Synthesis, conformational characteristics and anti-influenza virus A activity of some 2-adamantylsubstituted azacycles
Several compounds between 2-(2-adamantyl)piperidines, 3-(2-adamantyl)pyrrolidines and 2-(2-adamantylmethyl)piperidines were potent against influenza A H 3N 2 virus. The diamine derivatives 21e– g and particularly 35a– c possessing three pharmocophoric groups, the adamantanyl and the two amine groups...
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Published in: | Bioorganic chemistry 2006-10, Vol.34 (5), p.248-273 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | Several compounds between 2-(2-adamantyl)piperidines, 3-(2-adamantyl)pyrrolidines and 2-(2-adamantylmethyl)piperidines were potent against influenza A H
3N
2 virus. The diamine derivatives
21e–
g and particularly
35a–
c possessing three pharmocophoric groups, the adamantanyl and the two amine groups, exhibited high potency. Parent structures
11 and
27 adopt a fixed
trans conformation around C2
C2′ bond. The different shape and distance between nitrogen and adamantyl pharmacophoric groups of the bioactive parent amines
11,
27, and
30 suggest that the influenza virus A receptor can accommodate different in size and orientation lipophilic cages.
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
3N
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
Å for
27,
30 and 2.5
Å for
11 suggesting that M2 receptor site can accommodate different in size and orientation lipophilic cages. |
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ISSN: | 0045-2068 1090-2120 |
DOI: | 10.1016/j.bioorg.2006.05.004 |