Synthesis, conformational characteristics and anti-influenza virus A activity of some 2-adamantylsubstituted azacycles |
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Authors: | Setaki Despina Tataridis Dimitris Stamatiou George Kolocouris Antonios Foscolos George B Fytas George Kolocouris Nicolas Padalko Elizaveta Neyts Johan De Clercq Erik |
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Affiliation: | School of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou, GR-15771 Athens, Greece. |
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Abstract: | 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. |
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Keywords: | Anti-influenza virus agent H3N2 Aminoadamantanes Adamantanamine Rimantadine Heterocycles Diamines NOE Conformation |
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