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 H3N2 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 C2C2′ bond. In the parent amines, which proved to be active compounds, the distance between nitrogen and adamantyl pharmacophoric groups was different; NC2′ 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.

Graphical abstractSeveral compounds between 2-(2-adamantyl)piperidines, 3-(2-adamantyl)pyrrolidines and 2-(2-adamantylmethyl)piperidines were potent against influenza A H3N2 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 C2C2′ 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.Figure optionsDownload full-size imageDownload as PowerPoint slide