Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV

Bovine viral diarrhea virus (BVDV) is a major pathogen of cattle with a great economic impact. The identification of antivirals for the treatment of BVDV infections and outbreak control is relevant. After drug-modulation of 5,6-TSC, a compound previously identified as a non-nucleoside inhibitor (NNI...

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Autor principal: Fabiani, Matias
Otros Autores: Castro, Eliana
Formato: Tesis doctoral acceptedVersion
Lenguaje:Español
Publicado: Facultad de Farmacia y Bioquímica 2020
Materias:
BVDV
Tiosemicarbozonas
N4-ariltiosemicarbazonas
1-indanona
Ciencias de la vida
Acceso en línea:http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_6335
http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6335.dir/6335.PDF
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Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires
id I28-R145-HWA_6335
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spelling I28-R145-HWA_63352023-04-20 Bovine viral diarrhea virus (BVDV) is a major pathogen of cattle with a great economic impact. The identification of antivirals for the treatment of BVDV infections and outbreak control is relevant. After drug-modulation of 5,6-TSC, a compound previously identified as a non-nucleoside inhibitor (NNI) of BVDV RNA-polymerase (RdRp), a series of thiosemicarbazones (TSC) and N4-arylthiosemicarbazones derived from 1-indanones was synthesized. Two compounds with higher anti-BVDV activity were identified: N4-(p-nitrophenyl)-TSC derived from 5,6-dimethoxy-1-indanone (N4-TSC) and TSC derived from 6-nitro-1-indanone (6NO2-TSC), which were active against BVDV strains from different genotypes and biotypes and inactive against other RNA viruses. It was demonstrated that these compounds act in intermediate stages of the viral replication cycle. Particularly, N4-TSC acts by blocking viral RNA synthesis, and by means of BVDV resistance selection (N4-TSCR), viral RdRp was identified as the molecular target. Docking and molecular dynamics studies showed that the mutations N264D and A392E, found in N4-TSCR viruses, alter the interactions of N4-TSC with RdRp and are responsible for antiviral resistance. Fil: Fabiani, Matias. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina Castro, Eliana Facultad de Farmacia y Bioquímica Cavallaro, Lucía Fabiani, Matias 2020-04-21 El virus de la diarrea viral bovina (BVDV) es un patógeno importante del ganado bovino de gran impacto económico, por lo que la identificación de antivirales para el tratamiento de las infecciones y control de los brotes por BVDV resulta de interés. Mediante fármaco-modulación de 5,6-TSC, un compuesto previamente identificado como un inhibidor no nucleosídico (INN) de la ARN-polimerasa (RdRp) de BVDV, se sintetizaron una serie de tiosemicarbazonas (TSC) y N4-ariltiosemicarbazonas derivadas de 1-indanonas. A partir de esto, en este trabajo de tesis se identificaron dos compuestos con mayor actividad anti-BVDV: N4-(p-nitrofenil)-TSC derivada de la 5,6-dimetoxi-1-indanona (N4-TSC) y la TSC derivada de 6-nitro-1-indanona (6NO2-TSC), que fueron activos frente a BVDV de distintos genotipos y biotipos e inactivos frente a otros ARN virus. Se demostró que estos compuestos actúan en etapas intermedias del ciclo de replicación viral. Particularmente, N4-TSC actúa inhibiendo la síntesis del ARN viral, y mediante la selección de BVDV resistentes (N4-TSCR) se identificó a la RdRp como el blanco de acción. Mediante estudios de docking y dinámica molecular se demostró que las mutaciones encontradas en N4-TSCR (N264D y A392E) alteran la interacción de N4-TSC con RdRp y son responsables de la resistencia antiviral. application/pdf Fernández, Marisa Garcáa, Cybele Álvarez, Diego BVDV Tiosemicarbozonas N4-ariltiosemicarbazonas 1-indanona spa Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Ciencias de la vida Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV info:eu-repo/semantics/doctoralThesis info:ar-repo/semantics/tesis doctoral info:eu-repo/semantics/acceptedVersion http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_6335 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6335.dir/6335.PDF
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-145
collection Repositorio Digital de la Universidad de Buenos Aires (UBA)
language Español
orig_language_str_mv spa
topic BVDV
Tiosemicarbozonas
N4-ariltiosemicarbazonas
1-indanona
Ciencias de la vida
spellingShingle BVDV
Tiosemicarbozonas
N4-ariltiosemicarbazonas
1-indanona
Ciencias de la vida
Fabiani, Matias
Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV
topic_facet BVDV
Tiosemicarbozonas
N4-ariltiosemicarbazonas
1-indanona
Ciencias de la vida
description Bovine viral diarrhea virus (BVDV) is a major pathogen of cattle with a great economic impact. The identification of antivirals for the treatment of BVDV infections and outbreak control is relevant. After drug-modulation of 5,6-TSC, a compound previously identified as a non-nucleoside inhibitor (NNI) of BVDV RNA-polymerase (RdRp), a series of thiosemicarbazones (TSC) and N4-arylthiosemicarbazones derived from 1-indanones was synthesized. Two compounds with higher anti-BVDV activity were identified: N4-(p-nitrophenyl)-TSC derived from 5,6-dimethoxy-1-indanone (N4-TSC) and TSC derived from 6-nitro-1-indanone (6NO2-TSC), which were active against BVDV strains from different genotypes and biotypes and inactive against other RNA viruses. It was demonstrated that these compounds act in intermediate stages of the viral replication cycle. Particularly, N4-TSC acts by blocking viral RNA synthesis, and by means of BVDV resistance selection (N4-TSCR), viral RdRp was identified as the molecular target. Docking and molecular dynamics studies showed that the mutations N264D and A392E, found in N4-TSCR viruses, alter the interactions of N4-TSC with RdRp and are responsible for antiviral resistance.
author2 Castro, Eliana
author_facet Castro, Eliana
Fabiani, Matias
format Tesis doctoral
Tesis doctoral
acceptedVersion
author Fabiani, Matias
author_sort Fabiani, Matias
title Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV
title_short Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV
title_full Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV
title_fullStr Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV
title_full_unstemmed Actividad antiviral de tiosemicarbazonas y N4-ariltiosemicarbazonas derivadas de 1-indanonas frente a BVDV
title_sort actividad antiviral de tiosemicarbazonas y n4-ariltiosemicarbazonas derivadas de 1-indanonas frente a bvdv
publisher Facultad de Farmacia y Bioquímica
publishDate 2020
url http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_6335
http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6335.dir/6335.PDF
work_keys_str_mv AT fabianimatias actividadantiviraldetiosemicarbazonasyn4ariltiosemicarbazonasderivadasde1indanonasfrenteabvdv
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