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

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

2022-01-01

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Abstract

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 conservedenzyme, highlighting a potentiality against emerging HCoVs outbreaks.