Design And Synthesis Of Acrylamides Derivatives Containing Heterocycle As Inhibitors Of Hepatitis B Virus

Objective:Chronic hepatitis B caused by hepatitis B virus is a refractory disease which has caused a serious public health problem.Nucleoside analogues are the most commonly-used antiviral agents for HBV.However,the drug resistance caused by long-term nucleoside analogues treatment finally leads to antiviral-lost,viral resistance,viral load breakthrough and worse liver disease.Therefore,looking for new non-nucleosideanti-HBV drugs especially anti-HBV drugs possessing new modes of action is very urgent.Because of the diversity and structures and new antiviral mechanism,non-nucleoside HBV inhibitors become a hot spot.According to preliminary studies,acrylamide derivatives Containing 1,2,3-thiadiazole heterocyclic have good anti-HBV activity.Based on these researches,the compound possessing high anti-HBV activity is used as template.Then modify and optimize the template molecule so as to gain novel class of acrylamide anti-HBV lead compounds containing heterocyclic and to study their structure-activity relationships..Methods:According to principles of biological isostere,similar synthesis and mosaic of active fragment,two series of acrylamide derivatives Containing heterocyclic were designed.As the crystal structure of HBV-DNA has not been reported yet,so the ligand-based pharmacophore model method is an effective way of designing drug molecules.According to the structure and good biological activity data of reported activity of HBV inhibitors,use Discovery Studio 3.5-HipHop module to build the Pharmacophore model,and then selecte the best pharmacophore model,and then continue the matching verification using the selected pharmacophore model.Combined with the difficulty of organic synthesis and other factors,methods of synthesis route were determined.Starting from substituted benzoic acid,substituted benzaldehyde and Ethyl acetoacetate as the raw material,the target compounds were obtained by chemical synthesis and their structures were confirmed by 1H MMR,13C NMR and MS.Results:The optimum synthesis conditions were studied,and 17 novel compounds are obtained through the Erlenmeyer reaction,Amination reaction and bromine replacement,with a high level of product purity and yield.The target compounds were purified and then confirmed by 1H NMR,13C NMR and MS.And the activity detection is on going.Conclusion:Combined with the effective pharmacophore model and the advantage of bio-isostere,the phenylpropenamide scaffold based HBV inhibitors were designed.The designed compounds were screened using the CADD technology,and some potencial lead compounds were identified.By chemical synthesis,17 class propenamide HBV inhibitors were obtained and confirmed by 1H MMR,13C NMR and MS.Further activity studies were underway.