Design,Synthesis And Biological Evaluation Of Oseltamivir Derivatives Targeting 150-Cavity Of Influenza Virus Neuraminidase

Influenza(flu),is caused by influenza viruses and can directly affect the respiratory tract and immune system.In severe cases,influenza can threaten human life and lead to death,which has the characteristics of rapid transmission,high infectivity,short incubation period,high pathogenicity.Neuraminidase(NA)is a functional protein of influenza virus,and its main role is to catalyze the cleavage of the glycosidic bond between sialic acid and glycoprotein.Neuraminidase inhibitors(NAIs)have become an important means of fighting influenza virus.Since the approved of zanamivir and oseltamivir,NA inhibitors have become the first choice for the prevention and treatment of influenza and are stockpiled by governments in response to influenza pandemic.With the widespread use of NA inhibitors,drug-resistant strains have been reported,especially for oseltamivir.Therefore,the development of novel,highly effective and anti-drug resistant NA inhibitors is currently urgently needed.Fortunately,the discovery of 150-cavity provides a new opportunity for the development of novel anti-influenza drugs.In our early study,we analyzed the combination of N1 and oseltamivir through the reported crystal structure,and found that the C-5 amino of oseltamivir was well exposed to 150-cavity.Therefore,the modification by introducing a substituent group to occupy the 150-cavity,can improve the activity,anti-drug resistance and selectivity of the compounds.In the cause of overcome the appeared drawbacks,we designed and synthesized A series(22 compounds)and B(20 compounds)series of oseltamivir derivatives(A-series,thiourea substituted oseltamivir derivatives;(B-series,biphenyl substituted oseltamivir derivative)using bioisosterism and multi-site binding strategies,based on the analysis of the structural characteristics of 150-cavity.The results of enzymatic assay and cellular assay was noticed that all the the synthesized compounds displayed an-flu activities.A-series compounds displayed moderate anti-NA activities.Among them,compound A1 showed the best inhibitory activity against H3N2(IC50=1.64?M)and H1N1(IC50=1.64 ?M)NAs.Although its anti-flu activity is far from that of OSC in cellular level,it also provides valuable experience for the design of new oseltamivir derivatives.On the other hand,B-series compounds display great antiviral activities.Among them,B-20 showed excellent H1N1 NA inhibition(IC50=21 nM),which was better than OSC(IC50=24 nM).Meanwhile,B-20 showed a strong potency(IC50=9.73 ?M)equivalent to OSC(IC50=6.59 ?M)against H5N1-H274Y subtypes.Besides,B-20 also exerted similar antiviral activity to oseltamivir at cellular level.Conclusion:In this thesis,we have designed and synthesized two series(series-A&series-B)of C-5 modified oseltamivir derivatives by targeting the 150-cavity of NA.Some of the compounds have moderate or potent inhibitory activity against influenza virus NA.Among them,compound B-20 was the most promising candidate with favorable anti-flu activity against N1 strains,which deserved further optimization.In view of the current severe situation against influenza virus,our structure-activity relationship studies have important practical significance.