Synthesis and antiviral effect of novel fluoxetine analogues as enterovirus 2C inhibitors

Roberto Manganaro, Birgit Zonsics, Lisa Bauer, Moira Lorenzo Lopez, Tim Donselaar, Marleen Zwaagstra, Fabiana Saporito, Salvatore Ferla, Jeroen R P M Strating, Bruno Coutard, Daniel L Hurdiss, Frank J M van Kuppeveld, Andrea Brancale

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Enteroviruses (EV) are a group of positive-strand RNA (+RNA) viruses that include many important human pathogens (e.g. poliovirus, coxsackievirus, echovirus, numbered enteroviruses and rhinoviruses). Fluoxetine was identified in drug repurposing screens as potent inhibitor of enterovirus B and enterovirus D replication. In this paper we are reporting the synthesis and the antiviral effect of a series of fluoxetine analogues. The results obtained offer a preliminary insight into the structure-activity relationship of its chemical scaffold and confirm the importance of the chiral configuration. We identified a racemic fluoxetine analogue, 2b, which showed a similar antiviral activity compared to (S)-fluoxetine. Investigating the stereochemistry of 2b revealed that the S-enantiomer exerts potent antiviral activity and increased the antiviral spectrum compared to the racemic mixture of 2b. In line with the observed antiviral effect, the S-enantiomer displayed a dose-dependent shift in the melting temperature in thermal shift assay, indicative for direct binding to the recombinant 2C protein.

Original languageEnglish
Article number104781
JournalAntiviral Research
Early online date2020
Publication statusPublished - Jun 2020


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