rupestonic-acid and Influenza--Human

In spired by the important role of amide groups of anti-influenza drugs oseltamivir, zanamivir and peramivir in bioactivity, a series of novel amides modified rupestonic acid derivatives were designed and synthesized. The absolute configuration of critical intermediate bearing chloride with newly formed stereocenter was confirmed by X-ray crystallographic analysis. And all new compounds were evaluated for their in vitro inhibitory activities against influenza A (H1N1 and H3N2) and influenza B viruses. The bioassay results showed that 5h with 4-fluorbenzylsulfonyl modified to 2 position of methyl rupestonate displayed the highest activity against influenza A (H1N1 and H3N2) viruses, even stronger than reference drugs oseltamivir and ribavirin (RVB), and might be recommended as a lead compound to further develop the new anti-influenza reagent.

Topics: Amides; Antiviral Agents; Azulenes; Crystallography, X-Ray; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Sesquiterpenes

Given the limitation of available antiviral drugs and vaccines, there remains to be a pressing need for novel anti-influenza drugs. Rupestonic acid derivatives were reported to have an anti-influenza virus activity, but their mechanism remains to be elucidated. Herein, we aim to evaluate the antiviral activity of YZH-106, a rupestonic acid derivative, against a broad-spectrum of influenza viruses and to dissect its antiviral mechanisms. Our results demonstrated that YZH-106 exhibited a broad-spectrum antiviral activity against influenza viruses, including drug-resistant strains in vitro. Furthermore, YZH-106 provided partial protection of the mice to Influenza A virus (IAV) infection, as judged by decreased viral load in lungs, improved lung pathology, reduced body weight loss and partial survival benefits. Mechanistically, YZH-106 induced p38 MAPK and ERK1/2 phosphorylation, which led to the activation of erythroid 2-related factor 2 (Nrf2) that up-regulated heme oxygenase-1 (HO-1) expression in addition to other genes. HO-1 inhibited IAV replication by activation of type I IFN expression and subsequent induction of IFN-stimulated genes (ISGs), possibly in a HO-1 enzymatic activity-independent manner. These results suggest that YZH-106 inhibits IAV by up-regulating HO-1-mediated IFN response. HO-1 is thus a promising host target for antiviral therapeutics against influenza and other viral infectious diseases.

Topics: Animals; Antiviral Agents; Azulenes; Disease Models, Animal; Epithelial Cells; Gene Expression Regulation; Heme Oxygenase-1; Host-Pathogen Interactions; Humans; Indans; Influenza A virus; Influenza, Human; Interferons; Isoxazoles; Lung; MAP Kinase Signaling System; Membrane Proteins; Mice; NF-E2-Related Factor 2; p38 Mitogen-Activated Protein Kinases; Sesquiterpenes; Viral Load; Virus Replication

Topics: Azulenes; Heme Oxygenase-1; Humans; Influenza, Human; Interferons; Sesquiterpenes; Virus Replication

The pharmacophore modeling and 3D-QSAR studies were performed on a series of amino alkyl rupestonates (Rupestonic Acid) derivatives reported for H1N1, H3N2 and Influenza B virus, NA inhibition. In order to improve the efficacy of amino alkyl rupestonates derivatives, a four point pharmacophore model with one acceptor and three hydrophobic regions was developed. Furthermore, the 3D-QSAR model was generated based on the pharmacophore hypothesis (AHHH) for each subtype. The hypothesis was more significant with R(2)=0.9204, Q(2)=0.917 for H1N1, R(2)=0.8911, Q(2)=0.8905 for H3N2 and R(2)=0.8385, Q(2)=0.7043 for Influenza B virus. The 3D-QSAR results provided an invaluable insight into structure activity correlation and it was shown that the hydrophobic regions were crucial for inhibitory activity. CoMFA and COMSIA validation had been done by leave one out and no validation methods.

Topics: Antiviral Agents; Azulenes; Betainfluenzavirus; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Models, Molecular; Quantitative Structure-Activity Relationship; Sesquiterpenes

A series of aminoalkyl rupestonates were designed and synthesized by reacting rupestonic acid with 1,ω-dibromoalkanes, followed by amination. All of the new compounds were bioassayed in vitro to determine their activities against influenza A (H3N2, H1N1) and B viruses. The results showed that compounds 5a-5g, which each contain a 1H-1,2,4-triazolyl moiety, were found to be the most potent set of compounds. Compound 5g was demonstrated to possess the highest inhibitory activity against influenza H3N2 and H1N1, with IC(50) values of 0.97 and 0.42 μM, respectively. Our results also indicated that compounds 2g, 3g, 4g and 5g, which contain ten-CH(2)-unit spacers between the rupestonic acid and amino functional groups, were the most potent inhibitors of influenza H1N1 among the synthesized compounds. Unfortunately, most of the synthesized compounds did not show an obvious activity against influenza B; the only exceptions were compounds 5d and 5f, which had IC(50) values of 17.3 and 3.2 μM, respectively. Compounds 4g and 5g were potent inhibitors of influenza H1N1, and they might be potentially developed as new lead anti-influenza virus compounds. Further studies of the mechanism of action are underway.

Topics: Amination; Animals; Antiviral Agents; Azulenes; Cell Line; Dogs; Halogenation; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Sesquiterpenes; Structure-Activity Relationship