Design,Synthesis And Biological Activity Evaluation Of Novel Inhibitors Targeting Influenza A Virus Neuraminidase

Influenza A is an acute respiratory infectious disease caused by the influenza A virus,referred to as IAV.Neuraminidase（NA）is an effective target for the research and development of anti influenza A drugs.150-cavity and 430-cavity are novel sites adjacent to the active site of NA.In this thesis,an oxalamide lead compound,ZINC05250774,was identified as a potential NA inhibitor by molecular docking virtual screening and molecular dynamics simulations using receptor structure-based drug design.Through structural modification of ZINC05250774,a series of novel inhibitors Z1-Z10 were designed and synthesized.From the inhibition results,compound Z2 in oxalamide series has the best inhibitory activity on NA(IC₅₀=0.09μM),which is superior to the positive control OSC(IC₅₀=0.10μM)and ZINC05250774(IC₅₀=1.91μM).The results of molecular docking suggested that the excellent inhibitory activity of Z2 might be attributed to3-chloro-substituted phenyl,which could be extended into 430-cavity through oxalamide chain.In addition,oxalamide group is also important for this series of compounds,as it can form strong hydrogen bonding interactions with three key arginine residues（Arg118,Arg292,Arg371）at the active site.A similar virtual screening method was also applied to screen a sulfamethazine lead compound,ZINC670537.Through structural modification of ZINC670537,a series of novel NA inhibitors,X1-X10,were designed.The results of molecular docking and molecular dynamics showed that the good inhibitory activity of X3could be attributed to the good binding of the 3,4-dimethoxy substituted phenyl to the active site and the sulfamethazine part can be connected to the 150-cavity via the succinamide chain.The theoretical and experimental results of this thesis may provide theoretical support and reference guidance for the development of novel and efficient NA inhibitors.