Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease
Identifieur interne : 003510 ( Main/Exploration ); précédent : 003509; suivant : 003511Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease
Auteurs : Yi-Ming Shao [Taïwan] ; Wen-Bin Yang [Taïwan] ; Tun-Hsun Kuo [Taïwan] ; Keng-Chang Tsai [Taïwan] ; Chun-Hung Lin [Taïwan] ; An-Suei Yang [Taïwan] ; Po-Huang Liang [Taïwan] ; Chi-Huey Wong [Taïwan, États-Unis]Source :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2008.
Descripteurs français
- KwdFr :
- Composés du fluor (), Composés du fluor (pharmacologie), Composés du fluor (synthèse chimique), Conception de médicament, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Cétones (), Cétones (pharmacologie), Cétones (synthèse chimique), Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Inhibiteurs de protéases (synthèse chimique), Liaison hydrogène, Modèles moléculaires, Méthylation, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Structure moléculaire, Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- métabolisme : Cysteine endopeptidases, Protéines virales.
- pharmacologie : Composés du fluor, Cétones, Inhibiteurs de protéases.
- synthèse chimique : Composés du fluor, Cétones, Inhibiteurs de protéases.
- Pascal (Inist)
- Composés du fluor, Conception de médicament, Cysteine endopeptidases, Cétones, Inhibiteurs de protéases, Liaison hydrogène, Modèles moléculaires, Méthylation, Protéines virales, Structure moléculaire, Synthèse chimique, Halogénocétone, Fluor Composé organique, Inhibiteur protease, Virus syndrome respiratoire aigu sévère, Peptidases, Dépendance du temps, Inhibition, Cysteine endopeptidases, Antiviral, Activité biologique, Modèle moléculaire, Tripeptide, In vitro, Inhibiteur enzyme, Modélisation, Peptide, Phénylalanine(benzyloxycarbonylalalnyl-valyl-leucyl-1-déoxy-1-trifluorométhyl).
English descriptors
- KwdEn :
- Antiviral, Biological activity, Chemical synthesis, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Cysteine endopeptidases, Drug Design, Enzyme inhibitor, Fluorine Compounds (chemical synthesis), Fluorine Compounds (chemistry), Fluorine Compounds (pharmacology), Fluorine Organic compounds, Haloketone, Hydrogen Bonding, In vitro, Inhibition, Ketones (chemical synthesis), Ketones (chemistry), Ketones (pharmacology), Methylation, Modeling, Models, Molecular, Molecular Structure, Molecular model, Peptidases, Peptides, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), Protease inhibitor, SARS Virus (enzymology), Severe acute respiratory syndrome virus, Time dependence, Tripeptide, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Fluorine Compounds, Ketones, Protease Inhibitors.
- chemical , chemistry : Cysteine Endopeptidases, Fluorine Compounds, Ketones, Protease Inhibitors, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Viral Proteins.
- chemical , pharmacology : Fluorine Compounds, Ketones, Protease Inhibitors.
- enzymology : SARS Virus.
- Drug Design, Hydrogen Bonding, Methylation, Models, Molecular, Molecular Structure.
Abstract
-A series of trifluoromethyl ketones as SARS-CoV 3CL protease inhibitors was developed. The inhibitors were synthesized in four steps from commercially available compounds. Three different amino acids were explored in the PI-position and in the P2-P4 positions varying amino acids and long alkyl chain were incorporated. All inhibitors were evaluated in an in vitro assay using purified enzyme and fluorogenic substrate peptide. One of the inhibitors showed a time-dependent inhibition, with a Ki value of 0.3 μM after 4 h incubation.
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Affiliations:
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Le document en format XML
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Academia Sinica, No.128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Institute of Biochemical Sciences, National Taiwan University, No. 1, Section 4, Roosevelt Road</s1><s2>Taipei 10617</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 10617</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Wen Bin" sort="Yang, Wen Bin" uniqKey="Yang W" first="Wen-Bin" last="Yang">Wen-Bin Yang</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation></author><author><name sortKey="Kuo, Tun Hsun" sort="Kuo, Tun Hsun" uniqKey="Kuo T" first="Tun-Hsun" last="Kuo">Tun-Hsun Kuo</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute of Biological Chemistry. Academia Sinica, No.128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation></author><author><name sortKey="Tsai, Keng Chang" sort="Tsai, Keng Chang" uniqKey="Tsai K" first="Keng-Chang" last="Tsai">Keng-Chang Tsai</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation></author><author><name sortKey="Lin, Chun Hung" sort="Lin, Chun Hung" uniqKey="Lin C" first="Chun-Hung" last="Lin">Chun-Hung Lin</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute of Biological Chemistry. Academia Sinica, No.128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Institute of Biochemical Sciences, National Taiwan University, No. 1, Section 4, Roosevelt Road</s1><s2>Taipei 10617</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 10617</wicri:noRegion></affiliation></author><author><name sortKey="Yang, An Suei" sort="Yang, An Suei" uniqKey="Yang A" first="An-Suei" last="Yang">An-Suei Yang</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute of Biological Chemistry. Academia Sinica, No.128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Institute of Biochemical Sciences, National Taiwan University, No. 1, Section 4, Roosevelt Road</s1><s2>Taipei 10617</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 10617</wicri:noRegion></affiliation></author><author><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute of Biological Chemistry. Academia Sinica, No.128, Section 2, Academia Road</s1><s2>Taipei 11529</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 11529</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Institute of Biochemical Sciences, National Taiwan University, No. 1, Section 4, Roosevelt Road</s1><s2>Taipei 10617</s2><s3>TWN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Taïwan</country><wicri:noRegion>Taipei 10617</wicri:noRegion></affiliation><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road</s1><s2>La Jolla, CA 92037</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Bioorganic & medicinal chemistry</title><title level="j" type="abbreviated">Bioorg. med. chem.