Antiviral agents derived from novel 1-adamantyl singlet nitrenes

• Type of Material: Article
• Authors: Andreas J. Kesel, Chammünsterstr 47; Hans-Christoph Weiss, Currenta GmbH & Co. OHG; Andreas Schönleber, Universität Bayreuth; Craig W. Day, Utah State University; Dale L. Barnard, Utah State University; Mervi Detorio, Emory University; Raymond Schinazi, Emory University
• Language: English
• Date: 2013-12-17
• Publisher: Sage Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2012
• Final Published Version (URL): http://dx.doi.org/10.3851/IMP2485
• Title of Journal or Parent Work: Antiviral Chemistry and Chemotherapy
• Volume: 23
• Issue: 3
• Start Page: 113
• End Page: 128
• Grant/Funding Information: This work was supported in part by NIH grant 2P30–AI–050409 (Center for AIDS Research), and by the Department of Veterans Affairs (to RFS). In vitro work with respiratory viruses was partially supported by NIH/NIAID contract numbers HHSN272201100019I/HHSN27200001/B01 and HHSN272201100019I/HHSN27200002/B05.
• Keywords: SARS Virus; HIV-1; Imines; Respirovirus Infections; Parainfluenza Virus 3, Human; Cells, Cultured; Severe Acute Respiratory Syndrome; Crystallography, X-Ray; Influenza B virus; Influenza, Human; Amantadine; Influenza A virus; Antiviral Agents; Models, Molecular; Humans
• Research Categories: Health Sciences, Public Health; Biology, Virology; Health Sciences, Immunology

Abstract

Background: Amantadine constitutes an interesting, diamond crystal lattice-shaped, antivirally active amine with an inhibitory effect on influenza A viruses causing common 'fu' in humans. Unfortunately, amantadine forfeited most of its therapeutic potential because of resistance development in recent infuenza A virus isolates. The antiviral efficacy of amantadine congeners can be chemically modified, resulting in re-constitution, improvement and/or extension of antiviral activities mediated by amino-adamantyls. Methods: Newly synthesized compounds were evaluated towards HIV type-1 (HIV-1) replication in primary human lymphocytes. One N-phenacyl amantadine derivative was investigated for inhibiting the in vitro replication of respiratory viruses (influenza A viruses, influenza B virus, human parainfluenza virus type 3 and severe acute respiratory syndrome coronavirus). Results: Two ketone-stabilized 1-adamantyl singlet nitrenes were discovered serendipitously. To our best knowledge these are the first persistently stable nitrenes to be reported. Their structure was proved by determining the X-ray single crystal structure of one hydrolytic elaboration product. This salt adduct revealed an incommensurately modulated crystal structure, which was solved by extensive computational refinement. We could show that ketone-stabilized 1-adamantyl singlet nitrenes are versatile synthons for the synthesis of antiviral drug candidates. An amantadine-folate conjugate was inhibitory on HIV-1 replication in primary human lymphocytes, and one N-phenacyl amantadine derivative was inhibitory towards low pathogenic avian influenza A virus (H5N1) replication in vitro. Conclusions: These results indicate that the aromatic-aliphatic ketone-stabilized 1-adamantyl singlet nitrenes, beyond being of fundamental interest in organic chemistry, represent versatile synthons for the synthesis of new amantadine-related potentially antiviral drugs. © 2013 International Medical Press.