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Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus

Bovine viral diarrhea virus (BVDV) belongs to the Pestivirus genus (Flaviviridae). In spite of the availability of vaccines, the virus is still causing substantial financial losses to the livestock industry. In this context, the use of antiviral agents could be an alternative strategy to control and...

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Autores principales: Fernández, Gabriela A., Castro, Eliana F., Rosas, Rocío A., Fidalgo, Daniela M., Adler, Natalia S., Battini, Leandro, España de Marco, Maria J., Fabiani, Matias, Bruno, Ana M., Bollini, Mariela, Cavallaro, Lucia V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793975/
https://www.ncbi.nlm.nih.gov/pubmed/33425849
http://dx.doi.org/10.3389/fchem.2020.590235
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author Fernández, Gabriela A.
Castro, Eliana F.
Rosas, Rocío A.
Fidalgo, Daniela M.
Adler, Natalia S.
Battini, Leandro
España de Marco, Maria J.
Fabiani, Matias
Bruno, Ana M.
Bollini, Mariela
Cavallaro, Lucia V.
author_facet Fernández, Gabriela A.
Castro, Eliana F.
Rosas, Rocío A.
Fidalgo, Daniela M.
Adler, Natalia S.
Battini, Leandro
España de Marco, Maria J.
Fabiani, Matias
Bruno, Ana M.
Bollini, Mariela
Cavallaro, Lucia V.
author_sort Fernández, Gabriela A.
collection PubMed
description Bovine viral diarrhea virus (BVDV) belongs to the Pestivirus genus (Flaviviridae). In spite of the availability of vaccines, the virus is still causing substantial financial losses to the livestock industry. In this context, the use of antiviral agents could be an alternative strategy to control and reduce viral infections. The viral RNA-dependent RNA polymerase (RdRp) is essential for the replication of the viral genome and constitutes an attractive target for the identification of antiviral compounds. In a previous work, we have identified potential molecules that dock into an allosteric binding pocket of BVDV RdRp via a structure-based virtual screening approach. One of them, N-(2-morpholinoethyl)-2-phenylquinazolin-4-amine [1, 50% effective concentration (EC(50)) = 9.7 ± 0.5 μM], was selected to perform different chemical modifications. Among 24 derivatives synthesized, eight of them showed considerable antiviral activity. Molecular modeling of the most active compounds showed that they bind to a pocket located in the fingers and thumb domains in BVDV RdRp, which is different from that identified for other non-nucleoside inhibitors (NNIs) such as thiosemicarbazone (TSC). We selected compound 2-[4-(2-phenylquinazolin-4-yl)piperazin-1-yl]ethanol (1.9; EC(50) = 1.7 ± 0.4 μM) for further analysis. Compound 1.9 was found to inhibit the in vitro replication of TSC-resistant BVDV variants, which carry the N264D mutation in the RdRp. In addition, 1.9 presented adequate solubility in different media and a high-stability profile in murine and bovine plasma.
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spelling pubmed-77939752021-01-09 Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus Fernández, Gabriela A. Castro, Eliana F. Rosas, Rocío A. Fidalgo, Daniela M. Adler, Natalia S. Battini, Leandro España de Marco, Maria J. Fabiani, Matias Bruno, Ana M. Bollini, Mariela Cavallaro, Lucia V. Front Chem Chemistry Bovine viral diarrhea virus (BVDV) belongs to the Pestivirus genus (Flaviviridae). In spite of the availability of vaccines, the virus is still causing substantial financial losses to the livestock industry. In this context, the use of antiviral agents could be an alternative strategy to control and reduce viral infections. The viral RNA-dependent RNA polymerase (RdRp) is essential for the replication of the viral genome and constitutes an attractive target for the identification of antiviral compounds. In a previous work, we have identified potential molecules that dock into an allosteric binding pocket of BVDV RdRp via a structure-based virtual screening approach. One of them, N-(2-morpholinoethyl)-2-phenylquinazolin-4-amine [1, 50% effective concentration (EC(50)) = 9.7 ± 0.5 μM], was selected to perform different chemical modifications. Among 24 derivatives synthesized, eight of them showed considerable antiviral activity. Molecular modeling of the most active compounds showed that they bind to a pocket located in the fingers and thumb domains in BVDV RdRp, which is different from that identified for other non-nucleoside inhibitors (NNIs) such as thiosemicarbazone (TSC). We selected compound 2-[4-(2-phenylquinazolin-4-yl)piperazin-1-yl]ethanol (1.9; EC(50) = 1.7 ± 0.4 μM) for further analysis. Compound 1.9 was found to inhibit the in vitro replication of TSC-resistant BVDV variants, which carry the N264D mutation in the RdRp. In addition, 1.9 presented adequate solubility in different media and a high-stability profile in murine and bovine plasma. Frontiers Media S.A. 2020-12-10 /pmc/articles/PMC7793975/ /pubmed/33425849 http://dx.doi.org/10.3389/fchem.2020.590235 Text en Copyright © 2020 Fernández, Castro, Rosas, Fidalgo, Adler, Battini, España de Marco, Fabiani, Bruno, Bollini and Cavallaro. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Fernández, Gabriela A.
Castro, Eliana F.
Rosas, Rocío A.
Fidalgo, Daniela M.
Adler, Natalia S.
Battini, Leandro
España de Marco, Maria J.
Fabiani, Matias
Bruno, Ana M.
Bollini, Mariela
Cavallaro, Lucia V.
Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus
title Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus
title_full Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus
title_fullStr Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus
title_full_unstemmed Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus
title_short Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus
title_sort design and optimization of quinazoline derivatives: new non-nucleoside inhibitors of bovine viral diarrhea virus
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793975/
https://www.ncbi.nlm.nih.gov/pubmed/33425849
http://dx.doi.org/10.3389/fchem.2020.590235
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