Design, Synthesis And Virtual Screening Of Acyl Thiourea Derivatives As Influenza Neuraminidase Inhibitors

Influenza, an acute viral infection of the upper respiratory tract, has been a threat to people's health and taken an economic toll to the society. The frequent outbreaks of highly pathogenic avian influenza (HPAI) in human have been a serious public health problem. Influenza neuraminidase is a major envelope glycoprotein in viral A and B surface and essential for viral replication and the infective cycle of influenza. The catalytic site of neuraminidase in all A and B viruses is completely conserved, which makes NA an attractive target for antiviral drug development. On the basis of available structure activity relationship of neuraminidase inhibitors, our study focused on the design and synthesis of acyl thiourea derivatives in hope of finding lead compound which possess remarkable anti-viral activity.Method Benzoic acid analogues possess good inhibitory activity against influenza neuraminidase. But it is less effective in vivo because of its pharmacokinetics properties. In order to develop potent and specific neuraminidase inhibitor with proper pharmacokinetic properties and novel structure, two series of compounds were designed and synthesized by fragment based drug discovery and scaffold hopping approaches, using substituted benzoic acid as lead compound. The neuraminidase inhibitory activity was evaluated via virtual screening using molecular docking programm. Zanamivir was taken as reference ligand.Results Five of N′-(4, 6-dimethyl pyrimidin-2-yl)-N-(substituted benzoyl) thioureas and seven of N′-(4, 6-dimethyl pyrimidin-2-yl)-N-[(2E)-(3-substituted phenyl)-2-acryloyl] thioureas were synthesized. Ten of these compounds have been unreported, which were confirmed by 1H-NMR, MS and element analysis. The virtual screening results indicate that, except for compounds YK5 and YH3, all target compounds show well binding affinity with influenza neuraminidase theoretically. The estimated inhibition constants (Ki) of compounds YK4, YH4, YH5 and YH6 are nearly approximate to that of zanamivir. The pattern of neuraminidase-compound interactions demonstrate that the acyl backbone and the nitrogen between thiocarbonyl group and pyrimidine ring both form hydrogen bonds to the amino acid residues in active site. The substituted pyrimidine ring inserts into the active site and makes hydrophobic interaction with amino acid residues. Structure-activity relationship was preliminarily discussed. Compound structure affects the activity, especially the space effect. Large bulk substituents in the para-position of benzene ring will reduce the activity. Induction of hydrophobic and electron-donating groups in meta-position of benzene ring will strengthen the activity obviously.Conclusion N′-(4, 6-dimethyl pyrimidin-2-yl)-N-substituted acyl thiourea derivatives show well binding affinity with influenza neuraminidase and possess potential neuraminidase inhibitory activity.