Library of Selenocyanate and Diselenide Derivatives as In Vivo Antichagasic Compounds Targeting Trypanosoma cruzi Mitochondrion.

Rubén Martín-Escolano,Esther Moreno,María J Rosales,Carmen Sanmartín,Manuel Sánchez-Moreno,Carlos Aydillo,Daniel Plano,Clotilde Marín,Socorro Espuelas,Daniel Molina-Carreño

doi:10.3390/ph14050419

Abstract

Chagas disease is usually caused by tropical infection with the insect-transmitted protozoan Trypanosoma cruzi. Currently, Chagas disease is a major public health concern worldwide due to globalization, and there are no treatments neither vaccines because of the long-term nature of the disease and its complex pathology. Current treatments are limited to two obsolete drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Taking into account the urgent need for strict research efforts to find new therapies, here, we describe the in vitro and in vivo trypanocidal activity of a library of selected forty-eight selenocyanate and diselenide derivatives that exhibited leishmanicidal properties. The inclusion of selenium, an essential trace element, was due to the well-known extensive pharmacological activities for selenium compounds including parasitic diseases as T. cruzi. Here we present compound 8 as a potential compound that exhibits a better profile than benznidazole both in vitro and in vivo. It shows a fast-acting behaviour that could be attributed to its mode of action: it acts in a mitochondrion-dependent manner, causing cell death by bioenergetic collapse. This finding provides a step forward for the development of a new antichagasic agent.

Highlights

Chagas disease (CD), known as American trypanosomiasis, is caused by tropical infection with the insect-transmitted protozoan parasite Trypanosoma cruzi
The selectivity index (SI) for the drugs was determined by the ratio of the IC50 of Vero cells over the IC50 obtained for the corresponding form of the parasite
The cytotoxicity values registered against Vero indicated that the activity of many of these derivatives was not specific against T. cruzi as it is showed in the SI

Summary

Introduction

Chagas disease (CD), known as American trypanosomiasis, is caused by tropical infection with the insect-transmitted protozoan parasite Trypanosoma cruzi. T. cruzi infection is far from innocuous and, in mammal hosts, it is an obligate intracellular parasite for its replication, which can infect most nucleated cells [5,6]. During the initial acute stage of the disease, which occurs 2–8 weeks post-infection in humans, Pharmaceuticals 2021, 14, 419. Pharmaceuticals 2021, 14, 419 parasite become widely disseminated in tissues and organs and can be detected in the bloodstream, and CD generally manifests as a mild febrile illness. Following suppression of the acute stage by the adaptive immune response [7,8], the disease progresses to a longlasting asymptomatic chronic stag, which is characterized by an extremely low parasite burden. ~30% of those infected will advance to a symptomatic stage, developing pathology such as cardiomyopathy and digestive tract megasyndromes, outcomes for which there are few therapeutic options [9,10,11]

Methods

Results

Conclusion