2. Academic Validation
  3. Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PAN endonuclease

Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PAN endonuclease

  • Eur J Med Chem. 2020 Mar 1;189:112048. doi: 10.1016/j.ejmech.2020.112048.
Yixian Liao 1,  Yilu Ye 2,  Sumei Li 3,  Yilian Zhuang 4,  Liye Chen 4,  Jianxin Chen 5,  Zining Cui 6,  Lijian Huo 4,  Shuwen Liu 7,  Gaopeng Song 8
Affiliations

Affiliations

  • 1 College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China; State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China.
  • 2 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou, 510632, China.
  • 4 College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
  • 5 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
  • 6 State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China.
  • 7 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 8 College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China. Electronic address: [email protected].
PMID: 31954881 DOI: 10.1016/j.ejmech.2020.112048
Abstract

Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against Influenza Virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent Antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify Amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.

Keywords

Influenza a virus; PA(N) endonuclease inhibitors; Polyphenols; SARs.

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