Design, Synthesis And Evaluation Of Neuraminidase Inhibitors Based On The Structure Of Neuraminidase Receptor

Influenza is an acute respiratory illness caused by influenza virus which affected tens of thousands of people every year. It is a great threaten to human health. Up to now, neuraminidase inhibitor is a mainly drug for preventing and fighting against influenza virus. However, more and more drug resistance virus came out because of mutation of virus, NA has became a hot spot for finding new neuraminidase inhibitor in fighting against influenza virus.Recently, scientists have revealed the interaction bewteen ligands and receptor of NA by eutectic structure, which provide a important reference to design and find novel neuraminidase inhibitors. To date, there were three mainly NA inhibitors called zanamivir、oseltamivir and peramivir, especially oseltamivir was widely used for its good oral bioavailability. However, oseltamivir almost completely lost inhibitory activity to new virus which was produced by mutation of some specific amino acid of H5N1or H1N1. There are two different structure was revealed by studying the structure of protein of NA and it can be divided into two subtype, group1contains N1, N4, N5, N8and group2contains N2, N3, N6, N7, N9. There was apparent difference in structure for big cavity called150-cavity existed in group1but not in group2. In most condition, group1can change into group2induced by ligands, so oseltamivir keep its inhibitory activity to NA of group1. If some specific amino such as His274change into Try274in group1which can lead NAIs lost its binding force with NA of group-1. Based on these point, we try to modify the structure of oseltamivir by bring hydrophobic group to C-5of oseltamivir and hope it interactive with150-cavity. At last, we hope to prepare a seried of highly effective, highly selective NA inhibitors. The specific work was showed in the following four sections:Section1:the mainly contents of these parts was introducing the mechanism of influenza virus, the methods of fighting against influenza virus, the structure-relationship of ligands with NA, the current situation of NA inhibitors and its classification and at last we give the design thinking of my thesis.Section2:the structure-relationship of oseltamivir with NA showed us that amino in C-5of oseltamivir were toward to150-cavity, so we used shikimic acid as starting material and prepared twenty compounds with hydrophobic group at amino C-5of oseltamivir. We have evaluated the inhibitory activity of compounds in vivo, the result showed that all those compounds have moderated inhibitory activity of NA in vivo. Finally we verified the result by molecular docking, it shows that the hydrophobic group of amino in C-5of oseltamivir can interact with150-cavity.Section3:Up to now, all the NA inhibitors were hard to synthesize for its flexibility core structure. As we all kown, the core structure has no affection to the inhibitory activity of NA inhibitors. So we hope to use solid core structure benzene ring to replace flexibility core structure such as fatty five or six rings. We prepared twenty-five compounds use benzene ring as core structure. The structure of all these compounds were proved by some method.and evaluated the inhibitory activity in vivo. Finally we verified the result by molecular docking, it show that the hydrophobic group of amino in C-5of can interacted with150-cavity.Section4:we can know that the inhibitory activity of NA inhibitors has no relationship with its core structure by studying the relationship-structure of ligand and NA. Based on the conclusion, we designed and synthesized a serried of6-oxo-1,4,5,6-tetrahydro-pyrimidine-5-carboxylate compounds as NA inhibitors. All these compounds were evaluated the inhibitory activity in vivo. The result showed that most of compounds have a moderate inhibitory activity in vivo and we have evaluated the relationship of substituent of benzene with inhibitory activity of NA. At last we illustrated how those compounds interacted with NA by molecular docking. The result of molecular docking showed that these compounds interacted with NA similar with oseltamivir or zanamivir.In conclusion, we have designed,synthesized and evaluated three kind of NAIs with different structure. At the same time we study that how did the compounds interacted with proteins by autodock. It has given us more information for finding novel NA inhibitors.