Design and synthesis of phosphono-zanamivir derivatives against influenza virus

• Main Authors: Yu-Cheng Liu, 劉宥承
• Other Authors: Jim-Min Fang
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/5822vd

碩士 === 國立臺灣大學 === 化學研究所 === 101 === Influenza is a severe viral infection of respiratory system. The outbreaks of worldwide H5N1 avian influenza and the new type pandemic H1N1 human flu have heightened the threat of public health. Zanamivir and oseltamivir are the main anti-influenza drugs targeting the neuraminidase (NA) of influenza virus. NA plays an important role in the life cycle of influenza viruses. There are two phylogenetically distinct groups of NAs of influenza A viruses: group-1 NAs include the N1, N4, N5, and N8 subtypes, and group-2 NAs include the N2, N3, N6, N7, and N9 subtypes. The group-1 NA contains a flexible loop and a cavity, so-called “150-cavity” near the binding pocket S2. Based on this rationale, we designed new inhibitors, which targeted 150-cavity of group-1 NA for better inhibitory activity. On the other hand, the uncontrolled virus-induced cytokines could cause the high mortality of human infected by H5N1 avian influenza virus. We explored the novel dual-target bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. Our research group has developed the zanamivir phosphonate congeners, which have better inhibitory activities. In this study I synthesized the pivotal intermediate compound 26, and further modified the C4-substituent for two specific aims. We successfully synthesized compounds 34 and 39 by conjugating the phosphono-zanamivir with anti-inflammatory agents as new dual-target drugs against influenza viruses. The bioactivity of compounds 34 and 39 is currently under investigation. We also designed the phosphono-zanamivir derivatives 42 and 43 having additional bindings to the 150-cavity of group-1 NAs. The synthetic work is in progress.