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Eur J Med Chem ; 224: 113684, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1292698

ABSTRACT

Respiratory syncytial virus (RSV) causes serious lower respiratory tract infections. Currently, the only clinical anti-RSV drug is ribavirin, but ribavirin has serious toxic side effect and can only be used by critically ill patients. A series of benzimidazole derivatives were synthesized starting from 1,4:3,6-dianhydro-d-fructose and a variety of o-phenylenediamines. Evaluation of their antiviral activity showed that compound a27 had the highest antiviral activity with a half maximal effective concentration (EC50) of 9.49 µM. Investigation of the antiviral mechanism of compound a27 indicated that it can inhibit the replication of RSV by inhibiting apoptosis and autophagy pathways. Retinoic acid-inducible gene (RIG)-I, TNF receptor associated factor (TRAF)-3, TANK binding kinase (TBK)-1, interferon regulatory factor (IRF)-3, nuclear factor Kappa-B (NF-κB), interferon (IFN)-ß, Toll-like receptor (TLR)-3, interleukin (IL)-6 were suppressed at the cellular level. Mouse lung tissue was subjected to hematoxylin and eosin (HE) staining and immunohistochemistry, which showed that RSV antigen and M gene expression could be reduced by compound a27. Decreased expression of RIG-I, IRF-3, IFN-ß, TLR-3, IL-6, interleukin (IL)-8, interleukin (IL)-10, inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α was also found in vivo.


Subject(s)
Antiviral Agents/chemical synthesis , Benzimidazoles/chemistry , Drug Design , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Apoptosis/drug effects , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Cell Line , Cytokines/metabolism , Humans , Isomerism , Lung/metabolism , Lung/pathology , Mice , Molecular Conformation , Reactive Oxygen Species/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/physiology , Structure-Activity Relationship , Toll-Like Receptor 3/metabolism , Virus Replication/drug effects
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