title: Synthesis and biological evaluation of 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers as inhibitors of influenza A viruses.
abstract: 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 8a, with high antiviral activities (IC50 = 7.41, 5.63 μm for H3N2 and H1N1, respectively) and remarkable low cytotoxicity (TC50 > 200 μm), 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 SARs.
authors: School of Chemistry and Chemical Engineering, Shanghai JiaoTong University, Shanghai, 200240, China.
authors: Jingjing
authors: J
authors: Gao
authors: Xianjin
authors: X
authors: Luo
authors: Yuhuan
authors: Y
authors: Li
authors: Rongmei
authors: R
authors: Gao
authors: Haifeng
authors: H
authors: Chen
authors: Dingjue
authors: D
authors: Ji
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000201:enzymology / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000602515:4-(7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo(2.2.1)heptan-3-yl)-3-oxo-3,4-dihydropyrazine-2-carboxamide; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D011719:Pyrazines; D012324:RNA-Dependent RNA Polymerase
keywords: binding mode; influenza A H1N1; influenza A H3N2; nucleoside analogues; pyrazinecarboxamide derivatives