Novel 6-Aminoquinazolinone Derivatives as Potential Cross GT1-4 HCV NS5B Inhibitors

Tamer Nasr; Ahmed M Aboshanab; George Mpekoulis; Antonios Drakopoulos; Niki Vassilaki; Grigoris Zoidis; Khaled A M Abouzid; Wafaa Zaghary

doi:10.3390/v14122767

Novel 6-Aminoquinazolinone Derivatives as Potential Cross GT1-4 HCV NS5B Inhibitors

Viruses. 2022 Dec 12;14(12):2767. doi: 10.3390/v14122767.

Authors

Tamer Nasr^{1

2}, Ahmed M Aboshanab¹, George Mpekoulis³, Antonios Drakopoulos⁴, Niki Vassilaki³, Grigoris Zoidis⁵, Khaled A M Abouzid⁶, Wafaa Zaghary¹

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain-Helwan, Cairo 11795, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, MTI University, Cairo 12055, Egypt.
³ Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece.
⁴ Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Gothenburg, Sweden.
⁵ Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.

Abstract

Chronic hepatitis C virus (HCV) infections are a worldwide medical problem responsible for diverse types of liver diseases. The NS5B polymerase enzyme has become a very interesting target for the development of anti-HCV drugs owing to its fundamental role in viral replication. Here we report the synthesis of a novel series of 1-substituted phenyl-4(1H)-quinazolinone and 2-methyl-1-substituted phenyl-4(1H)-quinazolinone derivatives and evaluate their activity against HCV in HCV subgenomic replicon assays. The biological data revealed that compound 11a showed the highest activity against HCV GT1b at a micromolar concentration (EC₅₀ = 0.984 µM) followed by compound 11b (EC₅₀ = 1.38 µM). Both compounds 11a and 11b had high selectivity indices (SI = CC₅₀/EC₅₀), 160.71 and 71.75, respectively, which make them very interesting candidates for further development of more potent and selective anti-HCV agents.

Keywords: 6-Aminoquinazolinone; Anti HCV; Hepatitis C; NS5B inhibitors; daclatasvir; molecular docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents* / pharmacology
Enzyme Inhibitors* / pharmacology
Hepacivirus* / drug effects
Hepatitis C, Chronic
Humans
Quinazolinones / pharmacology
Structure-Activity Relationship
Viral Nonstructural Proteins
Virus Replication

Substances

Antiviral Agents
Enzyme Inhibitors
Quinazolinones
Viral Nonstructural Proteins

Grants and funding

G.Z. would like to thank the Special Account for Research Grants (Funding Number: 17454) and the National and Kapodistrian University of Athens for funding the APC of this publication.