학술논문
Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication.
Document Type
Article
Author
Bardiot, Dorothée; Vangeel, Laura; Koukni, Mohamed; Arzel, Philippe; Zwaagstra, Marleen; Lyoo, Heyrhyoung; Wanningen, Patrick; Ahmad, Shamshad; Zhang, Linlin; Sun, Xinyuanyuan; Delpal, Adrien; Eydoux, Cecilia; Guillemot, Jean-Claude; Lescrinier, Eveline; Klaassen, Hugo; Leyssen, Pieter; Jochmans, Dirk; Castermans, Karolien; Hilgenfeld, Rolf; Robinson, Colin
Source
Subject
*SARS-CoV-2
*STRUCTURE-activity relationships
*ANTIVIRAL agents
*
*
Language
ISSN
1420-3049
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. [ABSTRACT FROM AUTHOR]