Discovery of 2‑Phenylquinolines with Broad-Spectrum Anti-coronavirus Activity

• Published in: ACS medicinal chemistry letters 2022-05, Vol.13 (5), p.855-864
• Main Authors: Nizi, Maria Giulia, Persoons, Leentje, Corona, Angela, Felicetti, Tommaso, Cernicchi, Giada, Massari, Serena, Manfroni, Giuseppe, Vangeel, Laura, Barreca, Maria Letizia, Esposito, Francesca, Jochmans, Dirk, Milia, Jessica, Cecchetti, Violetta, Schols, Dominique, Neyts, Johan, Tramontano, Enzo, Sabatini, Stefano, De Jonghe, Steven, Tabarrini, Oriana
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00123

A selection of compounds from a proprietary library, based on chemical diversity and various biological activities, was evaluated as potential inhibitors of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a phenotypic-based screening assay. A compound based on a 2-phenyl­quinoline scaffold emerged as the most promising hit, with EC50 and CC50 values of 6 and 18 μM, respectively. The subsequent selection of additional analogues, along with the synthesis of ad hoc derivatives, led to compounds that maintained low μM activity as inhibitors of SARS-CoV-2 replication and lacked cytotoxicity at 100 μM. In addition, the most promising congeners also show pronounced antiviral activity against the human corona­viruses HCoV-229E and HCoV-OC43, with EC50 values ranging from 0.2 to 9.4 μM. The presence of a 6,7-dimethoxy­tetrahydro­isoquinoline group at the C-4 position of the 2-phenyl­quinoline core gave compound 6g that showed potent activity against SARS-CoV-2 helicase (nsp13), a highly conserved enzyme, highlighting a potentiality against emerging HCoVs outbreaks.