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

• Main Authors: Antonella Messore (Author), Paolo Malune (Author), Elisa Patacchini (Author), Valentina Noemi Madia (Author), Davide Ialongo (Author), Merve Arpacioglu (Author), Aurora Albano (Author), Giuseppe Ruggieri (Author), Francesco Saccoliti (Author), Luigi Scipione (Author), Enzo Tramontano (Author), Serena Canton (Author), Angela Corona (Author), Sante Scognamiglio (Author), Annalaura Paulis (Author), Mustapha Suleiman (Author), Helmi Mohammed Al-Maqtari (Author), Fatma Mohamed A. Abid (Author), Sarkar M. A. Kawsar (Author), Murugesan Sankaranarayanan (Author), Roberto Di Santo (Author), Francesca Esposito (Author), Roberta Costi (Author)
• Format: Book
• Published: MDPI AG, 2024-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 (M^pro) has been deemed a promising drug target vs. COVID-19. Indeed, M^pro 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 M^pro 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 M^pro. 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.

Item Description

10.3390/ph17050650
1424-8247