Pharmaceuticals (May 2024)

New Thiazolidine-4-One Derivatives as SARS-CoV-2 Main Protease Inhibitors

  • Antonella Messore,
  • Paolo Malune,
  • Elisa Patacchini,
  • Valentina Noemi Madia,
  • Davide Ialongo,
  • Merve Arpacioglu,
  • Aurora Albano,
  • Giuseppe Ruggieri,
  • Francesco Saccoliti,
  • Luigi Scipione,
  • Enzo Tramontano,
  • Serena Canton,
  • Angela Corona,
  • Sante Scognamiglio,
  • Annalaura Paulis,
  • Mustapha Suleiman,
  • Helmi Mohammed Al-Maqtari,
  • Fatma Mohamed A. Abid,
  • Sarkar M. A. Kawsar,
  • Murugesan Sankaranarayanan,
  • Roberto Di Santo,
  • Francesca Esposito,
  • Roberta Costi

DOI
https://doi.org/10.3390/ph17050650
Journal volume & issue
Vol. 17, no. 5
p. 650

Abstract

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It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (Mpro) has been deemed a promising drug target vs. COVID-19. Indeed, Mpro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a Mpro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 Mpro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue.

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