Martin-Escolano, R. (Ruben)
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- In vitro and in vivo anti-Trypanosoma cruzi activity of new arylamine Mannich base-type derivatives(2016) Jimenez-Montes, C. (Carmen); Martin-Escolano, R. (Ruben); Lopez-de-Cerain, A. (Adela); Pérez-Silanes, S. (Silvia); Zamora-Ledesma, S. (Salvador); Sanchez-Moreno, M. (Manuel); Marin, C. (Clotilde); Cirauqui, N. (Nuria); Moreno-de-Viguri, E. (Elsa); Jimenez-Lopez, M. (Marina); Santivañez-Veliz, M. (Mery); Martin-Montes, A.(Alvaro); Azqueta, A. (Amaya)Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity and with a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7 and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high anti-parasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.
- Library of Seleno-Compounds as Novel Agents against Leishmania Species(2017) Alcolea-Devesa, V. (Verónica); Gutierrez-Sanchez, R. (Ramon); Sanmartin-Grijalba, C. (Carmen); Martin-Escolano, R. (Ruben); Pérez-Silanes, S. (Silvia); Sanchez-Moreno, M. (Manuel); Plano-Amatriain, D. (Daniel); Espuelas, S. (Socorro); Marin, C. (Clotilde); Diaz, M. (Marta); Moreno-Amatria, E. (Esther); Martin-Montes, A.(Alvaro)The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.
- In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives(2017-11) Jimenez-Montes, C. (Carmen); Gutierrez-Sanchez, R. (Ramon); Sanmartin-Grijalba, C. (Carmen); Martin-Escolano, R. (Ruben); Pérez-Silanes, S. (Silvia); Sanchez-Moreno, M. (Manuel); Marin, C. (Clotilde); Moreno-de-Viguri, E. (Elsa); Santivañez-Veliz, M. (Mery); Lopez-Gonzalez, C. (Catalia); Martin-Montes, A.(Alvaro)Leishmaniasis is one of the world’s most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight Leishmaniasis remains a crucial goal today. With this purpose in mind, we present twenty arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of L. infantum, L. donovani and L. braziliensis strains. Six out of the twenty Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at a IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of Fe-SOD (iron superoxide dismutase) inhibition. These molecules could be potential candidates for Leishmaniasis chemotherapy.
- Library of selenocyanate and diselenide derivatives as in vivo antichagasic compounds targeting trypanosoma cruzi mitochondrion(MDPI, 2021) Martin-Escolano, R. (Ruben); Molina-Carreño, D. (Daniel); Plano-Amatriain, D. (Daniel); Espuelas, S. (Socorro); Rosales, M.J. (María J.); Moreno, E. (Esther); Aydillo-Miguel, C. (Carlos); Sanmartin-Grijalba, C. (Carmen); Sanchez-Moreno, M. (Manuel); Marin, C. (Clotilde)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.
- Selenium derivatives as promising therapy for chagas disease: in vitro and in vivo studies(ACS Publications, 2021) Martin-Escolano, R. (Ruben); Etxebeste-Mitxeltorena, M. (Mikel); Martín-Escolano, J. (Javier); Plano-Amatriain, D. (Daniel); Rosales, M.J. (María J.); Espuelas, S. (Socorro); Moreno, E. (Esther); Sanchez-Moreno, M. (Manuel); Sanmartin-Grijalba, C. (Carmen); Marin, C. (Clotilde)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.