Discovery of 2-Phenylquinolines with Broad-Spectrum Anti-coronavirus Activity
Maria Giulia Nizi, Leentje Persoons, Angela Corona, Tommaso Felicetti, Giada Cernicchi, Serena Massari, Giuseppe Manfroni, Laura Vangeel, Maria Letizia Barreca, Francesca Esposito, Dirk Jochmans, Jessica Milia, Violetta Cecchetti, Dominique Schols, Johan H. Neyts, Enzo Tramontano, Stefano Sabatini, Steven De Jonghe, Oriana Tabarrini · ACS Medicinal Chemistry Letters · 2022
High Resolution Image Download MS PowerPoint Slide 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 EC 50 and CC 50 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 EC 50 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.