Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents. Issue 5 (1st March 2019)

• Record Type: Journal Article
• Authors: Guo, Shuang; Xu, Mingshuo; Guo, Qi; Zhu, Fuqiang; Jiang, Xiangrui; Xie, Yuanchao; Shen, Jingshan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 5(2019)
• Page Start: 748
• Page End: 759
• Publication Date: 2019-03-01
• Subjects: Nucleoside -- Double prodrug -- Phosphoramidate -- Anti-HCV -- Pyrazine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.01.007
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 as4e and8a –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(1 H )-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as25e (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.