Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs As Inhibitors of SARS-CoV-2 Replication - Archive ouverte HAL Access content directly
Journal Articles Molecules Year : 2022

Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs As Inhibitors of SARS-CoV-2 Replication

Dorothée Bardiot
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Mohamed Koukni
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  • PersonId : 1125524
Philippe Arzel
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Marleen Zwaagstra
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Heyrhyoung Lyoo
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Patrick Wanningen
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Shamshad Ahmad
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Linlin Zhang
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Xinyuanyuan Sun
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Adrien Delpal
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Jean-Claude Guillemot
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Hugo Klaassen
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Karolien Castermans
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Rolf Hilgenfeld
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Colin Robinson
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Bruno Canard
Eric J Snijder
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Martijn J Van Hemert
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Frank Van van Kuppeveld
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Arnaud Marchand
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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 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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hal-03561598 , version 1 (08-02-2022)

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Dorothée Bardiot, Laura Vangeel, Mohamed Koukni, Philippe Arzel, Marleen Zwaagstra, et al.. Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs As Inhibitors of SARS-CoV-2 Replication. Molecules, 2022, 27 (3), pp.1052. ⟨10.3390/molecules27031052⟩. ⟨hal-03561598⟩
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