2. Academic Validation
  3. Synthesis and Anti-Influenza Virus Effects of Novel Substituted Polycyclic Pyridone Derivatives Modified from Baloxavir

Synthesis and Anti-Influenza Virus Effects of Novel Substituted Polycyclic Pyridone Derivatives Modified from Baloxavir

  • J Med Chem. 2021 Oct 14;64(19):14465-14476. doi: 10.1021/acs.jmedchem.1c00979.
Lin Tang 1,  Haiyan Yan 2,  Weibin Wu 1 3,  Dawei Chen 1,  Zhenxiong Gao 4,  Jinqiang Hou 5,  Cunlong Zhang 1 3,  Yuyang Jiang 6 7
Affiliations

Affiliations

  • 1 Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, P. R. China.
  • 2 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
  • 3 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, P. R. China.
  • 4 Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China.
  • 5 Department of Chemistry, Lakehead University and Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, Ontario P7B 6V4, Canada.
  • 6 Joint Key State Laboratory of Tumor Chemogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, P. R. China.
  • 7 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, P. R. China.
PMID: 34549580 DOI: 10.1021/acs.jmedchem.1c00979
Abstract

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 (10a, 10d, and 10g) could significantly reduce the M2 RNA amounts and M2 protein expression of IAV and inhibit the activity of RNA-dependent RNA polymerase (RdRp). Among them, (R)-12-(5H-dibenzo[a,d][7]annulen-5-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (10a) 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.

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