Biological characteristics of the Trypanosoma cruzi Arequipa strain make it a good model for Chagas disease drug discovery

Trypanosoma cruzi, the causative agent of Chagas disease (CD), is a genuine parasite with tremendous genetic diversity and a complex life cycle. Scientists have studied this disease for more than 100 years, and CD drug discovery has been a mainstay due to the absence of an effective treatment. Technical advances in several areas have contributed to a better understanding of the complex biology and life cycle of this parasite, with the aim of designing the ideal profile of both drug and therapeutic options to treat CD. Here, we present the T. cruzi Arequipa strain (MHOM/Pe/2011/Arequipa) as an interesting model for CD drug discovery. We characterized acutephase parasitaemia and chronic-phase tropism in BALB/c mice and determined the in vitro and in vivo benznidazole susceptibility profile of the different morphological forms of this strain. The tropism of this strain makes it an interesting model for the screening of new compounds with a potential anti-Chagas profile for the treatment of this disease.Alfonso Martin Escudero Foundation Junta de Andalucia A-CTS-383-UGR1

Identification of Aryl Polyamines Derivatives as Anti-Trypanosoma cruzi Agents Targeting Iron Superoxide Dismutase

Chagas disease (CD) is a tropical and potentially fatal infection caused by Trypanosoma cruzi. Although CD was limited to Latin America as a silent disease, CD has become widespread as a result of globalization. Currently, 6–8 million people are infected worldwide, and no effective treatment is available. Here, we identify new effective agents against T. cruzi. In short, 16 aryl polyamines were screened in vitro against different T. cruzi strains, and lead compounds were evaluated in vivo after oral administration in both the acute and chronic infections. The mode of action was also evaluated at the energetic level, and its high activity profile could be ascribed to a mitochondria-dependent bioenergetic collapse and redox stress by inhibition of the Fe-SOD enzyme. We present compound 15 as a potential compound that provides a step forward for the development of new agents to combat CD.Ministerio de Economia, Industria y Competitividad (CONSOLIDER CSD2010–00065 and CTQ2017–90852-REDC)MINECO and FEDER funds from the EU (Projects PID2019-110751RB-I00, RED2018-102331-T and Unidad de Excelencia María de Maeztu CEX2019-000919-M)Alfonso Martín Escudero Foundatio

An Updated View of the Trypanosoma cruzi Life Cycle: Intervention Points for an Effective Treatment

Chagas disease (CD) is a parasitic, systemic, chronic, and often fatal illness caused by infection with the protozoan Trypanosoma cruzi. The World Health Organization classifies CD as the most prevalent of povertypromoting neglected tropical diseases, the most important parasitic one, and the third most infectious disease in Latin America. Currently, CD is a global public health issue that affects 6−8 million people. However, the current approved treatments are limited to two nitroheterocyclic drugs developed more than 50 years ago. Many efforts have been made in recent decades to find new therapies, but our limited understanding of the infection process, pathology development, and long-term nature of this disease has made it impossible to develop new drugs, effective treatment, or vaccines. This Review aims to provide a comprehensive update on our understanding of the current life cycle, new morphological forms, and genetic diversity of T. cruzi, as well as identify intervention points in the life cycle where new drugs and treatments could achieve a parasitic cure.Junta de Andalucia E-BIO-464-UGR20Junta de Andalucia (Proyectos I+D+I FEDER Andalucia 2014-2020)Alfonso Martin Escudero Foundatio

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

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 wellknown 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.Ministerio de Economia, Industria y Competitividad, grant number CSD2010–00065 and CTQ2017–90852-REDCConserjería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucia, grant number A-CTS-383-UGR18Institute of Tropical Health of University of Navarre (ISTUN)Caixa FoundationRoviralta and UbesolAlfonso Martín Escudero Foundatio

Cytotoxicity of three new triazolo-pyrimidine derivatives against the plant trypanosomatid: Phytomonas sp isolated from Euphorbia characias

There is no effective chemotherapy against diseases caused by Phytomonas sp., a plant trypanosomatid responsible for economic losses in major crops. We tested three triazolo-pyrimidine complexes [two with Pt(II), and another with Ru(III)] against promastigotes of Phytomonas sp. isolated from Euphorbia characias. The incorporation of radiolabelled precursors, ultrastructural alterations and changes in the pattern of metabolite excretion were examined. Different degrees of toxicity were found for each complex: the platinun compound showed an inhibition effect on nucleic acid synthesis, provoking alterations on the levels of mitochondria, nucleus and glycosomes. These results, together with others reported previously in our laboratory about the activity of pyrimidine derivatives, reflect the potential of these compounds as agents in the treatment of Phytomonas sp.Financial support Universidad de Granada (Spain), grant BIO 2000-1429

