SrasV1, Main, Exploration, bibRecord, 000B54

Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.

Identifieur interne : 000B54 ( Main/Exploration ); précédent : 000B53; suivant : 000B55

Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.

Auteurs : Tong Zhao [République populaire de Chine] ; Qing Meng [République populaire de Chine] ; Dongwei Kang [République populaire de Chine] ; Jianbo Ji [République populaire de Chine] ; Erik De Clercq [Belgique] ; Christophe Pannecouque [Belgique] ; Xinyong Liu [République populaire de Chine] ; Peng Zhan [République populaire de Chine]

Source :

European journal of medicinal chemistry [ 1768-3254 ] ; 2019.

RBID : pubmed:31434039

Descripteurs français

English descriptors

KwdEn :
- Animals, Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Cell Line, Cell Survival (drug effects), Dose-Response Relationship, Drug, Drug Discovery, Female, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (metabolism), HIV-1 (drug effects), HIV-1 (enzymology), HIV-1 (genetics), Humans, Indoles (chemical synthesis), Indoles (chemistry), Indoles (pharmacology), Male, Mice, Mice, Inbred Strains, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship, Sulfones (chemical synthesis), Sulfones (chemistry), Sulfones (pharmacology).
MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemical synthesis : Anti-HIV Agents, Indoles, Reverse Transcriptase Inhibitors, Sulfones.
- chemical , chemistry : Anti-HIV Agents, Indoles, Reverse Transcriptase Inhibitors, Sulfones.
- chemical , metabolism : HIV Reverse Transcriptase.
- chemical , pharmacology : Anti-HIV Agents, Indoles, Reverse Transcriptase Inhibitors, Sulfones.
- drug effects : Cell Survival, HIV-1.
- enzymology : HIV-1.
- genetics : HIV-1.
- Animals, Cell Line, Dose-Response Relationship, Drug, Drug Discovery, Female, Humans, Male, Mice, Mice, Inbred Strains, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Structure-Activity Relationship.

Abstract

For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC₅₀ values ranging from 0.0043 μM to 4.42 μM. Notably, compound 27 (EC₅₀ = 4.7 nM, SI = 5183) and 33 (EC₅₀ = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC₅₀ values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC₅₀ = 0.094 μM), and also showed exceptional activity against E138K (EC₅₀ = 0.014 μM), L100I (EC₅₀ = 0.011 μM) and K103 N (EC₅₀ = 0.025 μM). Additionally, most compounds showed markedly reduced cytotoxicity (CC₅₀) compared to lead compounds, especially 36 (CC₅₀ > 234.91 μM, SI > 18727) and 37 (CC₅₀ > 252.49 μM, SI > 15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.

DOI: 10.1016/j.ejmech.2019.111619
PubMed: 31434039

Affiliations:

