Antiviral agents derived from novel 1-adamantyl singlet nitrenes.
Antivir Chem Chemother
; 23(3): 113-28, 2012 Dec 07.
Article
en En
| MEDLINE
| ID: mdl-23234699
ABSTRACT
BACKGROUND:
Amantadine constitutes an interesting, diamond crystal lattice-shaped, antivirally active amine with an inhibitory effect on influenza A viruses causing common 'flu' in humans. Unfortunately, amantadine forfeited most of its therapeutic potential because of resistance development in recent influenza 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
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Virus de la Influenza A
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Virus de la Influenza B
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Amantadina
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VIH-1
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Virus de la Parainfluenza 3 Humana
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Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo
/
Iminas
Límite:
Humans
Idioma:
En
Revista:
Antivir Chem Chemother
Asunto de la revista:
QUIMICA
/
TERAPIA POR MEDICAMENTOS
/
VIROLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Alemania