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

  • ACS Med Chem Lett. 2022 May 3;13(5):855-864. doi: 10.1021/acsmedchemlett.2c00123.
Maria Giulia Nizi  1 ,  Leentje Persoons  2 ,  Angela Corona  3 ,  Tommaso Felicetti  1 ,  Giada Cernicchi  1 ,  Serena Massari  1 ,  Giuseppe Manfroni  1 ,  Laura Vangeel  2 ,  Maria Letizia Barreca  1 ,  Francesca Esposito  3 ,  Dirk Jochmans  2 ,  Jessica Milia  3 ,  Violetta Cecchetti  1 ,  Dominique Schols  2 ,  Johan Neyts  2 ,  Enzo Tramontano  3 ,  Stefano Sabatini  1 ,  Steven De Jonghe  2 ,  Oriana Tabarrini  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
  • 2. Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 3. Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09124 Cagliari, Italy.
PMID: 35571875 DOI: 10.1021/acsmedchemlett.2c00123
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 conserved enzyme, highlighting a potentiality against emerging HCoVs outbreaks.

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