Spiro[pyrrolidine-2,2'-adamantanes]: Synthesis, anti-influenza virus activity and conformational properties
Identifieur interne : 001735 ( Main/Exploration ); précédent : 001734; suivant : 001736Spiro[pyrrolidine-2,2'-adamantanes]: Synthesis, anti-influenza virus activity and conformational properties
Auteurs : Ioannis Stylianakis [Grèce] ; Antonios Kolocouris [Grèce] ; Nicolas Kolocouris [Grèce] ; George Fytas [Grèce] ; George B. Foscolos [Grèce] ; Elizaveta Padalko [Belgique] ; Johan Neyts [Belgique] ; Erik De Clercq [Belgique]Source :
- Bioorganic & medicinal chemistry letters [ 0960-894X ] ; 2003.
Descripteurs français
- Pascal (Inist)
- Relation structure activité, Synthèse chimique, Hétérocycle azote, Composé tricyclique, Spirane, Isomère position, Amine secondaire, Amine tertiaire, Analyse conformationnelle, Antiviral, Influenzavirus A, In vitro, Spiro[adamantane-2:2p-pyrrolidine](méthyl), Spiro[adamantane-2:2p-pyrrolidine](diméthyl).
English descriptors
- KwdEn :
Abstract
Synthetic spiro[pyrrolidine-2,2'-adamantanes] 2, 3, 11, 15, 12, 16, 18, 20 were evaluated in vitro and found to be active anti-influenza virus A compounds; the effect of the position of C-Me pyrrolidine ring substituent on antiviral activity was examined. Pyrrolidine 5-Me substitution appears to be optimal for H2N2 strain activity. From the four different possible protonated conformers, experimental observation using NMR spectroscopy and molecular mechanics calculations demonstrated only a pair of conformers A+H (N-Me (ps-ax), C-Me (ps-eq)) and B+H ((N-Me ps-ax, C-Me ps-ax)) which can contribute to the biological activity of C-Me, N-Me protonated derivatives 15+H, 16+H and 20+H. The relative populations were calculated from NMR spectra. For compounds 15+H and 20+H conformer A+H (cis dimethyl orientation) is the major one whereas a similar population of conformers A+H and B+H (trans dimethyl orientation) was observed for compound 16+H. Since this new series is characterized by a lipophilic part, that is the pyrrolidine ring, in addition to adamantane, that can interact with influenza A M2 protein, an ultimate future goal would be the in vitro mapping of M2 lipophilic pocket.
Affiliations:
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type="wicri:Area/Main/Exploration">001735</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Spiro[pyrrolidine-2,2'-adamantanes]: Synthesis, anti-influenza virus activity and conformational properties</title><author><name sortKey="Stylianakis, Ioannis" sort="Stylianakis, Ioannis" uniqKey="Stylianakis I" first="Ioannis" last="Stylianakis">Ioannis Stylianakis</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou</s1><s2>15 771 Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>15 771 Athens</wicri:noRegion></affiliation></author><author><name sortKey="Kolocouris, Antonios" sort="Kolocouris, Antonios" uniqKey="Kolocouris A" first="Antonios" last="Kolocouris">Antonios Kolocouris</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou</s1><s2>15 771 Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>15 771 Athens</wicri:noRegion></affiliation></author><author><name sortKey="Kolocouris, Nicolas" sort="Kolocouris, Nicolas" uniqKey="Kolocouris N" first="Nicolas" last="Kolocouris">Nicolas Kolocouris</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou</s1><s2>15 771 Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>15 771 Athens</wicri:noRegion></affiliation></author><author><name sortKey="Fytas, George" sort="Fytas, George" uniqKey="Fytas G" first="George" last="Fytas">George Fytas</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou</s1><s2>15 771 Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>15 771 Athens</wicri:noRegion></affiliation></author><author><name sortKey="Foscolos, George B" sort="Foscolos, George B" uniqKey="Foscolos G" first="George B." last="Foscolos">George B. Foscolos</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou</s1><s2>15 771 Athens</s2><s3>GRC</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Grèce</country><wicri:noRegion>15 771 Athens</wicri:noRegion></affiliation></author><author><name sortKey="Padalko, Elizaveta" sort="Padalko, Elizaveta" uniqKey="Padalko E" first="Elizaveta" last="Padalko">Elizaveta Padalko</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Rega Institute for Medical Research, Katholieke Universiteit Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Belgique</country><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName><orgName type="university">Katholieke Universiteit Leuven</orgName></affiliation></author><author><name sortKey="Neyts, Johan" sort="Neyts, Johan" uniqKey="Neyts J" first="Johan" last="Neyts">Johan Neyts</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Rega