Belgique, République populaire de Chine

Le document en format XML

<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.</title>
<author><name sortKey="Zhao, Tong" sort="Zhao, Tong" uniqKey="Zhao T" first="Tong" last="Zhao">Tong Zhao</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Meng, Qing" sort="Meng, Qing" uniqKey="Meng Q" first="Qing" last="Meng">Qing Meng</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ji, Jianbo" sort="Ji, Jianbo" uniqKey="Ji J" first="Jianbo" last="Ji">Jianbo Ji</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</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="1"><nlm:affiliation>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven</wicri:regionArea>
<wicri:noRegion>Leuven</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name>
<affiliation wicri:level="1"><nlm:affiliation>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium. Electronic address: christophe.pannecouque@rega.kuleuven.be.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven</wicri:regionArea>
<wicri:noRegion>Leuven</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China. Electronic address: xinyongl@sdu.edu.cn.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China. Electronic address: zhanpeng1982@sdu.edu.cn.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2019">2019</date>
<idno type="RBID">pubmed:31434039</idno>
<idno type="pmid">31434039</idno>
<idno type="doi">10.1016/j.ejmech.2019.111619</idno>
<idno type="wicri:Area/PubMed/Corpus">000882</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000882</idno>
<idno type="wicri:Area/PubMed/Curation">000882</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000882</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000908</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000908</idno>
<idno type="wicri:Area/Ncbi/Merge">003072</idno>
<idno type="wicri:Area/Ncbi/Curation">003072</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">003072</idno>
<idno type="wicri:Area/Main/Merge">000B55</idno>
<idno type="wicri:Area/Main/Curation">000B54</idno>
<idno type="wicri:Area/Main/Exploration">000B54</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.</title>
<author><name sortKey="Zhao, Tong" sort="Zhao, Tong" uniqKey="Zhao T" first="Tong" last="Zhao">Tong Zhao</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Meng, Qing" sort="Meng, Qing" uniqKey="Meng Q" first="Qing" last="Meng">Qing Meng</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ji, Jianbo" sort="Ji, Jianbo" uniqKey="Ji J" first="Jianbo" last="Ji">Jianbo Ji</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</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="1"><nlm:affiliation>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven</wicri:regionArea>
<wicri:noRegion>Leuven</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name>
<affiliation wicri:level="1"><nlm:affiliation>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium. Electronic address: christophe.pannecouque@rega.kuleuven.be.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven</wicri:regionArea>
<wicri:noRegion>Leuven</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China. Electronic address: xinyongl@sdu.edu.cn.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China. Electronic address: zhanpeng1982@sdu.edu.cn.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012</wicri:regionArea>
<wicri:noRegion>250012</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">European journal of medicinal chemistry</title>
<idno type="eISSN">1768-3254</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Anti-HIV Agents (chemical synthesis)</term>
<term>Anti-HIV Agents (chemistry)</term>
<term>Anti-HIV Agents (pharmacology)</term>
<term>Cell Line</term>
<term>Cell Survival (drug effects)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Discovery</term>
<term>Female</term>
<term>HIV Reverse Transcriptase (antagonists & inhibitors)</term>
<term>HIV Reverse Transcriptase (metabolism)</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 (enzymology)</term>
<term>HIV-1 (genetics)</term>
<term>Humans</term>
<term>Indoles (chemical synthesis)</term>
<term>Indoles (chemistry)</term>
<term>Indoles (pharmacology)</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred Strains</term>
<term>Microbial Sensitivity Tests</term>
<term>Models, Molecular</term>
<term>Molecular Structure</term>
<term>Reverse Transcriptase Inhibitors (chemical synthesis)</term>
<term>Reverse Transcriptase Inhibitors (chemistry)</term>
<term>Reverse Transcriptase Inhibitors (pharmacology)</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>Animaux</term>
<term>Découverte de médicament</term>
<term>Femelle</term>
<term>Humains</term>
<term>Indoles ()</term>
<term>Indoles (pharmacologie)</term>
<term>Indoles (synthèse chimique)</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</term>
<term>Lignées consanguines de souris</term>
<term>Modèles moléculaires</term>
<term>Mâle</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Souris</term>
<term>Structure moléculaire</term>
<term>Sulfones ()</term>
<term>Sulfones (pharmacologie)</term>
<term>Sulfones (synthèse chimique)</term>
<term>Survie cellulaire ()</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>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (enzymologie)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique)</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="chemical synthesis" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Indoles</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Sulfones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Indoles</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Sulfones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Reverse Transcriptase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Indoles</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Sulfones</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>Cell Survival</term>
<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="genetics" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term>
<term>Indoles</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>Indoles</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Sulfones</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Discovery</term>
<term>Female</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred Strains</term>
<term>Microbial Sensitivity Tests</term>
<term>Models, Molecular</term>
<term>Molecular Structure</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term>
<term>Animaux</term>
<term>Découverte de médicament</term>
<term>Femelle</term>
<term>Humains</term>
<term>Indoles</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Lignée cellulaire</term>
<term>Lignées consanguines de souris</term>
<term>Modèles moléculaires</term>
<term>Mâle</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Souris</term>
<term>Structure moléculaire</term>
<term>Sulfones</term>
<term>Survie cellulaire</term>
<term>Tests de sensibilité microbienne</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC<sub>50</sub>
 values ranging from 0.0043 μM to 4.42 μM. Notably, compound 27 (EC<sub>50</sub>
 = 4.7 nM, SI = 5183) and 33 (EC<sub>50</sub>
 = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC<sub>50</sub>
 values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC<sub>50</sub>
 = 0.094 μM), and also showed exceptional activity against E138K (EC<sub>50</sub>
 = 0.014 μM), L100I (EC<sub>50</sub>
 = 0.011 μM) and K103 N (EC<sub>50</sub>
 = 0.025 μM). Additionally, most compounds showed markedly reduced cytotoxicity (CC<sub>50</sub>
) compared to lead compounds, especially 36 (CC<sub>50</sub>
 > 234.91 μM, SI > 18727) and 37 (CC<sub>50</sub>
 > 252.49 μM, SI > 15152). 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="Zhao, Tong" sort="Zhao, Tong" uniqKey="Zhao T" first="Tong" last="Zhao">Tong Zhao</name>
</noRegion>
<name sortKey="Ji, Jianbo" sort="Ji, Jianbo" uniqKey="Ji J" first="Jianbo" last="Ji">Jianbo Ji</name>
<name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name>
<name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name>
<name sortKey="Meng, Qing" sort="Meng, Qing" uniqKey="Meng Q" first="Qing" last="Meng">Qing Meng</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="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name>
</country>
</tree>
</affiliations>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Exploration

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000B54 | SxmlIndent | more

HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000B54 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Sante
   |area=    SrasV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     pubmed:31434039
   |texte=   Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i   -Sk "pubmed:31434039" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd   \
       | NlmPubMed2Wicri -a SrasV1

This area was generated with Dilib version V0.6.33.
Data generation: Tue Apr 28 14:49:16 2020. Site generation: Sat Mar 27 22:06:49 2021

Serveur d'exploration SRAS

Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.

Discovery of novel indolylarylsulfones as potent HIV-1 NNRTIs via structure-guided scaffold morphing.

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki

	Serveur d'exploration SRAS
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.