1. Academic Validation
  2. Discovery of 2-Phenylquinolines with Broad-Spectrum Anti-coronavirus Activity

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

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.
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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