SrasV1, Main, Exploration, bibRecord, 000E51

Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement.

Identifieur interne : 000E51 ( Main/Exploration ); précédent : 000E50; suivant : 000E52

Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement.

Source :

European journal of medicinal chemistry [ 1768-3254 ] ; 2017.

RBID : pubmed:27750153

Descripteurs français

English descriptors

KwdEn :
- Cell Line, Drug Design, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (chemistry), HIV-1 (drug effects), HIV-1 (enzymology), Indoles (chemistry), Models, Molecular, Piperidines (chemistry), Piperidines (pharmacology), Protein Conformation, Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship.
MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemistry : HIV Reverse Transcriptase, Indoles, Piperidines, Reverse Transcriptase Inhibitors.
- drug effects : HIV-1.
- enzymology : HIV-1.
- chemical , pharmacology : Piperidines, Reverse Transcriptase Inhibitors.
- Cell Line, Drug Design, Models, Molecular, Protein Conformation, Structure-Activity Relationship.

Abstract

To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC₅₀ values ranging from 0.62 μM to 0.006 μM 8 (EC₅₀ = 6 nM) and 18 (EC₅₀ = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC₅₀ values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC₅₀ = 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC₅₀ = 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.

DOI: 10.1016/j.ejmech.2016.10.009
PubMed: 27750153

Affiliations:

Belgique, République populaire de Chine

Le document en format XML

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<author><name sortKey="Yuan, Zheng" sort="Yuan, Zheng" uniqKey="Yuan Z" first="Zheng" last="Yuan">Zheng Yuan</name>
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<country xml:lang="fr">République populaire de Chine</country>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pharmacology, Shandong University School of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
<wicri:noRegion>Shandong</wicri:noRegion>
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<author><name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name>
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<country xml:lang="fr">Belgique</country>
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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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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell Line</term>
<term>Drug Design</term>
<term>HIV Reverse Transcriptase (antagonists & inhibitors)</term>
<term>HIV Reverse Transcriptase (chemistry)</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 (enzymology)</term>
<term>Indoles (chemistry)</term>
<term>Models, Molecular</term>
<term>Piperidines (chemistry)</term>
<term>Piperidines (pharmacology)</term>
<term>Protein Conformation</term>
<term>Reverse Transcriptase Inhibitors (chemistry)</term>
<term>Reverse Transcriptase Inhibitors (pharmacology)</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Conception de médicament</term>
<term>Conformation des protéines</term>
<term>Indoles ()</term>
<term>Inhibiteurs de la transcriptase inverse ()</term>
<term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term>
<term>Lignée cellulaire</term>
<term>Modèles moléculaires</term>
<term>Pipéridines ()</term>
<term>Pipéridines (pharmacologie)</term>
<term>Relation structure-activité</term>
<term>Transcriptase inverse du VIH ()</term>
<term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (enzymologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Reverse Transcriptase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>HIV Reverse Transcriptase</term>
<term>Indoles</term>
<term>Piperidines</term>
<term>Reverse Transcriptase Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de la transcriptase inverse</term>
<term>Pipéridines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Piperidines</term>
<term>Reverse Transcriptase Inhibitors</term>
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<keywords scheme="MESH" xml:lang="en"><term>Cell Line</term>
<term>Drug Design</term>
<term>Models, Molecular</term>
<term>Protein Conformation</term>
<term>Structure-Activity Relationship</term>
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<term>Conformation des protéines</term>
<term>Indoles</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Lignée cellulaire</term>
<term>Modèles moléculaires</term>
<term>Pipéridines</term>
<term>Relation structure-activité</term>
<term>Transcriptase inverse du VIH</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
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<front><div type="abstract" xml:lang="en">To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC<sub>50</sub>
 values ranging from 0.62 μM to 0.006 μM 8 (EC<sub>50</sub>
 = 6 nM) and 18 (EC<sub>50</sub>
 = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC<sub>50</sub>
 values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC<sub>50</sub>
 = 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC<sub>50</sub>
 = 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.</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="Li, Xiao" sort="Li, Xiao" uniqKey="Li X" first="Xiao" last="Li">Xiao Li</name>
</noRegion>
<name sortKey="Gao, Ping" sort="Gao, Ping" uniqKey="Gao P" first="Ping" last="Gao">Ping Gao</name>
<name sortKey="Huang, Boshi" sort="Huang, Boshi" uniqKey="Huang B" first="Boshi" last="Huang">Boshi Huang</name>
<name sortKey="Liu, Huiqing" sort="Liu, Huiqing" uniqKey="Liu H" first="Huiqing" last="Liu">Huiqing Liu</name>
<name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name>
<name sortKey="Yu, Zhao" sort="Yu, Zhao" uniqKey="Yu Z" first="Zhao" last="Yu">Zhao Yu</name>
<name sortKey="Yuan, Zheng" sort="Yuan, Zheng" uniqKey="Yuan Z" first="Zheng" last="Yuan">Zheng Yuan</name>
<name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name>
<name sortKey="Zhou, Zhongxia" sort="Zhou, Zhongxia" uniqKey="Zhou Z" first="Zhongxia" last="Zhou">Zhongxia Zhou</name>
</country>
<country name="Belgique"><noRegion><name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name>
</noRegion>
<name sortKey="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name>
<name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name>
</country>
</tree>
</affiliations>
</record>

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Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement.

Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement.

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