Synthesis and Structure-activity Relationships of Flavonoids Derived from Scutellaria baicalensis Georgi as Potent Anti-flu Agents against Tamiflu- resistant H1N1 Virus and H3N2 Virus

Annual global pandemic and/or epidemic influenza threats continually threaten human beings. Despite annual vaccination and the use of four approved antiviral agents (amantadine, rimantadine, zanamivir, and oseltamivir) to control viral infectivity of influenza viruses, there is still a limited effectiveness and suffering of severe drug side effects as well as the emergence of drug-resistant variants after treatments that prompt the needs of new agents to be developed to treat flu. Some Chinese medicines have been shown potential treatment for influenza. In this study, the direct acylation of dimethoxyphenol with substituted cinnamoyl chlorides by fries reaction and cyclization affords a practical route as standard manipulations for the synthesis of novel flavonoids related to baicalein/oroxyllin-A, which functionalized on the A- and/or B-ring with good overall yields. All the flavonoids in this study were screened with anti- influenza activity against influenza virus (H1N1-Tamiflu resistant and H3N2)-infected in MDCK cell line. Our results showed that most of the synthetic products possessed significant activity. Among them, 4a, 4c, 5c were more potent than that of ribavirin (a positive control) against H1N1-Tamiflu resistant virus. The most potent compound was 4a that displayed an effectively anti-H1N1- Tamiflu resistant viral activity at 2.9 μM and a selectivity index > 103.4. Compound 4c and 5c also exhibited a good inhibitory activity in 5.2 and 5.4 μM, respectively, against H1N1-Tamiflu resistant virus and the corresponding selectivity index > 57.7 and 8.0, respectively. Moreover, in the screening test against H3N2 virus, some synthetic compounds in this study displayed more potent inhibitory activity than against H1N1-Tamiflu resistant virus. Among them, compounds 3a, 5a, 7c, 10 and 11 exhibited a good inhibitory action in 5.5, 6.2, 4.5 4.0 and 6.1 μM against H3N2 virus, and the corresponding selectivity index > 54.4, > 48.3, 4.0, 32.4 and > 49.2, respectively. Those findings in this study provide somewhat important chemical structural features of flavonoids relating their ability after SAR analysis to control the replication of influenza virus and would provide basis to expedite the design and development of chemical compounds with higher potency and lower toxicity to serve as potential NA inhibitors for influenza treatment.