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

Manganaro, Roberto, Zonsics, Birgit, Bauer, Lisa, Lorenzo Lopez, Moira, Donselaar, Tim, Zwaagstra, Marleen, Saporito, Fabiana, Ferla, Salvatore, Strating, Jeroen R. P. M., Coutard, Bruno, Hurdiss, Daniel L., van Kuppeveld, Frank J. M. and Brancale, Andrea 2020. Synthesis and antiviral effect of novel fluoxetine analogues as enterovirus 2C inhibitors. Antiviral Research 178 , 104781. 10.1016/j.antiviral.2020.104781
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Abstract

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 assays, indicative for direct binding to the recombinant 2C protein.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier Masson
ISSN: 0166-3542
Date of First Compliant Deposit: 8 April 2020
Date of Acceptance: 20 March 2020
Last Modified: 27 Nov 2020 12:32
URI: http://orca.cf.ac.uk/id/eprint/130902

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