Synthesis and Biological Evaluation of 2‐oxo‐pyrazine‐3‐carboxamide‐yl Nucleoside Analogues and Their Epimers as Inhibitors of Influenza A Viruses
Identifieur interne : 001412 ( Main/Exploration ); précédent : 001411; suivant : 001413Synthesis and Biological Evaluation of 2‐oxo‐pyrazine‐3‐carboxamide‐yl Nucleoside Analogues and Their Epimers as Inhibitors of Influenza A Viruses
Auteurs : Jingjing Gao [République populaire de Chine] ; Xianjin Luo [République populaire de Chine] ; Yuhuan Li [République populaire de Chine] ; Rongmei Gao [République populaire de Chine] ; Haifeng Chen [République populaire de Chine] ; Dingjue Ji [République populaire de Chine]Source :
- Chemical Biology & Drug Design [ 1747-0277 ] ; 2015-03.
Descripteurs français
- KwdFr :
- Animaux, Antienzymes (), Antienzymes (pharmacologie), Antienzymes (synthèse chimique), Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Cellules rénales canines Madin-Darby, Chiens, Domaine catalytique, Humains, Nucléosides (), Nucléosides (pharmacologie), Nucléosides (synthèse chimique), Pyrazines (), Pyrazines (pharmacologie), Pyrazines (synthèse chimique), RNA replicase (antagonistes et inhibiteurs), RNA replicase (métabolisme), Relation structure-activité, Réplication virale (), Simulation de docking moléculaire, Sites de fixation, Sous-type H1N1 du virus de la grippe A (enzymologie), Sous-type H1N1 du virus de la grippe A (physiologie), Sous-type H3N2 du virus de la grippe A (enzymologie), Sous-type H3N2 du virus de la grippe A (physiologie), Survie cellulaire ().
- MESH :
- antagonistes et inhibiteurs : RNA replicase.
- enzymologie : Sous-type H1N1 du virus de la grippe A, Sous-type H3N2 du virus de la grippe A.
- métabolisme : RNA replicase.
- pharmacologie : Antienzymes, Antiviraux, Nucléosides, Pyrazines.
- physiologie : Sous-type H1N1 du virus de la grippe A, Sous-type H3N2 du virus de la grippe A.
- synthèse chimique : Antienzymes, Antiviraux, Nucléosides, Pyrazines.
- Animaux, Antienzymes, Antiviraux, Cellules rénales canines Madin-Darby, Chiens, Domaine catalytique, Humains, Nucléosides, Pyrazines, Relation structure-activité, Réplication virale, Simulation de docking moléculaire, Sites de fixation, Survie cellulaire.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Binding Sites, Catalytic Domain, Cell Survival (drug effects), Dogs, Enzyme Inhibitors (chemical synthesis), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (pharmacology), Humans, Influenza A Virus, H1N1 Subtype (enzymology), Influenza A Virus, H1N1 Subtype (physiology), Influenza A Virus, H3N2 Subtype (enzymology), Influenza A Virus, H3N2 Subtype (physiology), Madin Darby Canine Kidney Cells, Molecular Docking Simulation, Nucleosides (chemical synthesis), Nucleosides (chemistry), Nucleosides (pharmacology), Pyrazines (chemical synthesis), Pyrazines (chemistry), Pyrazines (pharmacology), RNA Replicase (antagonists & inhibitors), RNA Replicase (metabolism), Structure-Activity Relationship, Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : RNA Replicase.
- chemical , chemical synthesis : Antiviral Agents, Enzyme Inhibitors, Nucleosides, Pyrazines.
- chemical , chemistry : Antiviral Agents, Enzyme Inhibitors, Nucleosides, Pyrazines.
- chemical , metabolism : RNA Replicase.
- chemical , pharmacology : Antiviral Agents, Enzyme Inhibitors, Nucleosides, Pyrazines.
- drug effects : Cell Survival, Virus Replication.
- enzymology : Influenza A Virus, H1N1 Subtype, Influenza A Virus, H3N2 Subtype.
- physiology : Influenza A Virus, H1N1 Subtype, Influenza A Virus, H3N2 Subtype.
- Animals, Binding Sites, Catalytic Domain, Dogs, Humans, Madin Darby Canine Kidney Cells, Molecular Docking Simulation, Structure-Activity Relationship.
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.
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 MDCK cells. All the compounds showed low cytotoxicities in these anti‐influenza tests. One of the epimers 8a shows high antiviral activity (IC50 = 7.41, 5.63 μm for H3N2 and H1N1, respectively) and remarkable low cytotoxicity (TC50 > 200 μm). 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.
Url:
DOI: 10.1111/cbdd.12382
Affiliations:
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Simulation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Antienzymes</term><term>Antiviraux</term><term>Cellules rénales canines Madin-Darby</term><term>Chiens</term><term>Domaine catalytique</term><term>Humains</term><term>Nucléosides</term><term>Pyrazines</term><term>Relation structure-activité</term><term>Réplication virale</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>Survie cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="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.</div><div type="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 MDCK cells. All the compounds showed low cytotoxicities in these anti‐influenza tests. One of the epimers 8a shows high antiviral activity (IC50 = 7.41, 5.63 μm for H3N2 and H1N1, respectively) and remarkable low cytotoxicity (TC50 > 200 μm). 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.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Pékin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Gao, Jingjing" sort="Gao, Jingjing" uniqKey="Gao J" first="Jingjing" last="Gao">Jingjing Gao</name></noRegion><name sortKey="Chen, Haifeng" sort="Chen, Haifeng" uniqKey="Chen H" first="Haifeng" last="Chen">Haifeng Chen</name><name sortKey="Gao, Rongmei" sort="Gao, Rongmei" uniqKey="Gao R" first="Rongmei" last="Gao">Rongmei Gao</name><name sortKey="Ji, Dingjue" sort="Ji, Dingjue" uniqKey="Ji D" first="Dingjue" last="Ji">Dingjue Ji</name><name sortKey="Li, Yuhuan" sort="Li, Yuhuan" uniqKey="Li Y" first="Yuhuan" last="Li">Yuhuan Li</name><name sortKey="Li, Yuhuan" sort="Li, Yuhuan" uniqKey="Li Y" first="Yuhuan" last="Li">Yuhuan Li</name><name sortKey="Luo, Xianjin" sort="Luo, Xianjin" uniqKey="Luo X" first="Xianjin" last="Luo">Xianjin Luo</name><name sortKey="Luo, Xianjin" sort="Luo, Xianjin" uniqKey="Luo X" first="Xianjin" last="Luo">Xianjin Luo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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