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

Molecules. 2022 Feb 4;27(3):1052. doi: 10.3390/molecules27031052.


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.

Keywords: 1,2,4-oxadiazole; 1-heteroaryl-2-alkoxyphenyl analogs; COVID-19; SARS-CoV-2.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Chlorocebus aethiops
  • Heterocyclic Compounds / pharmacology*
  • High-Throughput Screening Assays
  • Microbial Sensitivity Tests
  • SARS-CoV-2 / drug effects*
  • Structure-Activity Relationship
  • Vero Cells
  • Virus Replication / drug effects*


  • Antiviral Agents
  • Heterocyclic Compounds