Design,Synthesis And Biological Activity Analysis Of Novel Acyhydrazone Neuraminidase Inhibitors

Influenza has always been a major threat to human health because of its large-scale spread and high pathogenicity.The earliest drugs for the treatment of colds are M-protein ion channel inhibitors,but such drugs are very susceptible to drug resistance in clinical use.The best anti-influenza drugs on the market today are neuraminidase inhibitors.Neuraminidase?NA?is a glycoprotein on the surface of influenza virus,which plays a crucial role in the replication and transmission of influenza virus.In this paper,we screened the small molecule database SPECS containing more than 670,000 by the ligand-based pharmacophore model virtual screening method.Initially collected compounds that met the characteristics of the model pharmacophore.And then based on the receptor,using the virtual screening method of molecular docking further to reduce the range of compound libraries,and identify compounds that are more likely to be active.Finally,performing MD simulation verification of these potential molecules by Amber12.0 to obtain a lead compound 6a.MD simulation indicates that the morpholinyl group of 6a could be embedded in 430-loop of NA.To exploit the 430-loop in the active site,a series of novel acylhydrazone NA inhibitors 6b-6g were designed and synthesized based on the lead compound 6a.Compound 6e exerts the most potency,with IC₅₀0 value of 2.37?M against NA,which is lower than that of oseltamivir carboxylate?OC?(IC₅₀=3.84?M).Molecular docking studies have found that when the more hydrophobic structural benzene ring moiety binds to430-loop,the compound has a better inhibitory activity against neuraminidase.For example,the inhibitory concentration of these inhibitors on neuraminidase is lower than positive control OC?IC50=3.84?M?.In conclusion,the results of this work indicate that when a new inhibitor is designed for the 430-loop of neuraminidase,increasing the hydrophobicity of the ligand at430-loop is beneficial to increase the inhibitory activity of the inhibitor.This work provided unique insights in the discovery of potent inhibitors against NA.