Diseño, síntesis y evaluación biológica de compuestos orgánicos con calcógenos frente a enfermedades tropicales desatendidas
Neglected tropical diseases (NTDs) mainly affect impoverished areas of rural population. Among them, Chagas disease, sleeping sickness and leishmaniasis are caused by the trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp. The current treatments for these diseases are...
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| Tipo de recurso: | tesis doctoral |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Asociación Española de Audiología |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | español |
| OAI Identifier: | oai:dadun.unav.edu:10171/118392 |
| Acceso en línea: | https://hdl.handle.net/10171/118392 |
| Access Level: | acceso abierto |
| Palabra clave: | Diseño síntesis y estudio de nuevos fármacos Química organosulfurados Parasitología animal |
| Sumario: | Neglected tropical diseases (NTDs) mainly affect impoverished areas of rural population. Among them, Chagas disease, sleeping sickness and leishmaniasis are caused by the trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp. The current treatments for these diseases are old, ineffective and causes side effects, so we need to look for new derivatives. This Thesis is focused on selenium, a rare element in medicinal chemistry but known for its bioisosterism with sulfur. This feature allows us to switch both elements with minimal alterations to their physicochemical properties. New derivatives were tested against Chagas disease, sleeping sickness and leishmaniasis aiming to compare selenium vs. sulfur derivatives and to study their mechanism of action. In the end, we are looking for new active and safe derivatives to treat NTDs. Sulfur-containing compounds are common in medicinal chemistry. For this reason, we decided to implement the isosteric replacement of sulfur by selenium as a strategy to design new derivatives. Using this strategy, we expect to obtain improved seleno-derivatives, more active than sulfur-derivatives. We used thiosemicarbazones as the starting point because they are very well-known compounds, and they inhibit the main cysteine-proteases of trypanosomatids. We also performed the cyclation of thiosemicarbazones to obtain the corresponding thiazoles. Therefore, we designed and synthesized fifty-seven derivatives divided into two series, one containing thio- and selenosemicarbazones, and the second one containing thiazoles and selenazoles. This pool of compounds has shown activity against T. cruzi and T. brucei, so we evaluated their toxicity and mechanism of action. As these compounds are known inhibitors of cysteine-proteases, we tested them against cruzain and rhodesain (TbCatL), the main enzymes of T. cruzi and T. brucei. We also evaluated their antioxidant capacity. Furthermore, we studied the pharmacokinetic profile in vivo of the lead compound against T. cruzi because it improved the activity and selectivity data of the reference drug (benznidazole). This compound got promising results when administered orally. Last, we synthesized seventeen new selenoates that showed activity against Leishmania. We also studied their toxicity and mechanism of action which is related to the gene expression in Leishmania. |
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