Synthesis, structure activity relationship and in vitro anti-influenza virus activity of novel polyphenol-pentacyclic triterpene conjugates

It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain pentacyclic triterpene derivatives are effective inhibitors of influenza virus infection. In the present study, a series of C-28 modified pentacyclic triterpene derivatives via conjugation with a series of polyphenols were synthesized, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m , 23o , 23q and 23s displayed robust anti-influenza potency with averaged IC 50 values at the low-micromole level, surpassing the potency of oseltamivir . In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100  μ M. Further mechanism studies of compound 23s , one of the best representative conjugates with IC 50 value of 5.80  μ M and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin ( K D  = 15.6  μ M), thus blocking the invasion of influenza viruses into host cells.