2. Academic Validation
  3. Identification of novel 1,2,3-triazole isatin derivatives as potent SARS-CoV-2 3CLpro inhibitors via click-chemistry-based rapid screening

Identification of novel 1,2,3-triazole isatin derivatives as potent SARS-CoV-2 3CLpro inhibitors via click-chemistry-based rapid screening

  • RSC Med Chem. 2023 Aug 17;14(10):2068-2078. doi: 10.1039/d3md00306j.
Xiangyi Jiang 1,  Jing Li 1,  Antonio Viayna 2 3,  F Javier Luque 2 3 4,  Molly Woodson 5 6,  Lanlan Jing 1,  Shenghua Gao 1,  Fabao Zhao 1,  Minghui Xie 1,  Karoly Toth 5 6,  John Tavis 5 6,  Ann E Tollefson 5 6,  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, Cheeloo College of Medicine, Shandong University 44 West Culture Road 250012 Jinan Shandong PR China xinyongl@sdu.edu.cn zhanpeng1982@sdu.edu.cn.
  • 2 Departament de Nutrició, Ciències de l'Alimentació i Gastronomia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona (UB) Av. Prat de la Riba 171 08921 Santa Coloma de Gramenet Spain.
  • 3 Institut de Biomedicina (IBUB), Universitat de Barcelona (UB) Barcelona Spain.
  • 4 Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona (UB) Barcelona Spain.
  • 5 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine St. Louis Missouri 63104 USA ann.tollefson@health.slu.edu.
  • 6 Saint Louis University Institute for Drug and Biotherapeutic Innovation St. Louis Missouri 63104 USA.
PMID: 37859715 DOI: 10.1039/d3md00306j
Abstract

SARS-CoV-2 3-chymotrypsin-like Protease (3CLpro) is considered an attractive target for the development of anti-COVID-19 agents due to its vital function. The N-substituted isatin derivative L-26 is a potential SARS-CoV-2 3CLpro inhibitor, but it has poor cell-based Antiviral activity and high cytotoxicity. With L-26 as the lead compound, 58 isatin derivatives were prepared using click-chemistry-based miniaturized synthesis and their 3CLpro inhibitory activities were determined by a fluorescence resonance energy transfer-based enzymatic assay. Compounds D1N8 (IC50 = 0.44 ± 0.12 μM) and D1N52 (IC50 = 0.53 ± 0.21 μM) displayed excellent inhibitory potency against SARS-CoV-2 3CLpro, being equivalent to that of L-26 (IC50 = 0.30 ± 0.14 μM). In addition, the cytotoxicity of D1N8 (CC50 >20 μM) and D1N52 (CC50 >20 μM) decreased significantly compared with L-26 (CC50 <2.6 μM). Further molecular dynamics simulations revealed the potential binding interactions between D1N52 and SARS-CoV-2 3CLpro. These efforts lay a solid foundation for the research of novel anti-SARS-CoV-2 agents targeting 3CLpro.

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