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

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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https://hal.archives-ouvertes.fr/hal-03561598
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Submitted on : Tuesday, February 8, 2022 - 12:37:00 PM
Last modification on : Wednesday, February 9, 2022 - 3:45:50 AM
Long-term archiving on: : Monday, May 9, 2022 - 7:35:05 PM

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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, MDPI, 2022, 27 (3), pp.1052. ⟨10.3390/molecules27031052⟩. ⟨hal-03561598⟩

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