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

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

doi:10.3390/molecules27031052

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.

Highlights

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the human coronavirus disease 2019 (COVID-19)
Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experiments demonstrated that it interfered with viral entry
As a drug discovery program aiming at the development of SARS-CoV-2-specific antiviral drugs from scratch would take a long time, the initial focus has been on the repurposing of known drugs and drug candidates

Summary

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the human coronavirus disease 2019 (COVID-19). SARS-CoV-2 is a newly discovered coronavirus that was first identified in December 2019 in Wuhan, China, and spread quickly throughout the world, infecting and causing death to millions of people [1,2]. As of October 2021, more than 235 million people were infected with SARS-CoV-2 and almost 5 million people have died due to COVID-19 [3]. With different SARS-CoV-2infected cell lines and different readouts being used, the outcome has been heterogeneous and a wide variety of compounds has been discovered [5,6,7,8]

Methods

Results

Conclusion