Nuevas moléculas con actividad terapéutica frente a tripanosomátidosEvaluación y mecanismo de acción a nivel celular

Resumen

This Doctoral Thesis, included in the Doctoral Programme in Medical and Pharmaceutical Sciences, Development and Quality of Life of the University of La Laguna, has been carried out in the Antiparasitic Chemotherapy laboratory of the University Institute of Tropical Diseases and Public Health of the Canary Islands, belonging to the Department of Obstetrics and Gynaecology, Paediatrics, Preventive Medicine and Public Health, Toxicology, Legal and Forensic Medicine and Parasitology. Leishmaniasis, caused by species of the genus Leishmania, and Chagas disease, caused by Trypanosoma cruzi, are two serious pathologies that kill thousands of people every year. They mainly affect developing areas and are therefore linked to poverty and malnutrition. In addition, lack of hygiene or the characteristics of the home can be conducive to contagion, as they are pathologies transmitted by vectors, phlebotomine sandflies in leishmaniasis and bedbugs in Chagas disease. These characteristics, added to the fact that they are diseases that require humid and warm environments, mean that they are classified as neglected tropical diseases (NTDs). The treatments available for these pathologies are not very effective and, moreover, generate enormous side effects in patients. These treatments have not improved and are the same as 50 years ago, making it necessary to search for new treatments that are more effective and, above all, less toxic. The Antiparasitic Chemotherapy Laboratory of the University Institute of Tropical Diseases and Public Health of the Canary Islands has been developing research in this field for more than a decade. This Doctoral Thesis aims to deepen the research of new effective therapies against these pathologies. To this end, an in vitro study of the activity of several compounds against Leishmania amazonensis, Leishmania donovani and Trypanosoma cruzi was carried out using a colorimetric assay based on alamarBlueTM. Also, using the same method, cytotoxicity against murine macrophages was studied. The most selective compounds were selected for studies on the mechanism of action leading to parasite killing. Acrylonitrile derivatives have previously been shown to possess biological activity against other pathologies, being proposed as possible antitumor, antibacterial and antiparasitic agents. For this reason, the trypanocidal and leishmanicidal activity of 32 new acrylonitriles developed at the Institute of Natural Products and Agrobiology of Tenerife was evaluated. The results of this study shown good trypanocidal capacity of 5 of these acrylonitriles, as well as 3 of them show high leishmanicidal activity, inducing a programmed cell death mechanism in the parasites. Natural products have historically been a source of new compounds in the search for new therapies. Sesquiterpene lactones have shown a multitude of biological activities, such as anti-inflammatory, antiviral or antiparasitic. In this research the antichagasic and leishmanicidal activity, as well as the mechanism of action, of 13 sesquiterpene lactones from Palythoa aff. clavata obtained at the Antonio González University Institute of Bio- Organics of the University of La Laguna were studied. The results demonstrate the antikinetoplastid activity of 3 of these lactones, and it is also elucidated that they produce their effects on the parasites by inducing programmed cell death. In conclusion, acrylonitriles and sesquiterpene lactones shown antikinetoplastid activity, being able to produce programmed cell death on parasites, making them good candidates for the therapy of leishmaniasis and Chagas disease.