Tesis doctoral de Enrique Torres Pastor
Chagas disease, a chronic parasitosis caused by the protozoan trypanosoma cruzi, is considered a neglected tropical disease and it is endemic in 21 countries located on the american continent. It affects more than seven million people causing approximatelly 12500 deaths per year. Since the 1960s, only two drugs, nifurtimox and benznidazol, have been commercialized for use in the treatment of this disease. Both drugs have a number of limitations, including low activity in the chronic phase of the disease and toxicity. Therefore, the objective of this study is the search for new drugs to be used in the treatment of chagas disease, with said drugs having a central structure of quinoxaline 1,4-di-n-oxide due to the fact that this molecule has shown interesting in vitro activities against different neglected diseases. In the beginning of this study, all the in vitro activity results that our research team had obtained during the past decade were reviewed. After studying the corresponding structure-activity relationships made it possible to establish the working hypothesis that proposes the quinoxaline 1,4-di-n-oxide derivatives with a carbonyl group in position 2 and a trifluoromethyl group in position 3 of the quinoxaline ring as potential antichagasic agents. Based on this hypothesis, fifty-seven new quinoxaline derivatives were designed and synthesized by means various synthetic routes. A new microwave assisted synthesis method was optimized, greatly increasing the yields and significantly reducing the reaction times that had been previously obtained by our research team. Over 90% of the new derivatives exhibited an ic50 value against tulahuen 2 strain of t. Cruzi which was lower than the ic50 value shown by nifurtimox, thereby confirming the proposed working hypothesis. In addition, the new derivatives exhibited high in vitro activities against different parasite forms of another t. Cruzi strains. The study of the cytotoxicity against mammalian cells, mutagenicity and a preliminary in vivo assessment allowed us to identify interesting compounds against t. Cruzi. In order to perform an approximation to the mechanism through which the derivatives carry out their activity, an electrochemical study and a biological study were conducted. These studies suggested possible activation by means of a bio-reduction process of the n-oxide groups and inhibitory activity against mitochondrial dehydrogenases.
Datos académicos de la tesis doctoral «Diseño, síntesis y evaluación biológica de nuevos derivados de 1,4-di-n óxido de quinoxalina como potenciales agentes antichagásicos«
- Título de la tesis: Diseño, síntesis y evaluación biológica de nuevos derivados de 1,4-di-n óxido de quinoxalina como potenciales agentes antichagásicos
- Autor: Enrique Torres Pastor
- Universidad: Navarra
- Fecha de lectura de la tesis: 24/05/2013
Dirección y tribunal
- Director de la tesis
- Ignacio Aldana Moraza
- Tribunal
- Presidente del tribunal: Antonio Monge vega
- félix Calderón romo (vocal)
- Andrés Jaso amadoz (vocal)
- María yolanda Sáinz sánchez (vocal)