Heterocyclic rimantadine analogues with antiviral activity.
2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a-c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1.
Stamatiou
George
G
Department of Pharmacy, University of Athens, Panepistimioupoli-Zografou, GR-15771 Athens, Greece.
Foscolos
George B
GB
Fytas
George
G
Kolocouris
Antonios
A
Kolocouris
Nicolas
N
Pannecouque
Christophe
C
Witvrouw
Myriam
M
Padalko
Elizaveta
E
Neyts
Johan
J
De Clercq
Erik
E
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects; D009981:Influenza B virus / Q000187:drug effects; D015394:Molecular Structure; D012299:Rimantadine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D012299:Rimantadine