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 experi-ments 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.
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Bardiot, D., Vangeel, L., Koukni, M., Arzel, P., Zwaagstra, M., Lyoo, H., Wanningen, P., Ahmad, S., Zhang, L., Sun, X., Delpal, A., Eydoux, C., Guillemot, J., Lescrinier, E., Klaassen, H., Leyssen, P., Jochmans, D., Castermans, K., Hilgenfeld, R., Robinson, C., Decroly, E., Canard, B., Snijder, E., van Hemert, M., van Kuppeveld, F., Chaltin, P., Neyts, J., De Jonghe, S. & Marchand, A. 2022, 'Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication', Molecules, 27(3), article no: 1052. https://doi.org/10.3390/molecules27031052