Thus, influenza poses a substantial threat to public health. The World Health Organization (WHO) estimates that approximately 3 to 5 million cases of severe influenza infection occur annually, with approximately 290,000 to 650,000 mortalities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. TBU) and was also supported in part by the Japan Society for the Promotion of Science, Grants-in-Aid for Young Scientists 18K15173 (to MS). This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This work was supported by a Grant from Tokushima Bunri University for Educational Reform and Collaborative Research (No. Received: SeptemAccepted: MaPublished: March 26, 2021Ĭopyright: © 2021 Shoji et al. (2021) Organic synthesis and anti-influenza A virus activity of cyclobakuchiols A, B, C, and D. In addition, our results suggest that the suitably spatial configuration between oxidized isopropyl group and phenol moiety in the structure of cyclobakuchiols is required for their effect.Ĭitation: Shoji M, Esumi T, Tanaka N, Takeuchi M, Yamaji S, Watanabe M, et al. These findings demonstrate that cyclobakuchiols have anti-influenza viral activity involving host cell oxidative stress response. Notably, cyclobakuchiols A, B, and C, but not D, induced the Nrf2 activation pathway. In addition, cyclobakuchiols A–D upregulated the mRNA levels of NAD(P)H quinone oxidoreductase 1, an Nrf2-induced gene, in influenza A virus-infected cells. Additionally, these compounds markedly reduced the mRNA expression of the host cell influenza A virus-induced immune response genes, interferon-β and myxovirus-resistant protein 1. As a result, cyclobakuchiols A–D were found to inhibit influenza A viral infection, growth, and the reduction of expression of viral mRNAs and proteins in influenza A virus-infected cells. In this study, cyclobakuchiols A, B, and C along with cyclobakuchiol D, a new artificial compound derived from cyclobakuchiol B, were synthesized and examined for their anti-influenza A virus activities using Madin-Darby canine kidney cells. However, it remains unclear whether cyclobakuchiols A–C induce anti-influenza A virus activity. We previously reported that bakuchiol induces enantiospecific anti-influenza A virus activity involving nuclear factor erythroid 2-related factor 2 (Nrf2) activation. The structural differences between cyclobakuchiol A and C arise due to the oxidation state of isopropyl group, and these compounds can be derived from (+)-( S)-bakuchiol, a phenolic isoprenoid compound present in P. Cyclobakuchiols A and B have been isolated from Psoralea glandulosa, and cyclobakuchiol C has been isolated from P. Novel antiviral agents for influenza, which poses a substantial threat to humans, are required.