2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability

Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability

  • J Med Chem. 2023 Nov 22. doi: 10.1021/acs.jmedchem.3c01876.
Shenghua Gao 1 2,  Letian Song 1,  Katharina Sylvester 3,  Beatrice Mercorelli 4,  Arianna Loregian 4,  Karoly Toth 5,  Renato H Weiße 6,  Abibe Useini 6,  Norbert Sträter 6,  Mianling Yang 1,  Bing Ye 1,  Ann E Tollefson 5,  Christa E Müller 3,  Xinyong Liu 1,  Peng Zhan 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
  • 2 Shenzhen Research Institute of Shandong University, A301 Virtual University Park in South District of Shenzhen, Shenzhen, Guangdong 518057, PR China.
  • 3 PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53113 Bonn, Germany.
  • 4 Department of Molecular Medicine, University of Padua, Via Gabelli 63, 35121 Padua, Italy.
  • 5 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63103, United States.
  • 6 Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, Leipzig 04103, Germany.
PMID: 37992202 DOI: 10.1021/acs.jmedchem.3c01876
Abstract

The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent Antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (Mpro) inhibitors with prominent Antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal GC-78-HCl demonstrated high enzyme-inhibitory potency (IC50 = 0.19 μM) and exhibited excellent Antiviral activity (EC50 = 0.40 μM), reaching the same level as Nirmatrelvir (EC50 = 0.38 μM). Additionally, GC-78-HCl displayed potent Antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of GC-78-HCl were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic Mpro inhibitor with promising Antiviral activity and a favorable pharmacokinetic profile.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149774
    SARS-CoV-2 Mpro抑制剂
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