Heterocyclic rimantadine analogues with antiviral activity.

Abstract

2-(1-Adamantyl)-2-methyl-pyrrolidines 3 and 4, 2-(1-adamantyl)-2-methyl-azetidines 5 and 6, and 2-(1-adamantyl)-2-methyl-aziridines 7 and 8 were synthesized and tested for their antiviral activity against influenza A. Parent molecules 3, 5, and 7 contain the alpha-methyl-1-adamantan-methanamine 2 pharmacophoric moiety (rimantadine). The ring size effect on anti-influenza A activity was investigated. Pyrrolidine 3 was the most potent anti-influenza virus A compound, 9-fold more potent than rimantadine 2, 27-fold more potent than amantadine 1, and 22-fold more potent than ribavirin. Azetidines 5 and 6 were both markedly active against influenza A H2N2 virus, 10- to 20-fold more potent than amantadine. Aziridine 7 was almost devoid of any activity against H2N2 virus but exhibited borderline activity against H3N2 influenza A strain. Thus, it appears that changing the five-, to four- to a three-membered ring results in a drop of activity against influenza A virus.

• Authors: Grigoris Zoidis, Christos Fytas, Ioannis Papanastasiou, George B Foscolos, George Fytas, Elizaveta Padalko, Erik De Clercq, Lieve Naesens, Johan Neyts, Nicolas Kolocouris
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 10 Pg. 3341-8 (May 15 2006) ISSN: 0968-0896 [Print] England
• PMID: 16439137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Heterocyclic Compounds
• Rimantadine

Topics

• Animals
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Cells, Cultured
• Heterocyclic Compounds (chemical synthesis, chemistry, pharmacology)
• Humans
• Influenza A Virus, H2N2 Subtype (drug effects)
• Influenza A Virus, H3N2 Subtype (drug effects)
• Lethal Dose 50
• Microbial Sensitivity Tests
• Rimantadine (analogs & derivatives, pharmacology)