5′-Silylated 3′-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus
Identifieur interne : 001385 ( Main/Exploration ); précédent : 001384; suivant : 0013865′-Silylated 3′-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus
Auteurs : Sanjeev Kumar V. Vernekar [États-Unis] ; Li Qiu [États-Unis] ; Jing Zhang [États-Unis] ; Jayakanth Kankanala [États-Unis] ; Hongmin Li [États-Unis] ; Robert J. Geraghty [États-Unis] ; Zhengqiang Wang [États-Unis]Source :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2015.
Descripteurs français
- KwdFr :
- Adémétionine (), Antiviraux (), Antiviraux (pharmacologie), Fixation compétitive, Methyltransferases (), Relation dose-effet des médicaments, Relation structure-activité, Silanes (), Silanes (pharmacologie), Simulation de docking moléculaire, Stéréoisomérie, Triazoles (), Triazoles (pharmacologie), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), Virus de la dengue (), Virus du Nil occidental (), Zidovudine (), Zidovudine (analogues et dérivés), Zidovudine (pharmacologie).
- MESH :
- analogues et dérivés : Zidovudine.
- pharmacologie : Antiviraux, Silanes, Triazoles, Zidovudine.
- Adémétionine, Antiviraux, Fixation compétitive, Methyltransferases, Relation dose-effet des médicaments, Relation structure-activité, Silanes, Simulation de docking moléculaire, Stéréoisomérie, Triazoles, VIH-1 (Virus de l'Immunodéficience Humaine de type 1), Virus de la dengue, Virus du Nil occidental, Zidovudine.
English descriptors
- KwdEn :
- Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Binding, Competitive, Dengue Virus (drug effects), Dose-Response Relationship, Drug, HIV-1 (drug effects), Methyltransferases (chemistry), Molecular Docking Simulation, S-Adenosylmethionine (chemistry), Silanes (chemistry), Silanes (pharmacology), Stereoisomerism, Structure-Activity Relationship, Triazoles (chemistry), Triazoles (pharmacology), West Nile virus (drug effects), Zidovudine (analogs & derivatives), Zidovudine (chemistry), Zidovudine (pharmacology).
- MESH :
- chemical , analogs & derivatives : Zidovudine.
- chemical , chemistry : Antiviral Agents, Methyltransferases, S-Adenosylmethionine, Silanes, Triazoles, Zidovudine.
- chemical , pharmacology : Antiviral Agents, Silanes, Triazoles, Zidovudine.
- drug effects : Dengue Virus, HIV-1, West Nile virus.
- Binding, Competitive, Dose-Response Relationship, Drug, Molecular Docking Simulation, Stereoisomerism, Structure-Activity Relationship.
Abstract
West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5′-silylated nucleoside scaffold derived from 3′-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure–activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5′-silyl group and the substituent of 3′-triazole or its bioisosteres. Particularly interesting is the 5′ silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive
Url:
DOI: 10.1021/acs.jmedchem.5b00327
PubMed: 25909386
PubMed Central: 4465584
Affiliations:
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Le document en format XML
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Vernekar</name><affiliation wicri:level="1"><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455</wicri:regionArea><wicri:noRegion>Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Qiu, Li" sort="Qiu, Li" uniqKey="Qiu L" first="Li" last="Qiu">Li Qiu</name><affiliation wicri:level="1"><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455</wicri:regionArea><wicri:noRegion>Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name><affiliation wicri:level="1"><nlm:aff id="A2">Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208</wicri:regionArea><wicri:noRegion>New York 12208</wicri:noRegion></affiliation></author><author><name sortKey="Kankanala, Jayakanth" sort="Kankanala, Jayakanth" uniqKey="Kankanala J" first="Jayakanth" last="Kankanala">Jayakanth Kankanala</name><affiliation wicri:level="1"><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455</wicri:regionArea><wicri:noRegion>Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Li, Hongmin" sort="Li, Hongmin" uniqKey="Li H" first="Hongmin" last="Li">Hongmin Li</name><affiliation wicri:level="1"><nlm:aff id="A2">Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208</wicri:regionArea><wicri:noRegion>New York 12208</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A3">Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201</wicri:regionArea><wicri:noRegion>New York 12201</wicri:noRegion></affiliation></author><author><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><affiliation