Design,synthesis And Biological Evaluation Of Oleanolic Acid-Amino Acid Conjugates As Influenza Inhibitors

Influenza A virus,a member of the Orthomyxoviridae family,possesses a segmented,single-stranded RNA-genome with a negative orientation.Influenza is a contagious respiratory acute viral disease characterized by a short incubation period,high fever and respiratory and systemic symptoms.Influenza virus is a major human pathogen that causes annual epidemics and occasional pandemics.Influenza A virus is the major cause of seasonal or pandemic flu worldwide.Since the mid-90s a high incidence of rimantadine resistance in field isolates of influenza viruses has been reported,and resistance to adamantane drugs are now found in almost all isolates of influenza A virus.One of the major factors is the rapid mutation in the two surface antigens(hemagglutinin and neuraminidase),which results in the failure of vaccines prepared from existing viruses.However,a major problem with both classes of drugs that target viral proteins is the rapid emergence of drug-resistant viral strains which have limited their use.Recently,plant-derived pentacyclic triterpenes have been shown to act as highly potent anti-viral agents by efficiently preventing the attachment of the virion to the host cells.Since resistance to the existing anti-influenza drugs is rising,innovative inhibitors with a different mode of action are urgently needed.Influenza virus entry represents a favorable target for drug discovery because inhibition of the first step of virus infection should result in an efficient block to virus propagation.To continue our studies towards the development of novel antiviral inhibitors,we report certain pentacyclic triterpenoids with conserved structure features displaying in vitro anti-influenza virus activity.Here we prepared new types of molecules containing pentacyclic triterpene oleanolic acid(OA),moieties connected to amino acids via amide linker in the present study.The structure-activity relationship of the compounds blocked influenza viruses was systematically studied.Through the comparison of activity,we found that when the amino acid methyl ester was used as a functional fragment to conjugate OA,it had lower antiviral activity but lower toxicity.Due to the presence of aromatic rings on the amino acids,the toxicity of the compounds increases.Hydroxyl exposure after demethylation changes its lipid partition coefficient,and also increases the toxicity or activity of the compounds.Compounds Y-2-11 and M-1-35 have high activity and low toxicity to MDCK cell,and their protection rates were 11.48%and 1934%,respectively.The activity of these compounds was evaluated by the experimental mechanism for the preliminary study of the mechanism of action of compounds Y-2-11 and M-1-35 against influenza virus.