2. Academic Validation
  3. Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents

Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents

  • Bioorg Med Chem. 2019 Mar 1;27(5):748-759. doi: 10.1016/j.bmc.2019.01.007.
Shuang Guo 1,  Mingshuo Xu 1,  Qi Guo 1,  Fuqiang Zhu 2,  Xiangrui Jiang 3,  Yuanchao Xie 4,  Jingshan Shen 1
Affiliations

Affiliations

  • 1 CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 2 Topharman Shanghai Co., Ltd, No. 388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201203, China.
  • 3 CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 4 CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: xieyuanchao@simm.ac.cn.
PMID: 30683552 DOI: 10.1016/j.bmc.2019.01.007
Abstract

To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a-8c with similar EC50 values (0.20-0.22 μM) comparative to that of sofosbuvir (EC50 = 0.18 μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the Other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50 = 7.3 μM) and S-29b (EC50 = 19.5 μM). This kind of nucleosides were interesting and would open a new avenue for the development of Antiviral agents.

Keywords

Anti-HCV; Double prodrug; Nucleoside; Phosphoramidate; Pyrazine.

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