A selection of compounds from a proprietary library, based on chemical diversity and various biological activities, was evaluated as potential inhibitors of the Severe phenotypic-based screening assay. A compound based on a 2phenylquinoline scaffold emerged as the most promising hit, with EC50 and CC50 values of 6 and 18 mu M, respectively. The subsequent selection of additional analogues, along with the synthesis of ad hoc derivatives, led to compounds that maintained low mu M activity as inhibitors of SARS-CoV-2 replication and lacked cytotoxicity at 100 mu M. 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 mu M. The presence of a 6,7-dimethoxytetrahydroisoquinoline group at the C-4 position of the 2phenylquinoline 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.

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

Nizi, Maria Giulia;Felicetti, Tommaso;Cernicchi, Giada;Massari, Serena;Manfroni, Giuseppe;Barreca, Maria Letizia;Cecchetti, Violetta;Sabatini, Stefano
;
Tabarrini, Oriana
2022

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 phenotypic-based screening assay. A compound based on a 2phenylquinoline scaffold emerged as the most promising hit, with EC50 and CC50 values of 6 and 18 mu M, respectively. The subsequent selection of additional analogues, along with the synthesis of ad hoc derivatives, led to compounds that maintained low mu M activity as inhibitors of SARS-CoV-2 replication and lacked cytotoxicity at 100 mu M. 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 mu M. The presence of a 6,7-dimethoxytetrahydroisoquinoline group at the C-4 position of the 2phenylquinoline 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.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1533093
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 3
social impact