2. Academic Validation
  3. Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus

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

  • Front Chem. 2020 Dec 10;8:590235. doi: 10.3389/fchem.2020.590235.
Gabriela A Fernández 1,  Eliana F Castro 2 3,  Rocío A Rosas 4 5,  Daniela M Fidalgo 1,  Natalia S Adler 1,  Leandro Battini 1,  Maria J España de Marco 3,  Matias Fabiani 4 5,  Ana M Bruno 6,  Mariela Bollini 1,  Lucia V Cavallaro 4
Affiliations

Affiliations

  • 1 Laboratorio de Química Medicinal, Centro de Investigaciones en Bionanociencias (CIBION)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
  • 2 Centro de Investigaciones en Ciencias Veterinarias y Agronómicas, Instituto de Virología e Innovaciones Tecnológicas, Instituto Nacional de Tecnología Agropecuaria, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
  • 3 Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • 4 Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra Virología, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Universidad de Buenos Aires, Buenos Aires, Argentina.
  • 5 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
  • 6 Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
PMID: 33425849 DOI: 10.3389/fchem.2020.590235
Abstract

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.

Keywords

BVDV inhibitors; RdRp protein; molecular dynamics; pharmacokinetics in vitro properties; quinazoline derivatives.

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