TY - JOUR
T1 - Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication
AU - Bardiot, Dorothée
AU - Vangeel, Laura
AU - Koukni, Mohamed
AU - Arzel, Philippe
AU - Zwaagstra, Marleen
AU - Lyoo, Heyrhyoung
AU - Wanningen, Patrick
AU - Ahmad, Shamshad
AU - Zhang, Linlin
AU - Sun, Xinyuanyuan
AU - Delpal, Adrien
AU - Eydoux, Cecilia
AU - Guillemot, Jean Claude
AU - Lescrinier, Eveline
AU - Klaassen, Hugo
AU - Leyssen, Pieter
AU - Jochmans, Dirk
AU - Castermans, Karolien
AU - Hilgenfeld, Rolf
AU - Robinson, Colin
AU - Decroly, Etienne
AU - Canard, Bruno
AU - Snijder, Eric J.
AU - van Hemert, Martijn J.
AU - van Kuppeveld, Frank
AU - Chaltin, Patrick
AU - Neyts, Johan
AU - De Jonghe, Steven
AU - Marchand, Arnaud
N1 - Funding Information:
Funding: Part of this research work was performed using the ‘Caps-It’ research infrastructure (project ZW13-02) that was financially supported by the Hercules Foundation and Rega Foundation, KU Leuven’. This project has received funding from the European Union’s Horizon 2020 research and Innovation program under grant No 10100362 (the SCORE project). Part of this work was performed under the CARE project. The CARE project has received funding from the Innovative Medicines Initiative Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Bill & Melinda Gates Foundation, Global Health Drug Discovery Institute, University of Dundee. The content of this publication only reflects the author’s view and the JU is not responsible for any use that may be made of the information it contains.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/4
Y1 - 2022/2/4
N2 - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subsequent hit-to-lead optimization campaigns, we conducted a high-throughput screening of a 160 K compound library against SARS-CoV-2, yielding a 1-heteroaryl-2-alkoxyphenyl analog as a promising hit. Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experi-ments demonstrated that it interfered with viral entry. A systematic structure–activity relationship (SAR) study demonstrated that a 3-or 4-pyridyl moiety on the oxadiazole moiety is optimal, whereas the oxadiazole can be replaced by various other heteroaromatic cycles. In addition, the alkoxy group tolerates some structural diversity.
AB - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subsequent hit-to-lead optimization campaigns, we conducted a high-throughput screening of a 160 K compound library against SARS-CoV-2, yielding a 1-heteroaryl-2-alkoxyphenyl analog as a promising hit. Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experi-ments demonstrated that it interfered with viral entry. A systematic structure–activity relationship (SAR) study demonstrated that a 3-or 4-pyridyl moiety on the oxadiazole moiety is optimal, whereas the oxadiazole can be replaced by various other heteroaromatic cycles. In addition, the alkoxy group tolerates some structural diversity.
KW - 1,2,4-oxadiazole
KW - 1-heteroaryl-2-alkoxyphenyl analogs
KW - COVID-19
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85124186896&partnerID=8YFLogxK
U2 - 10.3390/molecules27031052
DO - 10.3390/molecules27031052
M3 - Article
C2 - 35164317
AN - SCOPUS:85124186896
SN - 1420-3049
VL - 27
JO - Molecules
JF - Molecules
IS - 3
M1 - 1052
ER -