Institute for Medical Research, Katholieke Universiteit Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Belgique</country><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName><orgName type="university">Katholieke Universiteit Leuven</orgName></affiliation></author><author><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Rega Institute for Medical Research, Katholieke Universiteit Leuven</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Belgique</country><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName><orgName type="university">Katholieke Universiteit Leuven</orgName></affiliation></author></analytic><series><title level="j" type="main">Bioorganic & medicinal chemistry letters</title><title level="j" type="abbreviated">Bioorg. med. chem. lett.</title><idno type="ISSN">0960-894X</idno><imprint><date when="2003">2003</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Bioorganic & medicinal chemistry letters</title><title level="j" type="abbreviated">Bioorg. med. chem. lett.</title><idno type="ISSN">0960-894X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Chemical synthesis</term><term>Conformational analysis</term><term>In vitro</term><term>Influenzavirus A</term><term>Nitrogen heterocycle</term><term>Position isomer</term><term>Secondary amine</term><term>Spiran</term><term>Structure activity relation</term><term>Tertiary amine</term><term>Tricyclic compound</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Relation structure activité</term><term>Synthèse chimique</term><term>Hétérocycle azote</term><term>Composé tricyclique</term><term>Spirane</term><term>Isomère position</term><term>Amine secondaire</term><term>Amine tertiaire</term><term>Analyse conformationnelle</term><term>Antiviral</term><term>Influenzavirus A</term><term>In vitro</term><term>Spiro[adamantane-2:2p-pyrrolidine](méthyl)</term><term>Spiro[adamantane-2:2p-pyrrolidine](diméthyl)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Synthetic spiro[pyrrolidine-2,2'-adamantanes] 2, 3, 11, 15, 12, 16, 18, 20 were evaluated in vitro and found to be active anti-influenza virus A compounds; the effect of the position of C-Me pyrrolidine ring substituent on antiviral activity was examined. Pyrrolidine 5-Me substitution appears to be optimal for H<sub>2</sub>N<sub>2</sub> strain activity. From the four different possible protonated conformers, experimental observation using NMR spectroscopy and molecular mechanics calculations demonstrated only a pair of conformers A<sup>+</sup>H (N-Me (ps-ax), C-Me (ps-eq)) and B<sup>+</sup>H ((N-Me ps-ax, C-Me ps-ax)) which can contribute to the biological activity of C-Me, N-Me protonated derivatives 15<sup>+</sup>H, 16<sup>+</sup>H and 20<sup>+</sup>H. The relative populations were calculated from NMR spectra. For compounds 15<sup>+</sup>H and 20<sup>+</sup>H conformer A<sup>+</sup>H (cis dimethyl orientation) is the major one whereas a similar population of conformers A<sup>+</sup>H and B<sup>+</sup>H (trans dimethyl orientation) was observed for compound 16<sup>+</sup>H. Since this new series is characterized by a lipophilic part, that is the pyrrolidine ring, in addition to adamantane, that can interact with influenza A M<sup>2</sup> protein, an ultimate future goal would be the in vitro mapping of M2 lipophilic pocket.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Grèce</li></country><region><li>Province du Brabant flamand</li></region><settlement><li>Louvain</li></settlement><orgName><li>Katholieke Universiteit Leuven</li></orgName></list><tree><country name="Grèce"><noRegion><name sortKey="Stylianakis, Ioannis" sort="Stylianakis, Ioannis" uniqKey="Stylianakis I" first="Ioannis" last="Stylianakis">Ioannis Stylianakis</name></noRegion><name sortKey="Foscolos, George B" sort="Foscolos, George B" uniqKey="Foscolos G" first="George B." last="Foscolos">George B. Foscolos</name><name sortKey="Fytas, George" sort="Fytas, George" uniqKey="Fytas G" first="George" last="Fytas">George Fytas</name><name sortKey="Kolocouris, Antonios" sort="Kolocouris, Antonios" uniqKey="Kolocouris A" first="Antonios" last="Kolocouris">Antonios Kolocouris</name><name sortKey="Kolocouris, Nicolas" sort="Kolocouris, Nicolas" uniqKey="Kolocouris N" first="Nicolas" last="Kolocouris">Nicolas Kolocouris</name></country><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Padalko, Elizaveta" sort="Padalko, Elizaveta" uniqKey="Padalko E" first="Elizaveta" last="Padalko">Elizaveta Padalko</name></region><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><name sortKey="Neyts, Johan" sort="Neyts, Johan" uniqKey="Neyts J" first="Johan" last="Neyts">Johan Neyts</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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