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A Conformational Mimetic Approach for the Synthesis of Carbocyclic Nucleosides as Anti‐HCV Leads
Author(s) -
Kasula Mohan,
Balaraju Tuniki,
Toyama Massaki,
Thiyagarajan Anandarajan,
Bal Chandralata,
Baba Masanori,
Sharon Ashoke
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300277
Subject(s) - nucleoside , stereochemistry , pyrimidine , chemistry , hepatitis c virus , molecular model , lead compound , polymerase , rna polymerase , combinatorial chemistry , biochemistry , rna , computational biology , biology , virus , enzyme , in vitro , virology , gene
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‐1 H ‐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 EC 50 value of 6.6 μ M as a preliminary anti‐HCV lead.