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

Dorothée Bardiot , Laura Vangeel (1) , Mohamed Koukni , Philippe Arzel , Marleen Zwaagstra , Heyrhyoung Lyoo , Patrick Wanningen , Shamshad Ahmad , Linlin Zhang , Xinyuanyuan Sun , Adrien Delpal , Cecilia Eydoux (2) , Jean-Claude Guillemot , Eveline Lescrinier (1) , Hugo Klaassen , Pieter Leyssen (1) , Dirk Jochmans (1) , Karolien Castermans , Rolf Hilgenfeld , Colin Robinson , Etienne Decroly (2) , Bruno Canard , Eric J Snijder , Martijn J Van Hemert , Frank Van van Kuppeveld , Patrick Chaltin (1) , Johan Neyts (1) , Steven De de Jonghe (1) , Arnaud Marchand

1 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
2 AFMB - Architecture et fonction des macromolécules biologiques

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.

Mots clés: COVID-19; SARS-CoV-2; 1 2 4-oxadiazole; 1-heteroaryl-2-alkoxyphenyl analogs

Domaines: Chimie thérapeutique

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⟩