A Conformational Mimetic Approach for the Synthesis of Carbocyclic Nucleosides as Anti‐HCV Leads
- 13 August 2013
- journal article
- research article
- Published by Wiley in ChemMedChem
- Vol. 8 (10) , 1673-1680
Abstract
Computer‐aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti‐hepatitis C virus (HCV) agents. Conformational analyses were carried out on 6‐amino‐1H‐pyrazolo[3,4‐d]pyrimidine (6‐APP)‐based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA‐dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6‐APP analogues were prepared and evaluated for anti‐HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC50 value of 6.6 μM as a preliminary anti‐HCV lead.Keywords
This publication has 32 references indexed in Scilit:
- Structure of Hepatitis C Virus Polymerase in Complex with Primer-Template RNAJournal of Virology, 2012
- Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosidesBioorganic & Medicinal Chemistry Letters, 2012
- Potent and selective inhibition of hepatitis C virus replication by novel phenanthridinone derivativesBiochemical and Biophysical Research Communications, 2011
- Evolving epidemiology of hepatitis C virusClinical Microbiology and Infection, 2011
- Synthesis and Anti-Hepatitis B Virus and Anti-Hepatitis C Virus Activities of 7-Deazaneplanocin A Analogues in VitroJournal of Medicinal Chemistry, 2008
- Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811Biochemical and Biophysical Research Communications, 2006
- Dissecting the Interferon-Induced Inhibition of Hepatitis C Virus Replication by Using a Novel Host Cell LineJournal of Virology, 2005
- Nucleosides, 381) The Ribonucleosides of AllopurinolEuropean Journal of Inorganic Chemistry, 1981
- Conformational analysis of 8-azanucleosides. Crystal and molecular structure of 8-azatubercidin monohydrate, a nucleoside analog exhibiting the "high anti" conformationJournal of the American Chemical Society, 1978
- Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted Pyrazolo [3,4-d] pyrimidines1Journal of the American Chemical Society, 1956