Design,Synthesis And Antiviral Activity Of Nucleoside Analogues

Nucleoside compounds can substitute natural nucleosides due to structural similarity.After being activated in the form of triphosphate,they can be incorporated into the virus genome to inhibit virus proliferation and play an antiviral role.This paper aims to explore nucleoside compounds with pharmaceutical potential from two aspects.1)Design and synthesize compounds with novel structure,and discover the leading structures or clue through biological activity tests for further structural optimization.2)Explore the effects of different prodrug types on their biological effects from the reported active compounds,to determine the prodrug forms with better drug properties.In the design and synthesis of novel compounds,two kinds of compounds were synthesized,including six carbocyclic nucleosides and eight base skeleton modified nucleosides.According to an in vitro antiviral activity test 2’-deoxy-6’α-Substituted carbocyclic nucleosides are a class of compounds that have an anti-HBV activity,of which the EC₅₀ value ofα-hydroxymethyl substituent 2b with the highest activity is0.08μM.The effect of 6’-substitution on the anti-HBV activity of carbocyclic nucleoside was evaluated.It was found that the configuration of the substituent was closely related to its antiviral activity.The overall activity ofαconfigurational compounds is high,while most of theβconfigurational compounds lack activity.The type of substituent has a limited effect on its activity.Some compounds with antiviral activity were found when nucleoside base was modified.3-deazapurine nucleosides 2j and 2k showed moderate inhibitory activity against SARS-Co V-2,with the inhibition of 61.3%and 48.2%at the concentration of 5μM respectively.6-azapyrimidine nucleoside 2i has anti influenza virus activity,with the inhibition of 92.2%at the concentration of 5μM.In terms of prodrug work,three 2’,3’-carbonate,hydroxylamine hydroxy ester compounds and four 2’,3’-acetal compounds were synthesized with N4-hydroxycytidine（NHC）as a parent compound.PK experiment in rats showed that introducing ester group into hydroxyl group at the position of N4 hydroxylamine would reduce the ability of parent drug to metabolize into target product NHC,2’,3’-acetal structure cannot be metabolized into NHC in vivo.Using 4’-F substituted uridine as the parent compound,two base modified derivatives and seven derivatives in the form of 2’,3’-carbonate and 5’-ester were synthesized.Most of the structurally modified compounds can still maintain good anti influenza virus and RSV activity.Three compounds were selected for the PK experiment in rats.It was found that based on the structure of 2’,3’-carbonate,the form of 5’-ester improved the metabolism of compounds to nucleosides and oral bioavailability,and the experimental data of isobutyrate was better than valine ester,which provided a basis for determining compounds with better PK properties.