Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity

  • J Med Chem. 2024 Aug 15. doi: 10.1021/acs.jmedchem.4c00535.
Angelo Oneto  1  2 ,  Ghazl Al Hamwi  1  2 ,  Laura Schäkel  1  2 ,  Nadine Krüger  3 ,  Katharina Sylvester  1  2 ,  Marvin Petry  1  2 ,  Rasha Abu Shamleh  1  2 ,  Thanigaimalai Pillaiyar  1  2 ,  Tobias Claff  1  2 ,  Anke C Schiedel  1  2 ,  Norbert Sträter  4 ,  Michael Gütschow  1  2 ,  Christa E Müller  1  2
Affiliations
  • 1. Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn D-53121, Germany.
  • 2. PharmaCenter Bonn, University of Bonn, Brühler Straße 7, Bonn D-53121, Germany.
  • 3. Platform Infection Models, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, Germany.
  • 4. Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, Leipzig 04103, Germany.
PMID: 39146284 DOI: 10.1021/acs.jmedchem.4c00535
Abstract

SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing a variety of substituents as irreversible inhibitors of the main viral protease (Mpro). Altogether, 55 benzoyl chloro/bromo-pyridyl esters were synthesized, with broad variation of the substitution pattern on the benzoyl moiety. A workflow was employed for multiparametric optimization, including Mpro inhibition assays of SARS-CoV-2 and related pathogenic coronaviruses, the duration of enzyme inhibition, the compounds' stability versus glutathione, cytotoxicity, and Antiviral activity. Several compounds showed IC50 values in the low nanomolar range, kinact/Ki values of >100,000 M-1 s-1 and high Antiviral activity. High-resolution X-ray cocrystal structures indicated an important role of ortho-fluorobenzoyl substitution, forming a water network that stabilizes the inhibitor-bound enzyme. The most potent Antiviral compound was the p-ethoxy-o-fluorobenzoyl chloropyridyl ester (PSB-21110, 29b, MW 296 g/mol; EC50 2.68 nM), which may serve as a lead structure for broad-spectrum anticoronaviral therapeutics.

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