Design,Synthesis And Biological Evaluation Of Oleanolic Acid-Oligosaccharide Conjugates As Influenza Inhibitors

Influenza pandemic is a serious threat to human health.With the emergence of influenza-resistant strains,the development of new anti-influenza drugs is an urgent task.Drugs developed for the entry phase of the virus are one of the ways to effectively delay the emergence of resistance to influenza virus due to the interaction between the virus and the host cell（low mutation rate）.Previous studies have shown that oleanolic acid（OA）binds to influenza virus hemagglutinin（HA）and inhibits influenza virus entry into host cells.In this dissertation,OA was used as the nucleus,and 20 OA derivatives conjugated with oligosaccharides as functional fragments were designed and synthesized.All of the synthesized OA-oligosaccharide conjugates were anti-influenza virus evaluated of drug activity.The structure-activity relationship of this compound against influenza virus was systematically studied.We found that all OA-oligosaccharide conjugates had no significant cytotoxicity against MDCK cells except for compounds 52,62 and 66.Among the 20 oligosaccharide conjugates,14 compounds had significantly higher anti-influenza activity than OA.The IC₅₀（semi-inhibitory concentration）of Compounds 58 and 59 against influenza A virus strain A/WSN/33 was 4.58μM and 6.52μM,respectively.Hemagglutination inhibition experiments show that compound 58 can effectively inhibits the hemagglutination of influenza A virus to host cells at a certain concentration.Furthermore,computer-simulated molecular docking data showed that compound 58 binds tightly to the sialic acid receptor binding site of the viral envelope protein HA with a minimμL binding energy of-10.63kcal/mol.Broad-spectrμL antiviral activity studies have shown that compound 58 has a certain inhibitory activity against a variety of oseltamivir-resistant strains.The above studies have contributed to the development of pentacyclic triterpenoid derivatives as inhibitors of influenza viruses.