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Synthesis and Biological Evaluation of 2‐oxo‐pyrazine‐3‐carboxamide‐yl Nucleoside Analogues and Their Epimers as Inhibitors of Influenza A Viruses
Author(s) -
Gao Jingjing,
Luo Xianjin,
Li Yuhuan,
Gao Rongmei,
Chen Haifeng,
Ji Dingjue
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12382
Subject(s) - epimer , carboxamide , nucleoside , chemistry , stereochemistry , docking (animal) , cytotoxicity , influenza a virus , ic50 , rna polymerase , pyrazine , hydroxymethyl , nucleoside analogue , biochemistry , rna , biology , virus , in vitro , virology , gene , medicine , nursing
Novel 2‐oxo‐pyrazine‐3‐carboxamide‐yl nucleoside analogues and their epimers were designed, synthesized and evaluated for their activities against influenza A viruses H1N1 and H3N2 in Madin‐Darby canine kidney cells. All the compounds showed low cytotoxicities in these anti‐influenza tests. One of the epimers, 4‐[(1S, 3R, 4R, 7R)‐7‐hydroxy‐1‐(hydroxymethyl)‐2,5‐dioxabicyclo[2.2.1]heptan‐3‐yl]‐3‐oxo‐3,4‐dihydropyrazine‐2‐carboxamide 8 a, with high antiviral activities ( IC 50 = 7.41, 5.63 μ m for H3N2 and H1N1, respectively) and remarkable low cytotoxicity ( TC 50 > 200 μ m ), has great potential for further development as a novel anti‐influenza A agent. Molecular docking of compound 8a with RNA ‐dependent RNA polymerase was performed to understand the binding mode between these inhibitors and the active site of RdRp and to rationalize some SAR s.