2. Academic Validation
  3. Discovery and optimization of new 6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives as potent influenza virus PAN inhibitors

Discovery and optimization of new 6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives as potent influenza virus PAN inhibitors

  • Eur J Med Chem. 2022 Jan 5:227:113929. doi: 10.1016/j.ejmech.2021.113929.
Zhihao Liu 1,  Shuyin Gu 2,  Xiang Zhu 3,  Mingjian Liu 1,  Zhenqing Cao 1,  Pengsen Qiu 1,  Sumei Li 4,  Shuwen Liu 5,  Gaopeng Song 6
Affiliations

Affiliations

  • 1 Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
  • 2 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 4 Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou, 510632, China. Electronic address: tlism@jnu.edu.cn.
  • 5 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: liusw@smu.edu.cn.
  • 6 Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China. Electronic address: songgp1021@scau.edu.cn.
PMID: 34700269 DOI: 10.1016/j.ejmech.2021.113929
Abstract

Annual unpredictable efficacy of vaccines, coupled with emerging drug resistance, underlines the development of new Antiviral drugs to treat influenza infections. The N-terminal domain of the PA (PAN) Endonuclease is both highly conserved across influenza strains and serotypes and is indispensable for the viral lifecycle, making it an attractive target for new Antiviral therapies. Here, we describe the discovery of a new class of PAN inhibitors derived from recently identified, highly active hits for PAN Endonuclease inhibition. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a fragment growing strategy, giving rise to a series of 1, 3-cis-2-substituted-1-(3, 4-dihydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid derivatives as potent PAN inhibitors. This approach ultimately resulted in the development of a new lead compound 13e, which exhibited an EC50 value of 4.50 μM against H1N1 Influenza Virus in MDCK cells.

Keywords

2; 3; 4-Tetrahydroisoquinoline-3-carboxylic acid derivatives; 6; 7-Dihydroxy-1; Anti-IAV activity; PA(N) endonuclease Inhibitors; Structure-activity relationships.

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