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

Dorothée Bardiot, Laura Vangeel, Mohamed Koukni, Philippe Arzel, Marleen Zwaagstra, Heyrhyoung Lyoo, Patrick Wanningen, Shamshad Ahmad, Linlin Zhang, Xinyuanyuan Sun, Adrien Delpal, Cecilia Eydoux, Jean Claude Guillemot, Eveline Lescrinier, Hugo Klaassen, Pieter Leyssen, Dirk Jochmans, Karolien Castermans, Rolf Hilgenfeld, Colin RobinsonEtienne Decroly, Bruno Canard, Eric J. Snijder, Martijn J. van Hemert, Frank van Kuppeveld, Patrick Chaltin, Johan Neyts, Steven De Jonghe (Lead / Corresponding author), Arnaud Marchand (Lead / Corresponding author)

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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 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.

Original languageEnglish
Article number1052
Number of pages26
JournalMolecules
Volume27
Issue number3
DOIs
Publication statusPublished - 4 Feb 2022

Keywords

  • 1,2,4-oxadiazole
  • 1-heteroaryl-2-alkoxyphenyl analogs
  • COVID-19
  • SARS-CoV-2

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