Study On Design,Synthesis And Antiviral Activity Of Dehydroabietic Acid Based N-containing Derivatives

As the major producer and exporter of rosin,China has the annual output more than400,000 tons.Design and synthesis of rosin derivatives with biological activity is an effective way to increase the level of deep processing and utilization of rosin.In this paper,dehydroabietic acid,the main component of disproportionated rosin was used as starting material,series of new dehydroabietic acid basedα-aminophosphonate and dehydroabietic acid based 3,4-dihydropyrimidinones were synthesized.Inhibitory activities against herpes simplex viruses 1（HSV-1）,influenza virus（H1N1）and（H3N2）of rosin-based derivatives were evaluated.The quantitative structure-activity relationship between the structures and antiviral activity of rosin-based dihydropyrimidone derivatives against influenza virus（H1N1）were established.With dehydroabietic acid as raw material,after preliminary chemical modification,groups such as amino,thiosemicarbazone were introduced.Series of new dehydroabietic acid basedα-aminophosphonate（1a～1l）and rosin-based 3,4-dihydropyrimidinones（3a～3q）were further synthesized.Their structures were characterized by fourier transform infrared spectroscopy（FT-IR）,nuclear magnetic resonance spectroscopy(¹H NMR,¹³C NMR)and electrospray ionization mass spectrometry（ESI-MS）.Inhibitory activities against herpes simplex viruses 1（HSV-1）of dehydroabietic acid basedα-aminophosphonate were evaluated.The results showed that the IC50 of theseα-aminophosphonate derivatives was 12.3～22.1μmol/m L,it showed increased antiviral activity than dehydroabietic acid(IC₅₀ 24.7μmol/m L),but worse than the commercially available antiviral drug cidofovir(IC₅₀ 1.9μmol/m L).Cytotoxicities and inhibitory activities against herpes simplex viruses 1（HSV-1）of rosin-based 3,4-dihydropyrimidinones were measured.By calculating the drug selection index（SI,SI=TC50/IC50）,it could be found that compound 3j had excellent inhibitory activity（SI 12.18）against HSV-1 compared with ribavirinand（SI 12.6）,the remaining compounds had weak antiviral activities.Inhibitory activities against influenza virus（H1N1）and（H3N2）of rosin-based3,4-dihydropyrimidines and 3,4-dihydropyrimidines without rosin structure were evaluated.By contrast,the anti-influenza activities of dihydropyrimidone derivatives introduced with rosin structure were significantly increased.In rosin-based dihydropyrimidone derivatives,compoud3a,3k,3m and 3o showed higher inhibitory activity against influenza virus（H1N1）than the commercial antiviral drug peramivir,meanwhile,these compouds showed good inhibitory activity against influenza virus（H3N2）.The quantitative structure-activity relationship between the structures and antiviral activity of rosin-based dihydropyrimidone derivatives against influenza virus（H1N1）were studied by heuristic regression method,the quantitative structure-activity relationships（QSAR）model between rosin-based dihydropyrimidone derivatives and the antiviral activity was established.The best QSAR model was tested by the triple internal test and the leave-one test,and the results show that the best QSAR model had good stability and predictive ability.The established QSAR model contains four molecular descriptors that were closely related to the anti-influenza virus activity.According to the analysis of these descriptors,the charge distribution on the surface of rosin derivative molecules,as well as the hydrogen bond related atoms and charge distribution were closely related to their antiviral activity.This result provides some useful preliminary information to further molecular design of new rosin derivatives with antiviral activity against influenza virus（H1N1）.