First-Row Transition 7-Oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes: Antiparasitic Activity and Release Studies

We are thankful for the funding from the research project RTI2018-094322-B-I00, financed by MCIN/AEI/10.13039/501100011033/; “ERDF A way of making Europe”; and the Research Thematic Network RED2022-134091-T, financed by MCIN/AEI/10.13039/501100011033. Á.M.-M. is grateful to the European Union and Junta de Andalucía for a post-doc grant (Ayuda a la contratación de personal investigador doctor).Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ph16101380/s1Leishmaniasis and Chagas disease are still considered neglected illnesses due to the lack of investment in research, despite the fact that almost one million new cases are reported every year. Four 7-oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (HftpO) first-row transition complexes (Cu, Co, Ni, Zn) have been studied for the first time in vitro against five different species of Leishmania spp. (L. infantum, L. braziliensis, L. donovani, L. peruviana and L. mexicana) as well as Trypanosoma cruzi, showing higher efficacy than the reference commercial drugs. UV and luminescence properties were also evaluated. As a proof of concept, anchoring of a model high-effective-metal complex as an antiparasitic agent on silica nanoparticles was carried out for the first time, and drug-release behaviour was evaluated, assessing this new approach for drug vehiculation.MCIN/AEI/10.13039/501100011033/ RTI2018-094322-B-I00, RED2022-134091-TERDF A way of making EuropeEuropean UnionJunta de Andalucí

Leishmanicidal Activity of Nine Novel Flavonoids from Delphinium staphisagria

Objectives. To evaluate the in vitro leishmanicidal activity of nine flavonoid derivatives from Delphinium staphisagria against L. infantum and L. braziliensis. Design and Methods. The in vitro activity of compounds 1–9 was assayed on extracellular promastigote and axenic amastigote forms and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were carried on J774.2 macrophage cells using Glucantime as the reference drug. The mechanisms of action were analysed performing metabolite excretion and transmission electronic microscope ultrastructural alteration studies. Results. Nine flavonoids showed leishmanicidal activity against promastigote as well as amastigote forms of Leishmania infantum and L. braziliensis. These compounds were nontoxic to mammalian cells and were effective at similar concentrations up to or lower than that of the reference drug (Glucantime). The results showed that 2″-acetylpetiolaroside (compound 8) was clearly the most active. Conclusion. This study has demonstrated that flavonoid derivatives are active against L. infantum and L. braziliensis

In vitro and in vivo studies of the trypanocidal activity of four terpenoid derivatives against Trypanosoma cruzi.

Four terpenoid derivatives were examined for their activity against Trypanosoma cruzi. Our results show that two compounds were very active in vitro against both extra- and intracellular forms. These compounds, non-toxic for the host cells, are more effective than the reference drug benznidazole. The capacity to infect cells was negatively affected and the number of amastigotes and trypomastigotes was reduced. A wide range of ultrastructural alterations was found in the epimastigote forms treated with these compounds. Some metabolic changes occurred presumably at the level of succinate and acetate production, perhaps caused by the disturbance of the enzymes involved in sugar metabolism inside the mitochondria. In vivo results were consistent with those observed in vitro. The parasitic load was significantly lower than in the control assay with benznidazole. The effects of these products showed the reduction of the anti-T. cruzi antibodies level during the chronic stage

Trypanosoma cruzi: Seroprevalence Detection in Suburban Population of Santiago de Querétaro (Mexico)

Objectives. To evaluate the potential of iron-oxide dismutase excreted (SODeCRU) by T. cruzi as the antigen fraction in the serodiagnosis of Chagas disease and compile new epidemiological data on the seroprevalence of this disease in the suburban population of the city of Santiago de Querétaro (Mexico). Design and Methods. 258 human sera were analyzed by the techniques of ELISA and Western blot and using the homogenate and the SODeCRU. Results. A total of 31 sera were positive against ELISA/SODeCRU (12.4%), while 30 sera proved positive by WB/SODeCRU (11.6%). The comparison between the technique of ELISA and WB showed a sensitivity of 93%, and a specificity of 99%. The positive predictive value was 93% and the negative predictive value was 99%, with a Kappa (κ) value of 1. Conclusions. These preliminary data reveal the degree of infection of nonrural areas of Mexico and demonstrated that SODeCRU is an antigen useful to diagnose Chagas disease

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

This work was financially supported by the Ministerio de Economia, Industria y Competitividad (CONSOLIDER CSD2010-00065 and CTQ2017-90852-REDC). R.M.-E. is grateful for the fellowship from the Alfonso Martin Escudero Foundation.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.Spanish Government CONSOLIDER CSD2010-00065 CTQ2017-90852-REDCAlfonso Martin Escudero Foundatio