Heterocyclic rimantadine analogues with antiviral activity.
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.
Zoidis
Grigoris
G
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, GR-15771 Athens, Greece. Zoidis@pharm.uoa.gr
Fytas
Christos
C
Papanastasiou
Ioannis
I
Foscolos
George B
GB
Fytas
George
G
Padalko
Elizaveta
E
De Clercq
Erik
E
Naesens
Lieve
L
Neyts
Johan
J
Kolocouris
Nicolas
N
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053121:Influenza A Virus, H2N2 Subtype / Q000187:drug effects*; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D007928:Lethal Dose 50; D008826:Microbial Sensitivity Tests; D012299:Rimantadine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D006571:Heterocyclic Compounds; D012299:Rimantadine