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
  • 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: [email protected].
  • 3. BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA. Electronic address: [email protected].
  • 4. BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA. Electronic address: [email protected].
  • 5. BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center, Building 200, Suite 200, Birmingham, Alabama 35244, USA. Electronic address: [email protected].
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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