2. Academic Validation
  3. Design, synthesis and biological evaluation of biaryl amide derivatives against SARS-CoV-2 with dual-target mechanism

Design, synthesis and biological evaluation of biaryl amide derivatives against SARS-CoV-2 with dual-target mechanism

  • Eur J Med Chem. 2023 Nov 25:264:115978. doi: 10.1016/j.ejmech.2023.115978.
Jiayu Li 1,  Xiuli Zhong 1,  Hongying Li 1,  Zhihui Yu 1,  Jianrui Li 1,  Qionglu Duan 1,  Yinghong Li 1,  Fenbei Chen 1,  Yanxiang Wang 1,  Zhiyun Wu 1,  Yonghua Liu 2,  Zonggen Peng 3,  Danqing Song 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 38061229 DOI: 10.1016/j.ejmech.2023.115978
Abstract

The COVID-19 pandemic highlights the urgent need to develop effective small-molecule antivirals. Thirty-three novel biaryl amide derivatives were synthesized and evaluated for anti-coronaviral activity. Some significant SARs were uncovered and the intensive structure modifications led to the most active compounds 8b and 8h. The broad-spectrum anti-coronaviral effects of 8h were validated at RNA and protein levels. 8h inhibits coronavirus replication at multiple stages, from virus entry to virus dsRNA synthesis. The mechanism of action showed that 8h may simultaneously act on 3CLpro and TMPRSS2 to display anti-coronaviral effects. 8h combined with RdRp inhibitor showed synergistic inhibitory activity against coronavirus. This study confirmed that biaryl amide derivatives may be a new class of potential therapeutic agents against coronavirus with multiple target effect, worthy of further investigation.

Keywords

3CL(pro); Antivirals; Biarylamide derivatives; SARS-CoV-2; TMPRSS2.

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