</title><idno type="ISSN">0968-0896</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Biological activity</term><term>Chemical synthesis</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Cysteine endopeptidases</term><term>Drug Design</term><term>Enzyme inhibitor</term><term>Fluorine Compounds (chemical synthesis)</term><term>Fluorine Compounds (chemistry)</term><term>Fluorine Compounds (pharmacology)</term><term>Fluorine Organic compounds</term><term>Haloketone</term><term>Hydrogen Bonding</term><term>In vitro</term><term>Inhibition</term><term>Ketones (chemical synthesis)</term><term>Ketones (chemistry)</term><term>Ketones (pharmacology)</term><term>Methylation</term><term>Modeling</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Molecular model</term><term>Peptidases</term><term>Peptides</term><term>Protease Inhibitors (chemical synthesis)</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (pharmacology)</term><term>Protease inhibitor</term><term>SARS Virus (enzymology)</term><term>Severe acute respiratory syndrome virus</term><term>Time dependence</term><term>Tripeptide</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Composés du fluor ()</term><term>Composés du fluor (pharmacologie)</term><term>Composés du fluor (synthèse chimique)</term><term>Conception de médicament</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (métabolisme)</term><term>Cétones ()</term><term>Cétones (pharmacologie)</term><term>Cétones (synthèse chimique)</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Inhibiteurs de protéases (synthèse chimique)</term><term>Liaison hydrogène</term><term>Modèles moléculaires</term><term>Méthylation</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Protéines virales (métabolisme)</term><term>Structure moléculaire</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Fluorine Compounds</term><term>Ketones</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Fluorine Compounds</term><term>Ketones</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Fluorine Compounds</term><term>Ketones</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Composés du fluor</term><term>Cétones</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Composés du fluor</term><term>Cétones</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Drug Design</term><term>Hydrogen Bonding</term><term>Methylation</term><term>Models, Molecular</term><term>Molecular Structure</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Composés du fluor</term><term>Conception de médicament</term><term>Cysteine endopeptidases</term><term>Cétones</term><term>Inhibiteurs de protéases</term><term>Liaison hydrogène</term><term>Modèles moléculaires</term><term>Méthylation</term><term>Protéines virales</term><term>Structure moléculaire</term><term>Synthèse chimique</term><term>Halogénocétone</term><term>Fluor Composé organique</term><term>Inhibiteur protease</term><term>Virus syndrome respiratoire aigu sévère</term><term>Peptidases</term><term>Dépendance du temps</term><term>Inhibition</term><term>Cysteine endopeptidases</term><term>Antiviral</term><term>Activité biologique</term><term>Modèle moléculaire</term><term>Tripeptide</term><term>In vitro</term><term>Inhibiteur enzyme</term><term>Modélisation</term><term>Peptide</term><term>Phénylalanine(benzyloxycarbonylalalnyl-valyl-leucyl-1-déoxy-1-trifluorométhyl)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">-A series of trifluoromethyl ketones as SARS-CoV 3CL protease inhibitors was developed. The inhibitors were synthesized in four steps from commercially available compounds. Three different amino acids were explored in the PI-position and in the P2-P4 positions varying amino acids and long alkyl chain were incorporated. All inhibitors were evaluated in an in vitro assay using purified enzyme and fluorogenic substrate peptide. One of the inhibitors showed a time-dependent inhibition, with a K<sub>i</sub> value of 0.3 μM after 4 h incubation.</div></front></TEI><affiliations><list><country><li>Taïwan</li><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><country name="Taïwan"><noRegion><name sortKey="Shao, Yi Ming" sort="Shao, Yi Ming" uniqKey="Shao Y" first="Yi-Ming" last="Shao">Yi-Ming Shao</name></noRegion><name sortKey="Kuo, Tun Hsun" sort="Kuo, Tun Hsun" uniqKey="Kuo T" first="Tun-Hsun" last="Kuo">Tun-Hsun Kuo</name><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><name sortKey="Lin, Chun Hung" sort="Lin, Chun Hung" uniqKey="Lin C" first="Chun-Hung" last="Lin">Chun-Hung Lin</name><name sortKey="Lin, Chun Hung" sort="Lin, Chun Hung" uniqKey="Lin C" first="Chun-Hung" last="Lin">Chun-Hung Lin</name><name sortKey="Lin, Chun Hung" sort="Lin, Chun Hung" uniqKey="Lin C" first="Chun-Hung" last="Lin">Chun-Hung Lin</name><name sortKey="Shao, Yi Ming" sort="Shao, Yi Ming" uniqKey="Shao Y" first="Yi-Ming" last="Shao">Yi-Ming Shao</name><name sortKey="Shao, Yi Ming" sort="Shao, Yi Ming" uniqKey="Shao Y" first="Yi-Ming" last="Shao">Yi-Ming Shao</name><name sortKey="Tsai, Keng Chang" sort="Tsai, Keng Chang" uniqKey="Tsai K" first="Keng-Chang" last="Tsai">Keng-Chang Tsai</name><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name><name sortKey="Yang, An Suei" sort="Yang, An Suei" uniqKey="Yang A" first="An-Suei" last="Yang">An-Suei Yang</name><name sortKey="Yang, Wen Bin" sort="Yang, Wen Bin" uniqKey="Yang W" first="Wen-Bin" last="Yang">Wen-Bin Yang</name></country><country name="États-Unis"><region name="Californie"><name sortKey="Wong, Chi Huey" sort="Wong, Chi Huey" uniqKey="Wong C" first="Chi-Huey" last="Wong">Chi-Huey Wong</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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