Pre-clinical evidences of the antileishmanial effects of diselenides and selenocyanates

Etxebeste-Mitxeltorena

et al. 2021

ACS Infect. Dis.

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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.

mentioning

confidence: 73%

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

Etxebeste-Mitxeltorena

et al. 2021

ACS Infect. Dis.

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“…Similarly, trypanothione reductase (TryR), catalyzing the reduction of trypanothione disulfide to trypanothione in trypanosomatids, remains a promising target due to its important role in the protection against ROS and its absence in vertebrates. Based on the analogy of sulfur and Se, diselenide and selenocyanate derivatives have been proposed as new TryR inhibitors (Baquedano et al 2016;Etxebeste-Mitxeltorena et al 2020;Garnica et al 2020). Among selenourea derivatives of diselenides series, 1,1´-(4,4´-Diselanediylbis(4,1-phenylene))bis(3-hexylselenourea) demonstrated an inhibitory activity of L. infantum TryR (Díaz et al 2019).…”

Section: Selenocompounds/se Derivatives Targeting Protozoan Proteins Involved In Vital Biological Pathwaysmentioning

confidence: 99%

Selenium and protozoan parasitic infections: selenocompounds and selenoproteins potential

et al. 2022

The current drug treatments against protozoan parasitic diseases including Chagas, malaria, leishmaniasis, and toxoplasmosis represent good examples of drug resistance mechanisms and have shown diverse side effects. Therefore, the identification of novel therapeutic strategies and drug compounds against such life-threatening diseases is urgent. According to the successful usage of selenium (Se) compounds-based therapy against some diseases, this therapeutic strategy has been recently further underlined against these parasitic diseases by targeting different parasite´s essential pathways. On the other hand, due to the important functions played by parasite selenoproteins in their biology (such as modulating the host immune response), they can be also considered as a novel therapeutic strategy by designing specific inhibitors against these important proteins. In addition, the immunomodulatory potentiality of these compounds to trigger T helper type 1 (Th1) cells and cytokinemediated immune response for the substantial induction of proinflammatory cytokines, thus, Se, selenoproteins, and parasite selenoproteins could be further investigated to find possible vaccine antigens. Herein, we collect and present the results of some studies regarding Se-based therapy against protozoan parasitic diseases and highlight relevant information and some viewpoints that might be insightful to advance toward more effective studies in the future.

Leishmaniasis - General Aspects of a Stigmatized Disease

“…Various chemical structures were reported with TR inhibitor activity and leishmaniacidal activity to the literature: Ag(0) nanoparticles encapsulated by ferritin molecules [89], Cu(II) diketonates [90], oxabicyclo[3.3.1]nonanones [73], azole-based compounds -e. pyrrole [91], β-carboline-quinazolinone hybrid [92], phenothiazine and phenoxazine derived chloroacetamides [93], selenocyanates and diselenide compounds [94,95], iminodibenzyl derivatives with ethylenediamine, ethanolamine and diethylenetriamine and their copper(II) complexes [96], diaryl sulfide derivatives [97], ammonium trichloro [1,2-ethanediolato-O,O′]-tellurat [98], all-hydrocarbon stapled peptides [99] chalcone derivatives [100], thiophene derivatives [101], imidazole-phenyl-thiazole compounds [102], isothiocyanate derivatives [103], (phenylthio)pyrimidin-4-amine derivatives [104], ferrocenylquinoline derivatives [105], triazole-phenyl-thiazoles derivatives [106], fluorene derivatives [107], adamantan derivatives, and their gold complexes [108] and natural products [109,110] (Figure 6).…”

Section: Trypanothione Reductase (Tr Tryr Trypanothione-disulfide Red...mentioning

confidence: 99%

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Istanbullu¹,

Bayraktar²

2022

The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.