Synthesis, conformational characteristics and anti-influenza virus A activity of some 2-adamantylsubstituted azacycles.
The broad-spectrum antiviral activity of 2-(2-adamantyl)piperidines 11, 13a,b, and 15, 3-(2-adamantyl)pyrrolidines 27, 21a-g and 2-(2-adamantylmethyl)piperidines 30, 32a-c, and 35a-d was examined. Several compounds in the new series were potent against influenza A H(3)N(2) virus. When 1-aminoethyl pharmacophore group of 2-rimantadine 4 (2-isomer of rimantadine) is included into a saturated nitrogen heterocycle, see compound 11, potency was retained. The diamine derivatives 21e-g and particularly 35a-c possessing three pharmocophoric groups, that is, the adamantyl and the two amine groups, exhibited high potency. The new compounds did not afford specific activity at non-toxic concentrations against any of the other viruses tested. According to NMR spectroscopy and molecular mechanics calculations it is striking that the parent structures 11 and 27 adopt a fixed trans conformation around C2-C2' bond. In the parent amines, which proved to be active compounds, the distance between nitrogen and adamantyl pharmacophoric groups was different; N-C2' distance is 3.7, 3.8 A for 27, 30 and 2.5 A for 11 suggesting that M2 receptor site can accommodate different in size and orientation lipophilic cages.
Setaki
Despina
D
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou, GR-15771 Athens, Greece.
Tataridis
Dimitris
D
Stamatiou
George
G
Kolocouris
Antonios
A
Foscolos
George B
GB
Fytas
George
G
Kolocouris
Nicolas
N
Padalko
Elizaveta
E
Neyts
Johan
J
De Clercq
Erik
E
D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006678:HIV / Q000187:drug effects; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014780:Viruses / Q000187:drug effects
D000998:Antiviral Agents; D010880:Piperidines; D011759:Pyrrolidines; D000218:Adamantane