Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches.
Identifieur interne : 001317 ( Main/Exploration ); précédent : 001316; suivant : 001318Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches.
Auteurs : Boshi Huang [République populaire de Chine] ; Cuicui Li [République populaire de Chine] ; Wenmin Chen [République populaire de Chine] ; Tao Liu [République populaire de Chine] ; Mingyan Yu [République populaire de Chine] ; Lu Fu [République populaire de Chine] ; Yueyue Sun [République populaire de Chine] ; Huiqing Liu [République populaire de Chine] ; Erik De Clercq [Belgique] ; Christophe Pannecouque [Belgique] ; Jan Balzarini [Belgique] ; Peng Zhan [République populaire de Chine] ; Xinyong Liu [République populaire de Chine]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2015.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Agents antiVIH (synthèse chimique), Azote (), Composés hétérobicycliques (), Composés hétérobicycliques (pharmacologie), Composés hétérobicycliques (synthèse chimique), Composés hétérocycliques (), Composés hétérocycliques (pharmacologie), Composés hétérocycliques (synthèse chimique), Humains, Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Inhibiteurs de la transcriptase inverse (synthèse chimique), Lignée cellulaire tumorale, Modèles moléculaires, Relation dose-effet des médicaments, Relation structure-activité, Solubilité, Structure moléculaire, Sulfones (), Sulfones (pharmacologie), Sulfones (synthèse chimique), Tests de sensibilité microbienne, Transcriptase inverse du VIH (antagonistes et inhibiteurs), Transcriptase inverse du VIH (métabolisme), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- métabolisme : Transcriptase inverse du VIH.
- pharmacologie : Agents antiVIH, Composés hétérobicycliques, Composés hétérocycliques, Inhibiteurs de la transcriptase inverse, Sulfones.
- synthèse chimique : Agents antiVIH, Composés hétérobicycliques, Composés hétérocycliques, Inhibiteurs de la transcriptase inverse, Sulfones.
- Agents antiVIH, Azote, Composés hétérobicycliques, Composés hétérocycliques, Humains, Inhibiteurs de la transcriptase inverse, Lignée cellulaire tumorale, Modèles moléculaires, Relation dose-effet des médicaments, Relation structure-activité, Solubilité, Structure moléculaire, Sulfones, Tests de sensibilité microbienne, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Cell Line, Tumor, Dose-Response Relationship, Drug, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (metabolism), HIV-1 (drug effects), Heterocyclic Compounds (chemical synthesis), Heterocyclic Compounds (chemistry), Heterocyclic Compounds (pharmacology), Heterocyclic Compounds, 2-Ring (chemical synthesis), Heterocyclic Compounds, 2-Ring (chemistry), Heterocyclic Compounds, 2-Ring (pharmacology), Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Nitrogen (chemistry), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Solubility, Structure-Activity Relationship, Sulfones (chemical synthesis), Sulfones (chemistry), Sulfones (pharmacology).
- MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemical synthesis : Anti-HIV Agents, Heterocyclic Compounds, Heterocyclic Compounds, 2-Ring, Reverse Transcriptase Inhibitors, Sulfones.
- chemical , chemistry : Anti-HIV Agents, Heterocyclic Compounds, Heterocyclic Compounds, 2-Ring, Nitrogen, Reverse Transcriptase Inhibitors, Sulfones.
- chemical , metabolism : HIV Reverse Transcriptase.
- chemical , pharmacology : Anti-HIV Agents, Heterocyclic Compounds, Heterocyclic Compounds, 2-Ring, Reverse Transcriptase Inhibitors, Sulfones.
- drug effects : HIV-1.
- Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Solubility, Structure-Activity Relationship.
Abstract
In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure-activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies.
