Synthesis of Benzoyl Andrographolide Derivatives as Potential Dual-function Anti-influenza Agents.

• Main Authors: Ko, Chinyi, 柯勤益
• Other Authors: Lee, Anrong and Huang, Wenhsing
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/50693715295643741209

碩士 === 國防醫學院 === 藥學研究所 === 99 === To conquer the drug resistance of influenza virus and improve the oral bioavalibility of current used neuraminidase inhibitors (NAIs), novel aromatic neuraminidase inhibitors (ANIs) based on ‘airplane model’ become an attractive issue in drug discovery. Besides, andrographolide (Andro), the active component of A. paniculata has effective neuraminidase inhibitory activity in vitro (EC50 = 35.69 μM, against H1N1) and one of its derivatives, 14-α-lipoyl andrographolide (AL-1), was reported that it has potent hemagglutinin inhibitory activity. Furthermore, the goal of incorporation of ANIs and andrographolide is to synthesize a series of potential dual-function anti-influenza agents against HA and NA activity of virus. According to ‘airplane model’, we modified 1 and 9 to synthesize two series of compounds, 9a-d and 10-13. 9b, 10 and 13 show inhibitory effects on Tamiflu resistant H1N1 virus in compounds. However, the incorporation of each compound with Andro 2 did not give the expected products. To overcome the difficulties in this project, MPA, an inosine monophosphate dehydrogenase inhibitor, was incorporated to Andro 2 via Mitsunobu reaction to give AnWen-K, showing potent inhibitory effect on A / WSN/ 33 (H1N1) virus in vitro (EC50 ＜ 1.78 μM). The mechanism of action of AnWen-K is about to be investigated. This is to suggest that it may be the basis for the development of anti-influenza agents in the future.