Synthesis and biological evaluation of novel anti-hepatitis C virus (HCV) agents: 2-hydroxylphenethyl sulfanyl-oxopyrimidines
A novel series of dihydro-hydroxyl-phene-thylsulfanyl-ω-cyclohexyl/phenyl-oxopyrimidine derivatives have been synthesized and their in vitro anti-hepatitis C virus activities have been evaluated using Huh 7.5.1 cells. Some of the compounds showed moderate anti-hepatitis C virus activities, with EC50 range from 7.53 to 0.13 μM. Among all the compounds, 6-(cyclohexylmethyl)-5-ethyl-2-((2-hydroxy-2-phenylethyl)thio)-pyrimidin-4 (3H)-one (3a) had the most promising potential in inhibiting hepatitis C virus with an EC50 value of 0.13 μM and SI value of 121. It was noticed that some of these compounds are both active on hepatitis C virus and human immunodeficiency virus. In addition to experimental evaluation, structure-activity relationships and the molecular modeling analysis of these new congeners are also discussed.
KeywordsAnti-HCV activity Drug Discovery Pyrimidone HCV NS5B SAR
This research was supported by the National Natural Science Foundation of China (Grant No. 21262044 and 81260248).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Alexandra A, Peter K (2015) Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals. Ann Gastroenterol 28:55–65Google Scholar
- Ferenci P, Fried MW, Shiffman ML, Smith CL, Marinos G, GoncalesJr FL, Haussinger D, Daigo M, Carosi G, Dhumeaux D, Craxi A, Chaneac M, Reddy KR (2005) Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD)/ribavirin. J Hepatol 43:425–433CrossRefPubMedGoogle Scholar
- Ronald C, Thomas C, Gregory K, James W (1993) A safe, economical method of the preparation of β–oxo esters. Synthesis 3:290–292Google Scholar
- Summa V, Petrocchi A, Matassa VG, Taliani M, Laufer R, De Francesco R, Altamura S, Pace P (2004) HCV NS5b RNA-dependent RNA polymerase inhibitors: from α,γ-Diketoacids to 4,5-Dihydroxypyrimidine- or 3-Methyl-5- hydroxypyrimidinonecarboxylic acids. Design and synthesis. J Med Chem 47:5336–5339CrossRefPubMedGoogle Scholar
- Wu DC, Zhuang DM, Liu XF, Lu LH, Wang H, Li C, Lai CC, Li JY, He YP (2013) Synthesis and biological evaluation of novel hydroxyphenethyl-S-DACOs as high active anti-HIV agents. Lett Drug Des Discov 10:271–276Google Scholar