DOI: 10.1016/j.ejmech.2015.01.042
PubMed: 25626145
Affiliations:
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Le document en format XML
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<author><name sortKey="Yu, Mingyan" sort="Yu, Mingyan" uniqKey="Yu M" first="Mingyan" last="Yu">Mingyan Yu</name>
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<author><name sortKey="Fu, Lu" sort="Fu, Lu" uniqKey="Fu L" first="Lu" last="Fu">Lu Fu</name>
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<author><name sortKey="Sun, Yueyue" sort="Sun, Yueyue" uniqKey="Sun Y" first="Yueyue" last="Sun">Yueyue Sun</name>
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<author><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name>
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<author><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name>
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<author><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name>
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<term>Anti-HIV Agents (chemistry)</term>
<term>Anti-HIV Agents (pharmacology)</term>
<term>Cell Line, Tumor</term>
<term>Dose-Response Relationship, Drug</term>
<term>HIV Reverse Transcriptase (antagonists & inhibitors)</term>
<term>HIV Reverse Transcriptase (metabolism)</term>
<term>HIV-1 (drug effects)</term>
<term>Heterocyclic Compounds (chemical synthesis)</term>
<term>Heterocyclic Compounds (chemistry)</term>
<term>Heterocyclic Compounds (pharmacology)</term>
<term>Heterocyclic Compounds, 2-Ring (chemical synthesis)</term>
<term>Heterocyclic Compounds, 2-Ring (chemistry)</term>
<term>Heterocyclic Compounds, 2-Ring (pharmacology)</term>
<term>Humans</term>
<term>Microbial Sensitivity Tests</term>
<term>Models, Molecular</term>
<term>Molecular Structure</term>
<term>Nitrogen (chemistry)</term>
<term>Reverse Transcriptase Inhibitors (chemical synthesis)</term>
<term>Reverse Transcriptase Inhibitors (chemistry)</term>
<term>Reverse Transcriptase Inhibitors (pharmacology)</term>
<term>Solubility</term>
<term>Structure-Activity Relationship</term>
<term>Sulfones (chemical synthesis)</term>
<term>Sulfones (chemistry)</term>
<term>Sulfones (pharmacology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term>
<term>Agents antiVIH (pharmacologie)</term>
<term>Agents antiVIH (synthèse chimique)</term>
<term>Azote ()</term>
<term>Composés hétérobicycliques ()</term>
<term>Composés hétérobicycliques (pharmacologie)</term>
<term>Composés hétérobicycliques (synthèse chimique)</term>
<term>Composés hétérocycliques ()</term>
<term>Composés hétérocycliques (pharmacologie)</term>
<term>Composés hétérocycliques (synthèse chimique)</term>
<term>Humains</term>
<term>Inhibiteurs de la transcriptase inverse ()</term>
<term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term>
<term>Inhibiteurs de la transcriptase inverse (synthèse chimique)</term>
<term>Lignée cellulaire tumorale</term>
<term>Modèles moléculaires</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Solubilité</term>
<term>Structure moléculaire</term>
<term>Sulfones ()</term>
<term>Sulfones (pharmacologie)</term>
<term>Sulfones (synthèse chimique)</term>
<term>Tests de sensibilité microbienne</term>
<term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term>
<term>Transcriptase inverse du VIH (métabolisme)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
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<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Reverse Transcriptase</term>
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<term>Heterocyclic Compounds</term>
<term>Heterocyclic Compounds, 2-Ring</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Sulfones</term>
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<term>Heterocyclic Compounds</term>
<term>Heterocyclic Compounds, 2-Ring</term>
<term>Nitrogen</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Sulfones</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Reverse Transcriptase</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Heterocyclic Compounds</term>
<term>Heterocyclic Compounds, 2-Ring</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Sulfones</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
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<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
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<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term>
<term>Composés hétérobicycliques</term>
<term>Composés hétérocycliques</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Sulfones</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Agents antiVIH</term>
<term>Composés hétérobicycliques</term>
<term>Composés hétérocycliques</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Sulfones</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term>
<term>Dose-Response Relationship, Drug</term>
<term>Humans</term>
<term>Microbial Sensitivity Tests</term>
<term>Models, Molecular</term>
<term>Molecular Structure</term>
<term>Solubility</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term>
<term>Azote</term>
<term>Composés hétérobicycliques</term>
<term>Composés hétérocycliques</term>
<term>Humains</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Lignée cellulaire tumorale</term>
<term>Modèles moléculaires</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Solubilité</term>
<term>Structure moléculaire</term>
<term>Sulfones</term>
<term>Tests de sensibilité microbienne</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
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<front><div type="abstract" xml:lang="en">In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure-activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies. </div>
</front>
</TEI>
<affiliations><list><country><li>Belgique</li>
<li>République populaire de Chine</li>
</country>
</list>
<tree><country name="République populaire de Chine"><noRegion><name sortKey="Huang, Boshi" sort="Huang, Boshi" uniqKey="Huang B" first="Boshi" last="Huang">Boshi Huang</name>
</noRegion>
<name sortKey="Chen, Wenmin" sort="Chen, Wenmin" uniqKey="Chen W" first="Wenmin" last="Chen">Wenmin Chen</name>
<name sortKey="Fu, Lu" sort="Fu, Lu" uniqKey="Fu L" first="Lu" last="Fu">Lu Fu</name>
<name sortKey="Li, Cuicui" sort="Li, Cuicui" uniqKey="Li C" first="Cuicui" last="Li">Cuicui Li</name>
<name sortKey="Liu, Huiqing" sort="Liu, Huiqing" uniqKey="Liu H" first="Huiqing" last="Liu">Huiqing Liu</name>
<name sortKey="Liu, Tao" sort="Liu, Tao" uniqKey="Liu T" first="Tao" last="Liu">Tao Liu</name>
<name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name>
<name sortKey="Sun, Yueyue" sort="Sun, Yueyue" uniqKey="Sun Y" first="Yueyue" last="Sun">Yueyue Sun</name>
<name sortKey="Yu, Mingyan" sort="Yu, Mingyan" uniqKey="Yu M" first="Mingyan" last="Yu">Mingyan Yu</name>
<name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name>
</country>
<country name="Belgique"><noRegion><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name>
</noRegion>
<name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name>
<name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name>
</country>
</tree>
</affiliations>
</record>
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