2. Academic Validation
  3. Synthesis and biological evaluation of Ribo 7-N/O/S pyrimidine 9-deaza C-nucleoside analogs as new antiviral agents for inhibiting HCV RNA-dependent RNA polymerases

Synthesis and biological evaluation of Ribo 7-N/O/S pyrimidine 9-deaza C-nucleoside analogs as new antiviral agents for inhibiting HCV RNA-dependent RNA polymerases

  • Eur J Med Chem. 2024 Jan 15:264:115991. doi: 10.1016/j.ejmech.2023.115991.
Minwan Wu 1,  Satish Vadlakonda 1,  Yahya El-Kattan 1,  Ajit Ghosh 2,  Tsu-Hsing Lin 1,  Ramanda Chambers-Wilson 1,  Xiaogang Cheng 1,  Shanta Bantia 3,  Debra Kellogg-Yelder 1,  Pooran Chand 4,  Y S Babu 1,  Pravin L Kotian 5
Affiliations

Affiliations

  • 1 BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA.
  • 2 BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA. Electronic address: ghoshajit1981@gmail.com.
  • 3 BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA. Electronic address: sbantia@nitortherapeutics.com.
  • 4 BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA. Electronic address: pchand@therachemlab.com.
  • 5 BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA. Electronic address: pkotian@biocryst.com.
PMID: 38118393 DOI: 10.1016/j.ejmech.2023.115991
Abstract

Hepatitis C Infection is caused by the bloodborne pathogen hepatitis C virus (HCV) and can lead to serious liver diseases and, ultimately, death if the treatment is ineffective. This work reports the synthesis and preclinical evaluation of 7 novel 9-O/N/S pyrimidine nucleosides, including compound 12, the triphosphate of known compound 7b. The nucleosides are 9-deaza modifications of adenosine and guanosine with β-2'-C-methyl substituent on the ribose. Within this series of compounds, a 9-deaza furopyrimidine analog of adenosine, compound 7b, showed high anti-HCV activity in vitro, good stability, low toxicity, and low genotoxicity when administrated in low doses, and an adequate pharmacokinetics profile. An improved synthesis of compound 7b compared to a previous study is also reported. Compound 12 was synthesized as a control to verify phosphorylation of 7b occurred in vivo.

Keywords

Antiviral; C-Nucleoside; Furopyrimidine; HCV; RNA polymerase.

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