tetano
Editor, Senior Moderator
ChemMedChem
. 2026 Apr 14;21(7):e202501063.
doi: 10.1002/cmdc.202501063.
2-Phenylquinolines Exhibit Anti-Severe Acute Respiratory Syndrome Coronavirus-2 Activity Through the Nonstructural Protein 13 Helicase Inhibition
Giada Cernicchi[SUP] 1 [/SUP], Maria Giulia Nizi[SUP] 1 [/SUP], Roberta Emmolo[SUP] 2 [/SUP], Leentje Persoons[SUP] 3 [/SUP], Manon Laporte[SUP] 4 [/SUP], Dirk Jochmans[SUP] 4 [/SUP], Isabella Romeo[SUP] 5 [/SUP], Giacomo Pepe[SUP] 6 [/SUP], Ciro Milite[SUP] 6 [/SUP], Pietro Campiglia[SUP] 6 [/SUP], Jacopo Spezzini[SUP] 7 [/SUP], Alma Martelli[SUP] 7 [/SUP], Simone Brogi[SUP] 7 [/SUP], Francesca Esposito[SUP] 2 [/SUP], Tommaso Felicetti[SUP] 1 [/SUP], Serena Massari[SUP] 1 [/SUP], Giuseppe Manfroni[SUP] 1 [/SUP], Stefano Sabatini[SUP] 1 [/SUP], Gianluca Sbardella[SUP] 6 [/SUP], Stefano Alcaro[SUP] 5 [/SUP], Johan Neyts[SUP] 4 [/SUP], Angela Corona[SUP] 2 [/SUP], Enzo Tramontano[SUP] 2 [/SUP], Steven De Jonghe[SUP] 8 [/SUP], Oriana Tabarrini[SUP] 1 [/SUP]
Affiliations
The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has highlighted the fragility of our therapeutic arsenal against human coronaviruses and the urgent need to develop new antivirals. They should exhibit broad-spectrum activity to address future pandemics and target alternative viral proteins to mitigate resistance. We have previously identified a hit compound based on a 2-phenylquinoline scaffold that is able to hinder SARS-CoV-2 replication through nonstructural protein 13 (nsp13) helicase inhibition. Here we reported a SAR study that led to identify new analogs such as 2-(4-butoxyphenyl)-4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]-5,7-dimethoxyquinoline (14) and 4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]-2-(4-isopropoxyphenyl)-5,7-dimethoxyquinoline (15), which exhibited a good antiviral profile (EC[SUB]50[/SUB] = 8.06 and 9.11 µM) coupled with a low micromolar inhibition of nsp13 helicase. Time-of-addition assays and binding analyses confirmed helicase as their primary target, while kinetic studies revealed ATP-competitive inhibition. The butoxy derivative 14 also inhibited HCoV-229E and HCoV-OC43 replication, indicating broad-spectrum potential. The safety of the compounds was validated in bronchial epithelium cells BEAS-2B cells and H9c2 cardiac cells, where they did not affect cell viability or reactive oxygen species (ROS) production. Finally, preliminary ADME studies on 15 showed a positive profile in terms of membrane permeability and metabolic stability in plasma and human liver microsomes. This SAR study, along with mechanistic exploration, paves the way for further optimization of 2-phenylquinoline-based compounds.
Keywords: 2‐phenylquinolines; antivirals; human coronaviruses (HCoVs); nonstructural protein 13 (nsp13) helicase; severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2).
. 2026 Apr 14;21(7):e202501063.
doi: 10.1002/cmdc.202501063.
2-Phenylquinolines Exhibit Anti-Severe Acute Respiratory Syndrome Coronavirus-2 Activity Through the Nonstructural Protein 13 Helicase Inhibition
Giada Cernicchi[SUP] 1 [/SUP], Maria Giulia Nizi[SUP] 1 [/SUP], Roberta Emmolo[SUP] 2 [/SUP], Leentje Persoons[SUP] 3 [/SUP], Manon Laporte[SUP] 4 [/SUP], Dirk Jochmans[SUP] 4 [/SUP], Isabella Romeo[SUP] 5 [/SUP], Giacomo Pepe[SUP] 6 [/SUP], Ciro Milite[SUP] 6 [/SUP], Pietro Campiglia[SUP] 6 [/SUP], Jacopo Spezzini[SUP] 7 [/SUP], Alma Martelli[SUP] 7 [/SUP], Simone Brogi[SUP] 7 [/SUP], Francesca Esposito[SUP] 2 [/SUP], Tommaso Felicetti[SUP] 1 [/SUP], Serena Massari[SUP] 1 [/SUP], Giuseppe Manfroni[SUP] 1 [/SUP], Stefano Sabatini[SUP] 1 [/SUP], Gianluca Sbardella[SUP] 6 [/SUP], Stefano Alcaro[SUP] 5 [/SUP], Johan Neyts[SUP] 4 [/SUP], Angela Corona[SUP] 2 [/SUP], Enzo Tramontano[SUP] 2 [/SUP], Steven De Jonghe[SUP] 8 [/SUP], Oriana Tabarrini[SUP] 1 [/SUP]
Affiliations
- PMID: 41963257
- PMCID: PMC13068633
- DOI: 10.1002/cmdc.202501063
The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has highlighted the fragility of our therapeutic arsenal against human coronaviruses and the urgent need to develop new antivirals. They should exhibit broad-spectrum activity to address future pandemics and target alternative viral proteins to mitigate resistance. We have previously identified a hit compound based on a 2-phenylquinoline scaffold that is able to hinder SARS-CoV-2 replication through nonstructural protein 13 (nsp13) helicase inhibition. Here we reported a SAR study that led to identify new analogs such as 2-(4-butoxyphenyl)-4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]-5,7-dimethoxyquinoline (14) and 4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]-2-(4-isopropoxyphenyl)-5,7-dimethoxyquinoline (15), which exhibited a good antiviral profile (EC[SUB]50[/SUB] = 8.06 and 9.11 µM) coupled with a low micromolar inhibition of nsp13 helicase. Time-of-addition assays and binding analyses confirmed helicase as their primary target, while kinetic studies revealed ATP-competitive inhibition. The butoxy derivative 14 also inhibited HCoV-229E and HCoV-OC43 replication, indicating broad-spectrum potential. The safety of the compounds was validated in bronchial epithelium cells BEAS-2B cells and H9c2 cardiac cells, where they did not affect cell viability or reactive oxygen species (ROS) production. Finally, preliminary ADME studies on 15 showed a positive profile in terms of membrane permeability and metabolic stability in plasma and human liver microsomes. This SAR study, along with mechanistic exploration, paves the way for further optimization of 2-phenylquinoline-based compounds.
Keywords: 2‐phenylquinolines; antivirals; human coronaviruses (HCoVs); nonstructural protein 13 (nsp13) helicase; severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2).