Synthesis And Anti-influenza Virus Testing Of Pterodontic Acid Derivative

Objectives:Used organic synthesis method to modify the structure of pterodontic acid(PA)and obtain a series of derivatives.Furthermore,used the in vitro cell model was used to detect the activity of pterodontic acid and its derivatives against influenza A H1N1 virus.Finally,the structure-activity relationship of tanopanelic acid and its derivatives in the anti-influenza virus was elucidated.Methods:In our current research,the chemical modification of pterodontic acid by reduction,oxidation,substitution,condensation and other chemical reactions:The carboxyl group of PA was condensed with amine compounds to obtained amide products(1-31).The carboxyl and hydroxyl groups of PA are dehydrated to form esters(32-34).Compounds 35-37 were obtained by oxidation of ester compounds.The double bond of PA is oxidized to form compound 38.Compound 38 reacted with ammonia compounds to form product 39-40.Compound 38 reacted with lewis acid to form compound 41.PA was reduced by lithium aluminum hydride to compound 42.Compound 42 reacted with carboxylic acid to get products 43-45.Compound 42 was chlorinated to obtain intermediate compound 46.Compound 46 was condensed with amine to form compounds 47-49.Compound 42 reacted with alkyl sulfonyl chloride to form compound 50.Compound 50 reacted with sodium azide to get the intermediate compound 51.Compound 51 and acetylene compounds were reacted electrophilically to form product 52-54.All synthetic of PA derivatives were reported for the first time,and their chemical structures were identified by NMR data.We established an in vitro cell model to detect the activity of derivatives against H1N1 influenza virus(PR8 strain).The cytotoxicity of derivatives was determined by MTT assay(TC50).Used cytopathic effect to detect the antiviral activity of derivatives.Used Reed-Muench Method to Calculate Half Inhibition Concentration(IC50).And used the selection index SI to indicate the therapeutic index of the derivative’s anti-influenza virus results(SI=TC50/IC50)Results:54 new PA derivatives were obtained in the structure modification results,the reaction process was simple and easy to operated,and the yield was good.In vitro anti-H1N1 influenza virus activity results showed:compared with the parent compound PA,the modified derivatives could showed good anti-influenza virus activity in different degrees(IC50<12.5),and some derivatives showed a better therapeutic index(SI>2).Compared with the control group,the amide derivatives showed better antiviral activity.After the carboxyl group was condensed into ester,the activity of the derivative against influenza virus decreased.The activity was enhanced when the 5-and 12-bit double bonds after elimination.There was no significant change in the activity of anti-influenza virus after carbonyl reduction.The introduction of special groups can significantly enhanced the activity of derivatives against influenza viruses.Conclusions:Pterodontic acid and its derivatives showed good activity in an in vitro anti-influenza virus model.Among them,compounds 10,11,17,20,28,45,49 and 52 were the most active against influenza A(H1N1)in vitro.The study found that:the double bond and carbonyl group in the structure of PA was not indispensable;after the carboxyl group becomes an ester,the activity decreased and the toxicity increased;carboxyl amidation had enhanced activity and reduced toxicity;after introduction of heterocycle,the activity was enhanced and the toxicity was reduced.Choosing the better functional group helps the biological activity and physical and chemical properties of the derivative to be further improved.This experiment provides a good basis for the further study of pterodontic acid and its derivatives.