Inhibition of influenza and human coronaviruses by 1,4,4-trisubstituted piperidines

Keywords: Influenza virus, Coronavirus, piperidine compounds, Ugi four-component reaction The recent outbreaks of the highly pathogenic avian A/H5N1 and pandemic A/H1N1/2009 influenza viruses have emphasized the urgent need for the discovery of new anti-influenza compounds. On the other hand, Coronaviruses (CoV) are common etiological agents of acute respiratory tract infections and of potentially pandemic viruses (eg SARS-CoV or MERS-CoV), for which neither a vaccine nor an antiviral therapy is yet available, thus highlighting the need of agents with broad antiviral activity against multiple respiratory viruses. The piperidine nucleus is an attractive drug scaffold present in agents with applications as anti-histaminic, anti-inflammatory, fungicidal, bactericidal, anticancer, analgesic, CNS stimulant and or anti-depressant activities. In an effort to discover novel broad spectrum antiviral compounds, several molecules of our diverse in-house library were screened against a panel of different influenza virus strains and human 229E coronavirus. Following this approach, we identified 1,4,4-trisubstituted piperidines as interesting hit compounds that display antiviral activity against influenza A/PR/8/34 virus (A/H1N1) and coronavirus (229E) in the low micromolar range. To investigate the structure-activity relationships, several analogues were easily synthesized, by a one-step Ugi four-component reaction, starting from commercially available amines, isocyanides, N-substituted piperidones and a variety of amino acids as carboxylic acid components. Mechanistic influenza experiments consisting of time-of-addition, resistance selection and functional assays for HA-mediated binding or membrane fusion with the most active compound will be reported.status: submitte