Synthesis and Anti-Influenza Virus Effects of Novel Substituted Polycyclic Pyridone Derivatives Modified from Baloxavir.
Tang L, Yan H, Wu W, Chen D, Gao Z, Hou J, Zhang C, Jiang Y.
In this work, a series of novel substituted polycyclic pyridone derivatives were designed and synthesized as potent anti-influenza agents. The cytopathic effect (CPE) assay and cytotoxicity assay indicated that all of the compounds possessed potent anti-influenza virus activity and relatively low cytotoxicity; some of them inhibited the replication of influenza A virus (IAV) at picomolar concentrations. Further studies revealed that, at a concentration of 3 nM, three compounds (<b>10a</b>, <b>10d</b>, and <b>10g</b>) could significantly reduce the <i>M2</i> RNA amounts and M2 protein expression of IAV and inhibit the activity of RNA-dependent RNA polymerase (RdRp). Among them, (<i>R</i>)-12-(5<i>H</i>-dibenzo[<i>a</i>,<i>d</i>][7]annulen-5-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1<i>H</i>-[1,4]oxazino[3,4-<i>c</i>]pyrido[2,1-<i>f</i>][1,2,4]triazine-6,8-dione (<b>10a</b>) was found to be a promising anti-influenza drug candidate with good human liver microsomal stability, as well as with better selectivity index and oral bioavailability than Baloxavir.