Selenium Derivatives as Promising Therapy for Chagas Disease: In Vitro and In Vivo Studies

Abstract

Chagas disease is a tropical infection caused by the protozoan parasite Trypanosoma cruzi and a global public health concern. It is a paradigmatic example of a chronic disease without an effective treatment. Current treatments targeting T. cruzi are limited to two obsolete nitroheterocyclic drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Hence, new, more effective, safer, and affordable drugs are urgently needed. Selenium and their derivatives have emerged as an interesting strategy for the treatment of different prozotoan diseases, such as African trypanosomiasis, leishmaniasis, and malaria. In the case of Chagas disease, diverse selenium scaffolds have been reported with antichagasic activity in vitro and in vivo . On the basis of these premises, we describe the in vitro and in vivo trypanocidal activity of 41 selenocompounds against the three morphological forms of different T. cruzi strains. For the most active selenocompounds, their effect on the metabolic and mitochondrial levels and superoxide dismutase enzyme inhibition capacity were measured in order to determine the possible mechanism of action. Derivative 26 , with a selenocyanate motif, fulfills the most stringent in vitro requirements for potential antichagasic agents and exhibits a better profile than benznidazole in vivo . This finding provides a step forward for the development of a new antichagasic agent.

Thianthrene Radical Cation as a TransientSETMediator: Photoinduced Thiocyanation and Selenocyanation of Arylthianthrenium Salts†

“…Our methodology could also facilitate the rapid synthesis of bioactive molecules. Selenocyanated product 8c’ , a potent trypanocidal activity against amastigotes and trypomastigotes of Trypanosoma cruzi strains, [ 15 ] could be readily prepared in 51% yield using N ‐phenyl 4‐trifluoromethylbenzamide ( 7c ) as the starting material. Its thiocyanated analogue 8c could also be accessed in 60% yield, which might possess similar bioactivities (Scheme 3c).…”

The Use of AlphaFold for In Silico Exploration of Drug Targets in the Parasite Trypanosoma cruzi

“…In the case of compounds C16-2, C26-6 and C8-3, they are all proposed to act at the mitochondrial level. These three compounds appear to cause a bioenergetic collapse of the cell ( 2021a ; 2021b ; Martín-Escolano et al., 2018a ). We found that the respiratory complex I NADH-ubiquinone oxidoreductase (TcCLB.506513.190, Q4DPI1), the catalytic first step in the electron transport chain, was selected in the top 3% in both C16-2 (position 35 out of 56) and C26-6 (position 2 out of 56), which would agree with what is described about these two compounds.…”

Alternative Approaches for the Treatment of Chagas Disease

“…[153] Filho et al (2021) synthesized and evaluated chlorinesubstituted 4-thiazolidinones, highlighting compound 10, displaying a good IC 50 of 0.85 μM, as a promising candidates for the treatment of T. cruzi infections.. [154] In 2021, Martín-Escolano et al conducted a comprehensive investigation on selenium derivatives as a potential therapeutic intervention for CD, revealing that in vitro study of compound 11 showing potential activity with an IC 50 value of 2.4 � 0.3 μM. [155] Martinho et al…”

“…In 2021, Martín‐Escolano et al . conducted a comprehensive investigation on selenium derivatives as a potential therapeutic intervention for CD, revealing that in vitro study of compound 11 showing potential activity with an IC 50 value of 2.4±0.3 μM [155] . Martinho et al .…”