Synthesis, Structure-Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication
Bardiot, Dorothée; Vangeel, Laura; Koukni, Mohamed; Arzel, Philippe; Zwaagstra, Marleen; Lyoo, Heyrhyoung; Wanningen, Patrick; Ahmad, Shamshad; Zhang, Linlin; Sun, Xinyuanyuan; Delpal, Adrien; Eydoux, Cecilia; Guillemot, Jean-Claude; Lescrinier, Eveline; Klaassen, Hugo; Leyssen, Pieter; Jochmans, Dirk; Castermans, Karolien; Hilgenfeld, Rolf; Robinson, Colin; Decroly, Etienne; Canard, Bruno; Snijder, Eric J; van Hemert, Martijn J; van Kuppeveld, Frank; Chaltin, Patrick; Neyts, Johan; De Jonghe, Steven; Marchand, Arnaud
(2022) Molecules (Basel, Switzerland), volume 27, issue 3, pp. 1 - 26
(Article)
Abstract
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
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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 experiments 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.
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Keywords: 1,2,4-oxadiazole, 1-heteroaryl-2-alkoxyphenyl analogs, COVID-19, SARS-CoV-2, Analytical Chemistry, Chemistry (miscellaneous), Molecular Medicine, Pharmaceutical Science, Drug Discovery, Physical and Theoretical Chemistry, Organic Chemistry
ISSN: 1420-3049
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: 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 2 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.
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