Noncovalent Inhibitors of SARS-CoV-2 Main Protease: 
A Rescaffolding Attempt

Tim Krischuns; Sylvain Paisant; Kuang-Yu Chen; Laura N. Thirion; Agnès Zettor; Jeanne Chiaravalli; Yves Jacob; Marco Bellinzoni; Nadia Naffakh; Yves L. Janin

doi:10.1055/a-2519-9876

Synthesis, Table of Contents

Synthesis 2025; 57(09): 1627-1634
DOI: 10.1055/a-2519-9876

paper

Noncovalent Inhibitors of SARS-CoV-2 Main Protease: A Rescaffolding Attempt

Authors

Tim Krischuns

^aRNA Biology and Influenza Virus Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France
Sylvain Paisant

^aRNA Biology and Influenza Virus Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France
Kuang-Yu Chen

^aRNA Biology and Influenza Virus Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France
Laura N. Thirion

^bStructure et Instabilité des Génomes (StrInG), Muséum National d′Histoire Naturelle, INSERM, CNRS, Alliance Sorbonne Université, 75005 Paris, France
Agnès Zettor

^cChemogenomic and Biological Screening Core Facility, Institut Pasteur, Université Paris Cité, CNRS UMR 3523, Paris, France
Jeanne Chiaravalli

^cChemogenomic and Biological Screening Core Facility, Institut Pasteur, Université Paris Cité, CNRS UMR 3523, Paris, France
Yves Jacob

^dMolecular Genetics of RNA Viruses Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France
Marco Bellinzoni

^eStructural Microbiology Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3528, 25-28 rue du Dr. Roux, 75015 Paris, France
Nadia Naffakh

^aRNA Biology and Influenza Virus Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, 25-28 rue du Dr. Roux, 75015 Paris, France
Yves L. Janin

^bStructure et Instabilité des Génomes (StrInG), Muséum National d′Histoire Naturelle, INSERM, CNRS, Alliance Sorbonne Université, 75005 Paris, France

Abstract

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Abstract

Out of the results of the sole large-scale screening for inhibitors of SARS-CoV-1 main protease reported in 2013, attempts to improve the identified 3-pyridyl-bearing hits have been conducted in research laboratories, either on this enzyme or more recently on the closely related SARS-CoV-2 main protease. From the resulting structural information reported, we sought to design analogues featuring some of the components providing an affinity for the active site of these proteases along with a different scaffold, which would allow for further structure-activity relationship studies and/or pharmacological improvements. We describe here the introduction of a bridging component with the aim of stabilizing the ligand conformation adopted when bound to these proteases. Accordingly, this led us to prepare 3,3-disubstituted piperazin-2-ones from an array of ketones, via either a Bargellini reaction or a multistage condensation/cyclization/hydrolysis involving ethylene diamine and potassium cyanide. However, even the most elaborate and lipophilic biphenyl-bearing analogues displayed only a weak effect in a bioluminescence-based SARS-CoV-2 main protease inhibition assay.

Key words

medicinal chemistry - phase-transfer catalysis - SARS-CoV-2 main protease - Bargellini reaction - piperazinone

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References

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Supplementary Material

Supporting Information (PDF)