Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative.

Mauricio Peixoto Cupello,Israel Felzenswalb,Natália Pereira Nogueira,Marcia Cristina Paes,Jessica Isis Oliveira Paula,Debora De Sousa Dos Santos Costa,Pedro Ippolito,Rubem Figueiredo Sadoko Menna-Barreto,Ayres Guimarães Dias,Andréia Da Silva Fernandes,Paulo Roberto Ribeiro Costa,Francis Monique Saraiva

doi:10.1155/2017/2483652

Abstract

The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi forms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC50 = 259.4 ± 6.1 μM) and intracellular amastigotes infecting peritoneal macrophages (IC50 = 188.2 ± 47.5 μM), with no harmful effects upon the mammalian cells (CC50 values greater than 4 mM), resulting in a high selectivity index (CC50/IC50 > 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC50 of about 191.8 ± 10.5 μM and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC50 of 255.1 ± 3.6 μM. Finally, we investigated the mutagenic potential of the nitrone by the Salmonella/microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000 μM. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms of T. cruzi, offering new insights into CD treatment suggesting additional in vivo tests.

Highlights

Chagas disease, recognized by WHO as one of the world most important neglected tropical diseases, is a relevant socioeconomic problem in many countries [1]; it infects approximately 7 million people worldwide and is the most relevant parasitic killer in the Americas, where it is endemic [2]
The treatment with LQB-123 was effective against epimastigotes, bloodstream, and metacyclic trypomastigotes with IC50 in the range of 75–1200 μM
It is important to point out that T. cruzi is genetically classified into six intraspecies lineages, currently called discrete typing units (DTUs): TcI–VI [23]

Summary

Introduction

Chagas disease, recognized by WHO as one of the world most important neglected tropical diseases, is a relevant socioeconomic problem in many countries [1]; it infects approximately 7 million people worldwide and is the most relevant parasitic killer in the Americas, where it is endemic [2]. The general chemical structure of nitrone is X-CH=NO-Y, where “X” is a phenyl group and “Y” is a tert-butyl group (PBN). This structure has been extensively studied in many experimental and biochemical systems over the past 30 years. The assessment of effectiveness against risk of adverse outcomes is imperative to support a clinical use [14]

Methods

Results

Conclusion