2. Academic Validation
  3. Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly

Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly

  • Eur J Med Chem. 2023 Nov 5;259:115634. doi: 10.1016/j.ejmech.2023.115634.
Nicky Hwang 1,  Shuo Wu 1,  Haiqun Ban 2,  Huixin Luo 1,  Julia Ma 1,  Junjun Cheng 1,  Qiong Zhao 1,  Jessilyn A Laney 3,  Na Du 4,  Junyang Guo 4,  Manasa Suresh 5,  Liangxian Shen 1,  Gideon Tolufashe 1,  Usha Viswanathan 1,  John Kulp 1,  Patrick Lam 1,  Jinhong Chang 1,  Jason A Clement 1,  Stephan Menne 5,  Ju-Tao Guo 6,  Yanming Du 7
Affiliations

Affiliations

  • 1 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA.
  • 2 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA; Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Pudong New District, Shanghai, 200127, China.
  • 3 United States Naval Academy, 121 Blake Rd, Annapolis, MD, 21402, USA.
  • 4 Pharmaron, 6 Taihe Road, BDA, Beijing, 100176, China.
  • 5 Georgetown University Medical Center, 3900 Reservoir Road, Washington, DC, 20057, USA.
  • 6 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA. Electronic address: ju-tao.guo@bblumberg.org.
  • 7 Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA. Electronic address: yanming.du@bblumberg.org.
PMID: 37499290 DOI: 10.1016/j.ejmech.2023.115634
Abstract

A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is β, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved Antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC50 values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes.

Keywords

1,2,3,4-Tetrahydroquinoxaline; Capsid assembly; Hepatitis B virus; Phenyl ureas.

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