Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease

Chagas disease is considered a neglected tropical disease that continues to endanger millions of people around the world. The current chemotherapy presents some disadvantages such as variable antiparasitic activity, undesired side effects and/or long treatment duration. Therefore, the development of...

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Autor: Paucar, R. (Rocío)|||/items/048f307d-a4a7-451f-96e6-ac555ae2a9a1
Tipo de recurso: tesis doctoral
Fecha de publicación:2019
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:español
OAI Identifier:oai:dadun.unav.edu:10171/57977
Acceso en línea:https://hdl.handle.net/10171/57977
Access Level:acceso abierto
Palabra clave:Materias Investigacion::Química
Diseño, síntesis y estudio de nuevos fármacos
Materias Investigacion::Farmacia::Farmacia y farmacología
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spelling Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas diseaseDiseño, síntesis y evaluación biológica de nuevos derivados para el tratamiento de la enfermedad de ChagasPaucar, R. (Rocío)|||/items/048f307d-a4a7-451f-96e6-ac555ae2a9a1Materias Investigacion::QuímicaDiseño, síntesis y estudio de nuevos fármacosMaterias Investigacion::Farmacia::Farmacia y farmacologíaChagas disease is considered a neglected tropical disease that continues to endanger millions of people around the world. The current chemotherapy presents some disadvantages such as variable antiparasitic activity, undesired side effects and/or long treatment duration. Therefore, the development of new drugs is mandatory. Several studies suggest the Mannich base derivatives as an attractive scaffold for new antiparasitic agents. Our research group has developed new Mannich bases with promising antichagasic activity. In this context, we have designed and synthesized forty-five Mannich bases to be tested against the T. cruzi parasite. The structural modifications made for the design of new derivatives have been made in order to obtain more effective and less toxic potential candidates to combat this parasitic disease. The novel Mannich bases containing the ferrocenyl, phenethylamines, anilines or piperazines groups, among others, have been tested against three different T. cruzi strains and forms. The cytotoxicity on Vero cells was also evaluated to determine their selectivity index. According to potency and SI, the most promising compounds were selected to evaluate the genotoxicity capacity via SOS/umu-test. Once demonstrated that these compounds are non-genotoxic, two compounds were selected for in vivo study in BALB/c mice. After the in vivo test, the non-mutagenic capacity of the compound with the most promising antichagasic profile was evaluated by the Ames test. On the other hand, the possible mechanism of action of these compounds was studied through the alteration of excreted metabolites by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase. Finally, computational studies were executed to propose the binding mode of the studied compounds to iron superoxide dismutase enzyme. The results obtained will allow us to promote further preclinical studies of the most promising compounds.Pérez-Silanes, S. (Silvia)Moreno-de-Viguri, E. (Elsa)Dadun. Depósito Académico Digital Universidad de Navarra20192019-07-1220192019-07-1220192019-07-1220192019-06-03doctoral thesishttp://purl.org/coar/resource_type/c_db06info:eu-repo/semantics/doctoralThesisapplication/pdfhttps://hdl.handle.net/10171/57977reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraEspañolspaopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/579772026-06-21T12:47:57Z
dc.title.none.fl_str_mv Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
Diseño, síntesis y evaluación biológica de nuevos derivados para el tratamiento de la enfermedad de Chagas
title Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
spellingShingle Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
Paucar, R. (Rocío)|||/items/048f307d-a4a7-451f-96e6-ac555ae2a9a1
Materias Investigacion::Química
Diseño, síntesis y estudio de nuevos fármacos
Materias Investigacion::Farmacia::Farmacia y farmacología
title_short Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
title_full Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
title_fullStr Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
title_full_unstemmed Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
title_sort Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease
dc.creator.none.fl_str_mv Paucar, R. (Rocío)|||/items/048f307d-a4a7-451f-96e6-ac555ae2a9a1
author Paucar, R. (Rocío)|||/items/048f307d-a4a7-451f-96e6-ac555ae2a9a1
author_facet Paucar, R. (Rocío)|||/items/048f307d-a4a7-451f-96e6-ac555ae2a9a1
author_role author
dc.contributor.none.fl_str_mv Pérez-Silanes, S. (Silvia)
Moreno-de-Viguri, E. (Elsa)
Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv Materias Investigacion::Química
Diseño, síntesis y estudio de nuevos fármacos
Materias Investigacion::Farmacia::Farmacia y farmacología
topic Materias Investigacion::Química
Diseño, síntesis y estudio de nuevos fármacos
Materias Investigacion::Farmacia::Farmacia y farmacología
description Chagas disease is considered a neglected tropical disease that continues to endanger millions of people around the world. The current chemotherapy presents some disadvantages such as variable antiparasitic activity, undesired side effects and/or long treatment duration. Therefore, the development of new drugs is mandatory. Several studies suggest the Mannich base derivatives as an attractive scaffold for new antiparasitic agents. Our research group has developed new Mannich bases with promising antichagasic activity. In this context, we have designed and synthesized forty-five Mannich bases to be tested against the T. cruzi parasite. The structural modifications made for the design of new derivatives have been made in order to obtain more effective and less toxic potential candidates to combat this parasitic disease. The novel Mannich bases containing the ferrocenyl, phenethylamines, anilines or piperazines groups, among others, have been tested against three different T. cruzi strains and forms. The cytotoxicity on Vero cells was also evaluated to determine their selectivity index. According to potency and SI, the most promising compounds were selected to evaluate the genotoxicity capacity via SOS/umu-test. Once demonstrated that these compounds are non-genotoxic, two compounds were selected for in vivo study in BALB/c mice. After the in vivo test, the non-mutagenic capacity of the compound with the most promising antichagasic profile was evaluated by the Ames test. On the other hand, the possible mechanism of action of these compounds was studied through the alteration of excreted metabolites by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase. Finally, computational studies were executed to propose the binding mode of the studied compounds to iron superoxide dismutase enzyme. The results obtained will allow us to promote further preclinical studies of the most promising compounds.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-07-12
2019
2019-07-12
2019
2019-07-12
2019
2019-06-03
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://hdl.handle.net/10171/57977
url https://hdl.handle.net/10171/57977
dc.language.none.fl_str_mv Español
spa
language_invalid_str_mv Español
language spa
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra
instname:Universidad de Navarra
instname_str Universidad de Navarra
reponame_str Dadun. Depósito Académico Digital de la Universidad de Navarra
collection Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
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