A conformational mimetic approach for the synthesis of carbocyclic nucleosides as anti-HCV leads.
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.
Department of Applied Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215 (India).
Mohan
M
Kasula
Tuniki
T
Balaraju
Massaki
M
Toyama
Anandarajan
A
Thiyagarajan
Chandralata
C
Bal
Masanori
M
Baba
Ashoke
A
Sharon
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D009705:Nucleosides; D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine; D012321:DNA-Directed RNA Polymerases
RNA‐dependent RNA polymerase; antiviral agents; carbocyclic nucleosides; hepatitis C; inhibitors