wicri:level="1"><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455</wicri:regionArea><wicri:noRegion>Minnesota 55455</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Zhengqiang" sort="Wang, Zhengqiang" uniqKey="Wang Z" first="Zhengqiang" last="Wang">Zhengqiang Wang</name><affiliation wicri:level="1"><nlm:aff id="A1">Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455</wicri:regionArea><wicri:noRegion>Minnesota 55455</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Binding, Competitive</term><term>Dengue Virus (drug effects)</term><term>Dose-Response Relationship, Drug</term><term>HIV-1 (drug effects)</term><term>Methyltransferases (chemistry)</term><term>Molecular Docking Simulation</term><term>S-Adenosylmethionine (chemistry)</term><term>Silanes (chemistry)</term><term>Silanes (pharmacology)</term><term>Stereoisomerism</term><term>Structure-Activity Relationship</term><term>Triazoles (chemistry)</term><term>Triazoles (pharmacology)</term><term>West Nile virus (drug effects)</term><term>Zidovudine (analogs & derivatives)</term><term>Zidovudine (chemistry)</term><term>Zidovudine (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adémétionine ()</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Fixation compétitive</term><term>Methyltransferases ()</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Silanes ()</term><term>Silanes (pharmacologie)</term><term>Simulation de docking moléculaire</term><term>Stéréoisomérie</term><term>Triazoles ()</term><term>Triazoles (pharmacologie)</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term><term>Virus de la dengue ()</term><term>Virus du Nil occidental ()</term><term>Zidovudine ()</term><term>Zidovudine (analogues et dérivés)</term><term>Zidovudine (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Zidovudine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Methyltransferases</term><term>S-Adenosylmethionine</term><term>Silanes</term><term>Triazoles</term><term>Zidovudine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Silanes</term><term>Triazoles</term><term>Zidovudine</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Zidovudine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Dengue Virus</term><term>HIV-1</term><term>West Nile virus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Silanes</term><term>Triazoles</term><term>Zidovudine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding, Competitive</term><term>Dose-Response Relationship, Drug</term><term>Molecular Docking Simulation</term><term>Stereoisomerism</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adémétionine</term><term>Antiviraux</term><term>Fixation compétitive</term><term>Methyltransferases</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Silanes</term><term>Simulation de docking moléculaire</term><term>Stéréoisomérie</term><term>Triazoles</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term><term>Virus de la dengue</term><term>Virus du Nil occidental</term><term>Zidovudine</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5′-silylated nucleoside scaffold derived from 3′-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure–activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5′-silyl group and the substituent of 3′-triazole or its bioisosteres. Particularly interesting is the 5′ silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive <italic>S</italic>-adenosyl-L-methionine (SAM) binding assay suggest that these compounds likely confer antiviral activity via binding to methyltransferase (MTase).</p></div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Vernekar, Sanjeev Kumar V" sort="Vernekar, Sanjeev Kumar V" uniqKey="Vernekar S" first="Sanjeev Kumar V." last="Vernekar">Sanjeev Kumar V. Vernekar</name></noRegion><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><name sortKey="Kankanala, Jayakanth" sort="Kankanala, Jayakanth" uniqKey="Kankanala J" first="Jayakanth" last="Kankanala">Jayakanth Kankanala</name><name sortKey="Li, Hongmin" sort="Li, Hongmin" uniqKey="Li H" first="Hongmin" last="Li">Hongmin Li</name><name sortKey="Li, Hongmin" sort="Li, Hongmin" uniqKey="Li H" first="Hongmin" last="Li">Hongmin Li</name><name sortKey="Qiu, Li" sort="Qiu, Li" uniqKey="Qiu L" first="Li" last="Qiu">Li Qiu</name><name sortKey="Wang, Zhengqiang" sort="Wang, Zhengqiang" uniqKey="Wang Z" first="Zhengqiang" last="Wang">Zhengqiang Wang</name><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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