine protease CPB (IC50: 4.5 μM). In vivo studies using an acute model of infection showed that compound 4f at 7.7 mg/Kg reduced ~90% of parasite burden in the liver and spleen of L. infantum-infected BALB/c mice. Altogether, these outcomes highlight furoxan 4f as a promising compound for further evaluation as an antileishmanial agent.

Highlights

Leishmaniasis is a neglected disease caused by more than 20 species of the genus Leishmania and affects 12 million individuals living mainly in developing countries [1,2,3]
Leishmaniasis is transmitted through the inoculation of promastigotes during the phlebotomines blood meal, followed by their entry and differentiation to amastigotes into mammalian hosts cells, primarily “professional phagocytes’’ such as macrophages [5]
We described the synthesis and antileishmanial properties of new N-oxide derivatives, developed based on the prototype Lapdesf14e focusing on a dual effect: cysteine protease LmCPB2.8ΔCTE (CPB) inhibition and nitric oxide (NO)-release [20, 47]

Summary

Introduction

Leishmaniasis is a neglected disease caused by more than 20 species of the genus Leishmania and affects 12 million individuals living mainly in developing countries [1,2,3]. The drug discovery pipeline for leishmaniasis has been affected by the severe scarcity of new drug candidates achieving clinical trials stages [4]. Efforts to discover new therapeutic alternatives are urgent. Leishmaniasis is transmitted through the inoculation of promastigotes during the phlebotomines blood meal, followed by their entry and differentiation to amastigotes into mammalian hosts cells, primarily “professional phagocytes’’ such as macrophages [5]. The parasite has developed different strategies to inactivate the macrophages functions, including the expression and secretion of cysteine protease (CPB) [6]. CPB, as well as the Trypanosoma cruzi

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Results

Conclusion