Messore, Antonella, Malune, Paolo, Patacchini, Elisa, Madia, Valentina Noemi, Ialongo, Davide, Arpacioglu, Merve, Albano, Aurora, Ruggieri, Giuseppe, Saccoliti, Francesco, Scipione, Luigi, Tramontano, Enzo, Canton, Serena, Corona, Angela, Scognamiglio, Sante, Paulis, Annalaura, Suleiman, Mustapha, Al-Maqtari, Helmi Mohammed, Abid, Fatma Mohamed A., Kawsar, Sarkar M. A., and Sankaranarayanan, Murugesan more...
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. [ABSTRACT FROM AUTHOR] more...