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

Gabriela A Fernández,Eliana F Castro,Lucia V Cavallaro,Leandro Battini,Natalia S Adler,Mariela Bollini,Maria J España De Marco,Daniela M Fidalgo,Ana M Bruno,Rocío A Rosas,Matias Fabiani

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.

Highlights

Bovine viral diarrhea virus 1 (BVDV) (Pestivirus A) belongs to the Pestivirus genus of the Flaviviridae family (Smith et al, 2017)
A negative-strand RNA is synthesized from a positive-strand RNA genome, resulting in dsRNA intermediates from which numerous positive strands are produced for progeny viruses (Choi et al, 2006)
Compound 4g was synthesized by reaction between 2-amino-4-chlorobenzoic acid (6) and formamide under reflux, followed by recrystallization from acetonitrile to give a product with an 80% yield

Summary

Introduction

Bovine viral diarrhea virus 1 (BVDV) (Pestivirus A) belongs to the Pestivirus genus of the Flaviviridae family (Smith et al, 2017). NIs are widely used to treat hepatitis B virus (HBV), hepatitis C virus (HCV), HIV-1, and herpesvirus infections They act by competing with nucleotide substrates for binding to the active site of the polymerase and induce termination of the nucleic acid chain synthesis (Finkielsztein et al, 2010). NNIs are highly specific and act allosterically by inhibiting the enzymatic activity of the polymerase This group includes a series of very diverse chemical structures, such as N-propyl-N-[2-(2H-1,2,4triazino[5,6-b]indol-3-ylthio)ethyl]-1-propanamine (VP32947) (Baginski et al, 2000), bromophenyl-imidazo-pyridines (BPIP) (Paeshuyse et al, 2007), ethyl 2-methylimidazo[1,2a]pyrrolo[2,3-c]pyridin-8-carboxylate (AG110) (Paeshuyse et al, 2007), pyrazolo-triazolo-pyrimidinamine (LZ37) (Paeshuyse et al, 2009), 2-(2-benzimidazolyl)-5-[4-(2imidazolino)phenyl]furan (DB772) (Newcomer et al, 2012), 5,6-dimethoxy-1-indanone [thiosemicarbazone (TSC)] (Castro et al, 2011; Soraires Santacruz et al, 2017), 2phenylbenzimidazole (Tonelli et al, 2010), and arylazoenamine derivatives (Giliberti et al, 2010)

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