Medicinal Chemistry Research

, Volume 26, Issue 7, pp 1388–1396 | Cite as

Synthesis and biological evaluation of novel anti-hepatitis C virus (HCV) agents: 2-hydroxylphenethyl sulfanyl-oxopyrimidines

  • Daochun Wu
  • Yue Feng
  • Hua Wang
  • Junfeng Yang
  • Xian Chen
  • Yueping Wang
  • Christopher Cong Lai
  • Yufang Zhang
  • Cong Li
  • Xueshan Xia
  • Yanping He
Original Research
  • 197 Downloads

Abstract

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.

Keywords

Anti-HCV activity Drug Discovery Pyrimidone HCV NS5B SAR 

Notes

Acknowledgements

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.

References

  1. 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
  2. Arataki K, Kumada H, Toyota K, Ohishi S, Takahashi S, Tazuma S, Chayama K (2006) Evolution of hepatitis C virus quasispecies during ribavirin and interferon-alpha-2b monotherapy. Intervirology 49:352–361CrossRefPubMedGoogle Scholar
  3. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362CrossRefPubMedGoogle Scholar
  4. Ding YL, Girardet JL, Smith KL, Larson G, Prigaro B, Wu JZ, Yao NH (2006) Parallel synthesis of 5-cyano-6-aryl-2-thiouracil derivatives as inhibitors for hepatitis C viral NS5B RNA-dependent RNA polymerase. Bioorg Chem 34:26–38CrossRefPubMedGoogle Scholar
  5. Fauvelle C, Lepiller Q, Felmlee DJ, Fofana I, Habersetzer F, Stoll-Keller F, Baumert TF, Fafi-Kremer S (2013) Hepatitis C virus vaccines-progress and perspectives. Microb Pathog 58:66–72CrossRefPubMedGoogle Scholar
  6. 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
  7. Ghany MG, Strader DB, Thomas DL, Seeff LB (2009) Diagnosis, management, and treatment of hepatitis C: an update, hepatology. Hepatology 49:1335–1374CrossRefPubMedGoogle Scholar
  8. He YP, Long J, Zhang SS, Li C, Lai CC, Zhang CS, Li DX, Zhang DH, Wang H, Cai QQ, Zheng YT (2011) Synthesis and biological evaluation of novel dihydro-aryl/alkyl sulfanyl-cyclohexyl-methyl-oxopyrimidines (S-DACOs) as high active anti-HIV agents. Bioorg Med Chem Lett 21:694–697CrossRefGoogle Scholar
  9. Huey R, Morris GM, Olson AJ (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145–1152CrossRefPubMedGoogle Scholar
  10. Lavanchy D (2011) Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 17:107–115CrossRefPubMedGoogle Scholar
  11. Li HM, Tang YL, Zhang ZH, Liu CJ, Li HZ, Li RT, Xia XS (2012) Compounds from arnebia euchroma and their related anti-HCV and antibacterial activities. Planta Med 78:39–45CrossRefPubMedGoogle Scholar
  12. Lim TR, Tan BH, Mutimer DJ (2014) Evolution and emergence of a new era of antiviral treatment for chronic hepatitis C infection. Int J Antimicrob Agents 43:17–25CrossRefPubMedGoogle Scholar
  13. Lindenbach BD (2005) Complete replication of hepatitis C virus in cell culture. Science 309:623–626CrossRefPubMedGoogle Scholar
  14. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  15. 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
  16. Sofia MJ, Chang W, Furman PA, Mosley RT, Ross BS (2012) Nucleoside, nucleotide, and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-Polymer-ase. J Med Chem 55:2481–2531CrossRefPubMedGoogle Scholar
  17. 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
  18. 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

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Daochun Wu
    • 1
  • Yue Feng
    • 2
  • Hua Wang
    • 1
  • Junfeng Yang
    • 1
  • Xian Chen
    • 1
  • Yueping Wang
    • 2
  • Christopher Cong Lai
    • 3
  • Yufang Zhang
    • 1
  • Cong Li
    • 1
  • Xueshan Xia
    • 2
  • Yanping He
    • 1
  1. 1.Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education, School of Chemical Science and TechnologyYunnan UniversityKunmingChina
  2. 2.College of Life Science and TechnologyKunming University of Science and TechnologyKunmingChina
  3. 3.Chemical Biology Laboratory, Center for Cancer ResearchNational Cancer InstituteFrederickUSA

Personalised recommendations