Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii

Conventional treatment for toxoplasmosis is a mix of pyrimethamine and sulfadiazine but this chemotherapy has severe side effects. Recent findings on the biological activity of the 4 thiazolidinones and taking into account the lack of effective medications used in the treatment of toxoplasmosis, in...

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Autores:
Molina Lara, Diego Alejandro
Tipo de recurso:
Doctoral thesis
Fecha de publicación:
2020
Institución:
Universidad del Quindío
Repositorio:
Repositorio Universidad del Quindío
Idioma:
spa
OAI Identifier:
oai:bdigital.uniquindio.edu.co:001/5687
Acceso en línea:
https://bdigital.uniquindio.edu.co/handle/001/5687
Palabra clave:
TD50: Dosis toxica
TI: Índice terapéutico
IC50: Concentración de inhibición del 50 % de la viabilidad
RON: Proteínas del cuello de las roptrias
Rights
openAccess
License
Derechos Reservados - Universidad del Quindio
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dc.title.spa.fl_str_mv Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
title Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
spellingShingle Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
TD50: Dosis toxica
TI: Índice terapéutico
IC50: Concentración de inhibición del 50 % de la viabilidad
RON: Proteínas del cuello de las roptrias
title_short Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
title_full Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
title_fullStr Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
title_full_unstemmed Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
title_sort Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondii
dc.creator.fl_str_mv Molina Lara, Diego Alejandro
dc.contributor.advisor.spa.fl_str_mv Universidad del Quindío - Colombia - Director - Jorge Enrique Gómez Marín
Universidad del Quindío - Colombia - Comité Tutorial - Dr. Edwar Cortés
Universidad del Quindío - Colombia - Comité Tutorial - Dr. Nelson Arenas
dc.contributor.author.spa.fl_str_mv Molina Lara, Diego Alejandro
dc.subject.proposal.spa.fl_str_mv TD50: Dosis toxica
TI: Índice terapéutico
IC50: Concentración de inhibición del 50 % de la viabilidad
RON: Proteínas del cuello de las roptrias
topic TD50: Dosis toxica
TI: Índice terapéutico
IC50: Concentración de inhibición del 50 % de la viabilidad
RON: Proteínas del cuello de las roptrias
description Conventional treatment for toxoplasmosis is a mix of pyrimethamine and sulfadiazine but this chemotherapy has severe side effects. Recent findings on the biological activity of the 4 thiazolidinones and taking into account the lack of effective medications used in the treatment of toxoplasmosis, in addition to the numerous side effects of pyrimethamine, led us to design and to synthesize new 5-aryliden 4- thiazolidinone and 2 hydrazono-4-thiazolidinone derivatives. In present work we first performed a bioinformatic analysis of molecular docking between thiazolidinones and protein kinase ROP18 and calmodulin of Toxoplasma gondii. Then, we evaluate the in vitro growth effect in T. gondii of 26 new compounds derived from 4- thiazolidinone was evaluated. To identify the growth rates of T.
publishDate 2020
dc.date.accessioned.spa.fl_str_mv 2020-06-25T21:17:22Z
dc.date.available.spa.fl_str_mv 2020-06-25T21:17:22Z
dc.date.issued.spa.fl_str_mv 2020-03-25
dc.type.spa.fl_str_mv Trabajo de grado - Doctorado
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dc.relation.references.spa.fl_str_mv Jasper S, Ss V, Ss J, Horo S, Yj S, Qd N. Corticosteroids as adjuvant therapy for ocular toxoplasmosis ( Review ). 2013;(4).
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CALGARY on November 19, 2012. For personal use only. No other uses without permission. Copyright © 1992 Massachusetts Medical Society. All rights reserved. 1992;
Dannemann B, Mccutchan JA, Israelski D, Antoniskis D, Leport C, Luft B, et al. Treatment of Toxoplasmic Encephalitis in Patients with AIDS A Randomized Trial Comparing Pyrimethamine plus Clindamycin to Pyrimethamine plus Sulfadiazine. 2017;116(1):33–43.
