Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus

Debin Zeng; Rui Zhang; Quandeng Nie; Lin Cao; Luqing Shang; Zheng Yin

doi:10.1021/acsmedchemlett.6b00270

Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus

ACS Med Chem Lett. 2016 Oct 19;7(12):1197-1201. doi: 10.1021/acsmedchemlett.6b00270. eCollection 2016 Dec 8.

Authors

Debin Zeng¹, Rui Zhang¹, Quandeng Nie¹, Lin Cao¹, Luqing Shang¹, Zheng Yin¹

Affiliation

¹ State Key Laboratory of Elemento-Organic Chemistry, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China.

Abstract

2'-α-C-Methyl-2'-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC₅₀ values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2'-β-F by Arg158, 3'-OH by N291, and the Watson-Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.

Keywords: Hint 1; docking; hepatitis C virus; inhibitor; phosphoramidate prodrugs.