Design、Synthesis And Anti-HCV Activity Of Novel HCV NS5B Polymerase Inhibitor

Hepatitis C virus(HCV) infection has been a global health problem. Currently,more than 35000 individuals die each year from hepatitis C virus infection related liver diseases, for instance, cirrhosis, liver failure and hepetocellular carcino. The drug for infections with hepatitis C virus has become current hot research field,such as the NS3/NS4 A inhibitor Telaprevir and Boceprevir approved in 2011, Sofobuvir which comes into the market in 2013 as NS5 B inhibitor, the NS5 A inhibitor Daclatasivir listed in 2014 and NS5 A inhibitor Elbasvir/Grazoprevir went public in2016.Our research group finds δ-soltones-γ-butenolide such novel double heterocyclic compounds can integrate well with the thumb domain of NS5 B polmerase by computer simulation tachnology. That is to say, these compounds produce anti-HCV activity by inhibiting the activity of NS5 B protease. Based on these findings, our groups carry out futher optimization and modification on the basis of preliminary experiments with expecting better active and more valuable novel NS5 B inhibitors.The specific research as follows:According to preliminary experiments and previous research experience,the four series of compounds are obtained by esterification reaction which use commercially available substituted phenyl acetic acid as raw material, Dieckmann condensation reaction, the hydroxy protacting reaction, adol condensation reaction, sulfonylation reaction and CSIC reaction.Through the above method, 5 the first series, 15 the second series, 30 the third series and 2 the fourth series of target compunds are designed and synthesized with the structures verified by 1H NMR, 13 C NMR and IR spectra. The structures of all compounds are new without any reports. Meanwhile, the cytotoxicity and anti-bovine diarrhea virus(BVDV) activity are studied by MTT assy. The results show that most these compounds have excellent anti-bovine diarrhea virus activity(IC50=0.012 ~ 1.2μM)with no significant cytotoxicity(CC50 > 2 5 μM). The compounds IIl, IIm and ?Io show the best activity with IC50 up to 12 n M, whose activities are one hundred times more than the positive control drug ribavirin. The activity of compounds ?Ic, ?Id, ?Ig, ?Ii and ?In are also prominent(IC50 = 0.12 μM).The activity of compounds IVa and III-2h respectively are 0.375μM and0.75μM.BVDV is considered as a valuable surrogate virus model for identifying and charactering antiviral agents for use against HCV. In general, the compunds with anti-BVDV activity have potential anti-HCV activity. The above results establish the foundation for the futher direct anti-HCV activity screening and molecular mechanism of antival.