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spelling Universidad del Quindío - Colombia - Director - Jorge Enrique Gómez MarínUniversidad del Quindío - Colombia - Comité Tutorial - Dr. Edwar CortésUniversidad del Quindío - Colombia - Comité Tutorial - Dr. Nelson ArenasMolina Lara, Diego Alejandro2020-06-25T21:17:22Z2020-06-25T21:17:22Z2020-03-25https://bdigital.uniquindio.edu.co/handle/001/5687Conventional treatment for toxoplasmosis is a mix of pyrimethamine and sulfadiazine but this chemotherapy has severe side effects. Recent findings on the biological activity of the 4 thiazolidinones and taking into account the lack of effective medications used in the treatment of toxoplasmosis, in addition to the numerous side effects of pyrimethamine, led us to design and to synthesize new 5-aryliden 4- thiazolidinone and 2 hydrazono-4-thiazolidinone derivatives. In present work we first performed a bioinformatic analysis of molecular docking between thiazolidinones and protein kinase ROP18 and calmodulin of Toxoplasma gondii. Then, we evaluate the in vitro growth effect in T. gondii of 26 new compounds derived from 4- thiazolidinone was evaluated. To identify the growth rates of T.El tratamiento convencional para la toxoplasmosis es una mezcla entre pirimetamina y sulfadiazina, pero esta quimioterapia presenta efectos secundarios severos. Algunos hallazgos recientes sobre la actividad biológica de las 4 tiazolidinonas y la necesidad de medicamentos que controlen la infección por Toxoplasma gondii en humanos, nos llevó a diseñar y sintetizar nuevos derivados 5 ariliden 4-tiazolidinona y 2 hidrazono-4-tiazolidinonas. En este trabajo, realizamos inicialmente un análisis bioinformático de acoplamientos moleculares de las moléculas tiazolidinonas reportadas con altos índices terapéuticos con sitios activos de las proteínas quinasa ROP18 y la calmodulina de T. gondii. Luego, se evaluó el efecto en el crecimiento de Toxoplasma gondii in vitro de 26 nuevos compuestos derivados de 4- tiazolidinona. Para identificar las tasas de crecimiento de los taquizoitos de T.1. Resumen iv2. Introducción 13. Objetivos 64. Métodos 75 Resultados 206 Conclusiones 797 Perspectivas 808 Anexos 859 Bibliografía 109DoctoradoDoctor en Ciencias Biomédicasapplication/pdfspaDerechos Reservados - Universidad del Quindiohttps://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessAtribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)http://purl.org/coar/access_right/c_abf2Evaluación in vitro del efecto de nuevas Tiazolidinonas sobre la invasión y crecimiento del parásito Toxoplasma gondiiTrabajo de grado - Doctoradohttp://purl.org/coar/resource_type/c_db06info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/updatedVersionTexthttps://purl.org/redcol/resource_type/TDhttp://purl.org/coar/version/c_dc82b40f9837b551TD50: Dosis toxicaTI: Índice terapéuticoIC50: Concentración de inhibición del 50 % de la viabilidadRON: Proteínas del cuello de las roptriasJasper S, Ss V, Ss J, Horo S, Yj S, Qd N. Corticosteroids as adjuvant therapy for ocular toxoplasmosis ( Review ). 2013;(4).The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CALGARY on November 19, 2012. For personal use only. No other uses without permission. Copyright © 1992 Massachusetts Medical Society. All rights reserved. 1992;Dannemann B, Mccutchan JA, Israelski D, Antoniskis D, Leport C, Luft B, et al. Treatment of Toxoplasmic Encephalitis in Patients with AIDS A Randomized Trial Comparing Pyrimethamine plus Clindamycin to Pyrimethamine plus Sulfadiazine. 2017;116(1):33–43.Ciencias de la Salud - Doctorado en Ciencias BiomédicasPublicationTHUMBNAILTesis Diego Molina revisada JEG-OA Mayo 2020 (3).pdf.jpgTesis Diego Molina revisada JEG-OA Mayo 2020 (3).pdf.jpgGenerated Thumbnailimage/jpeg5769https://bdigital.uniquindio.edu.co/bitstreams/5f0deb3b-b87c-40a5-968c-6f33816587b3/download7368776b45446075478ba80fa837aa86MD562017.10.11 LICENCIA Y AUTORIZACIÓN.pdf.jpg2017.10.11 LICENCIA Y AUTORIZACIÓN.pdf.jpgGenerated Thumbnailimage/jpeg14491https://bdigital.uniquindio.edu.co/bitstreams/22114827-c760-446b-a01d-d7f4c9df1888/downloadfcc5e6be26d0404e8a6a2962012b1312MD57TEXTTesis Diego Molina revisada JEG-OA Mayo 2020 (3).pdf.txtTesis Diego Molina revisada JEG-OA Mayo 2020 (3).pdf.txtExtracted 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