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.
【저자키워드】 COVID-19, SARS-CoV-2, 1,2,4-oxadiazole, 1-heteroaryl-2-alkoxyphenyl analogs, 【초록키워드】 public health, coronavirus, pandemic, Vaccines, antiviral drugs, viral entry, experiment, SAR, beta-coronavirus, acute respiratory syndrome, effort, identify, subsequent, addition, conducted, can be used, demonstrated, active against, replaced, yielding, 【제목키워드】 synthesis, Profiling,