ABSTRACT
A number of framework amides with a ginsenol backbone have been synthesized using the Ritter reaction. We named the acetamide as Ginsamide. A method was developed for the synthesis of the corresponding amine and thioacetamide. The new compounds revealed a high activity against H1N1 influenza, which was confirmed using an animal model. Biological experiments were performed to determine the mechanism of action of the new agents, a ginsamide-resistant strain of influenza virus was obtained, and the pathogenicity of the resistant strain and the control strain was studied. It was shown that the emergence of resistance to Ginsamide was accompanied by a reduction in the pathogenicity of the influenza virus.
Subject(s)
Antiviral Agents/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Amides/pharmacology , Animals , Antiviral Agents/isolation & purification , Cell Line , China , Drug Resistance, Viral , Female , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Influenza, Human/drug therapy , Mice , Mice, Inbred BALB C , Neuraminidase/pharmacology , Orthomyxoviridae Infections/drug therapy , Sesquiterpenes/metabolismABSTRACT
A series of compounds containing a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment were evaluated for their antiviral activity against influenza A virus strain A/Puerto Rico/8/34 (H1N1) in vitro. The most potent antiviral compound proved to be a quaternary ammonium salt based on (-)-borneol, 10a. In in vitro experiments, compound 10a inhibited influenza A viruses (H1, H1pdm09, and H3 subtypes), with an IC50 value of 2.4-16.8 µM (depending on the virus), and demonstrated low toxicity (CC50 = 1311 µM). Mechanism-of-action studies for compound 10a revealed it to be most effective when added at the early stages of the viral life cycle. In direct haemolysis inhibition tests, compound 10a was shown to decrease the membrane-disrupting activity of influenza A virus strain A/Puerto Rico/8/34. According to molecular modelling results, the lead compound 10a can bind to different sites in the stem region of the viral hemagglutinin.
Subject(s)
Alkanes/pharmacology , Ammonium Compounds/pharmacology , Camphanes/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Quaternary Ammonium Compounds/pharmacology , Salts/pharmacology , Animals , Antiviral Agents/pharmacology , Cell Line , Dogs , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Influenza A Virus, H1N1 Subtype/metabolism , Madin Darby Canine Kidney Cells , Orthomyxoviridae Infections/drug therapyABSTRACT
We synthesized a series of amides with a benzo[d][1,3]dithiol core. The chemical library of compounds was tested for their cytotoxicity and inhibiting activity against influenza virus A/California/07/09 (H1N1)pdm09 in MDCK cells. For each compound, values of CC50, IC50 and selectivity index (SI) were determined. Compounds of this structure type were for the first time found to exhibit anti-influenza activity. The structure of an amide substituent in the tested compounds was demonstrated to have a significant effect on their activity against the H1N1 influenza virus and cytotoxicity. Compound 4d has a high selectivity index of about 30. 4d was shown to be most potent at early stages of viral cycle. In direct fusogenic assay it demonstrated dose-dependent activity against fusogenic activity of hemagglutinin of influenza virus. Based on molecular docking and regression analysis data, viral hemagglutinin was suggested as possible target for these new antiviral agents.
