Artículo
Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus
Fernandez, Gabriela Araceli
; Castro, Eliana Florencia
; Rosas, Rocio Ayelen
; Fidalgo, Daniela Marina
; Adler, Natalia Sol
; Battini, Leandro
; España de Marco, Maria Jose
; Fabiani, Matias
; Bruno, Ana María; Bollini, Mariela
; Cavallaro, Lucia Vicenta
Fecha de publicación:
12/2020
Editorial:
Frontiers Media
Revista:
Frontiers in Chemistry
ISSN:
2296-2646
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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 (EC50) = 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; EC50 = 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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Articulos (IVIT)
Articulos de INSTITUTO DE VIROLOGIA E INNOVACIONES TECNOLOGICAS
Articulos de INSTITUTO DE VIROLOGIA E INNOVACIONES TECNOLOGICAS
Articulos(CIBION)
Articulos de CENTRO DE INVESTIGACIONES EN BIONANOCIENCIAS "ELIZABETH JARES ERIJMAN"
Articulos de CENTRO DE INVESTIGACIONES EN BIONANOCIENCIAS "ELIZABETH JARES ERIJMAN"
Citación
Fernandez, Gabriela Araceli; Castro, Eliana Florencia; Rosas, Rocio Ayelen; Fidalgo, Daniela Marina; Adler, Natalia Sol; et al.; Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus; Frontiers Media; Frontiers in Chemistry; 8; 12-2020; 1-14
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