Diseño, síntesis y evaluación biológica de nuevos derivados de bases de Mannich de tipo arilamina como potenciales agentes tripanocidas y leishmanicidas
Keywords: 
microbiología
diseño, síntesis y estudio de nuevos fármacos
compuestos heterocíclicos
espectroscopía de masas
Materias Investigacion::Ciencias de la vida::Biología
Issue Date: 
24-Jul-2018
Defense Date: 
18-Dec-2017
Citation: 
SANTIVÁÑEZ, M. "Diseño, síntesis y evaluación biológica de nuevos derivados de bases de Mannich de tipo arilamina como potenciales agentes tripanocidas y leishmanicidas". Pérez, S. y Moreno, E. (dirs.). Tesis doctoral. Universidad de Navarra, Pamplona, 2017.
Abstract
Chagas Disease (CD) and Leishmaniasis are two parasitic diseases transmitted by vectors and caused by protozoa from the Trypanosomatidae family. Both diseases are included within the neglected tropical diseases group and are caused by Trypanosoma cruzi and the Leishmania genus protozoa respectively. Chagas disease is endemic in 21 countries in the Americas and affects about 5 and 6 million people, causing 7,000 deaths annually. With regard to leishmaniasis, it is present in 98 countries of all continents, causing about 40,000 deaths annually. During its life cycle, T. cruzi and Leishmania spp acquire different development forms depending on the medium where they are. T. cruzi presents three stages: The trypomastigote form, highly infective for the mammalian host, epimastigote form, which is the replicative form in the insect vector and amastigote form, which is the reproductive form in mammalian cells. The genus Leishmania presents two evolutionary forms, the promastigote form, which is the infective form for humans and the amastigote form, which is the replicative form in mammalian cells. Regarding the treatment of CD and Leishmaniasis, despite its high prevalence and that they were discovered many years ago, there is still no fully an effective treatment from an activity, safety and cost point of view. In CD, only two drugs, Nifurtimox and Benznidazole, have an accepted clinical use. Both drugs have important limitations such as the multiple adverse reactions, their lower efficacy in the chronic phase of the disease, the complicated dosage, the long duration of the treatment and the resistant strains. With regard to leishmaniasis, the variety of available treatments is much wider than for CD. These treatments have a high efficacy, however, they have important limitations such as toxicity, adverse effects, high cost, the development of resistance, the long periods of treatment, the administration route and the need for hospitalization. Taking into account this situation of necessity in the acquisition and identification of new trypanocidal and leishmanicidal agents, after an extensive bibliographic review and considering the experience of the research group, a molecule repositioning strategy was applied as a starting point for the design of the presented arylaminoketone Mannich bases type derivatives. Sixty-two new derivatives were synthesized using two one-step and economically efficient synthetic methods. Fifty-eight were obtained by the Mannich reaction and four by an aliphatic nucleophilic substitution. The family of Mannich bases derivatives that has been published has shown great potential for the development of new agents against CD and Leishmaniasis. Compounds with excellent in vitro efficacy results have been identified against both kinetoplastids, with very low cytotoxicity against mammalian cells, a non-genotoxic profile and non-mutagenic. The leading compounds had a high in vivo activity against T. cruzi in the acute phase. In addition, no reactivation of parasitemia was observed in a immunosuppression murine model and they were very effectively in the presence prevention of the parasite in the target organs. In addition, the identified lead compounds had a high bioavailability. Because of this results we propose these compounds as a very promising molecules to continue their preclinical development as possible anti- kinetoplastids agentst.

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