SrasV1, Main, Exploration, bibRecord, 000E52

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.

Identifieur interne : 000E52 ( Main/Exploration ); précédent : 000E51; suivant : 000E53

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.

Source :

Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2017.

RBID : pubmed:28659246

Descripteurs français

English descriptors

KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Cell Line, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Discovery, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (metabolism), HIV-1 (drug effects), Humans, Indoles (chemistry), Indoles (pharmacology), Microbial Sensitivity Tests, Molecular Structure, Pyrimidines (chemistry), Pyrimidines (pharmacology), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship, Sulfones (chemistry), Sulfones (pharmacology).
MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemical synthesis : Anti-HIV Agents, Reverse Transcriptase Inhibitors.
- chemical , chemistry : Anti-HIV Agents, Indoles, Pyrimidines, Reverse Transcriptase Inhibitors, Sulfones.
- chemical , metabolism : HIV Reverse Transcriptase.
- chemical , pharmacology : Anti-HIV Agents, Indoles, Pyrimidines, Reverse Transcriptase Inhibitors, Sulfones.
- drug effects : HIV-1.
- Cell Line, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Discovery, Humans, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship.

Abstract

Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC₅₀ values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC₅₀=76.0μM) and comparable to 3TC (EC₅₀=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.

DOI: 10.1016/j.bmc.2017.06.022
PubMed: 28659246

Affiliations:

Belgique, République populaire de Chine

Le document en format XML

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<country xml:lang="fr">République populaire de Chine</country>
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<author><name sortKey="Sun, Songkai" sort="Sun, Songkai" uniqKey="Sun S" first="Songkai" last="Sun">Songkai Sun</name>
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<country xml:lang="fr">République populaire de Chine</country>
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<author><name sortKey="Liu, Huiqing" sort="Liu, Huiqing" uniqKey="Liu H" first="Huiqing" last="Liu">Huiqing Liu</name>
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<country xml:lang="fr">République populaire de Chine</country>
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<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea>
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<country xml:lang="fr">Belgique</country>
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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</term>
<term>Crystallography, X-Ray</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Discovery</term>
<term>HIV Reverse Transcriptase (antagonists & inhibitors)</term>
<term>HIV Reverse Transcriptase (metabolism)</term>
<term>HIV-1 (drug effects)</term>
<term>Humans</term>
<term>Indoles (chemistry)</term>
<term>Indoles (pharmacology)</term>
<term>Microbial Sensitivity Tests</term>
<term>Molecular Structure</term>
<term>Pyrimidines (chemistry)</term>
<term>Pyrimidines (pharmacology)</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 (chemistry)</term>
<term>Sulfones (pharmacology)</term>
</keywords>
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<term>Agents antiVIH (pharmacologie)</term>
<term>Agents antiVIH (synthèse chimique)</term>
<term>Cristallographie aux rayons X</term>
<term>Découverte de médicament</term>
<term>Humains</term>
<term>Indoles ()</term>
<term>Indoles (pharmacologie)</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>Pyrimidines ()</term>
<term>Pyrimidines (pharmacologie)</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Structure moléculaire</term>
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<term>Sulfones (pharmacologie)</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>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Indoles</term>
<term>Pyrimidines</term>
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<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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<term>Indoles</term>
<term>Pyrimidines</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Sulfones</term>
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<term>Microbial Sensitivity Tests</term>
<term>Molecular Structure</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term>
<term>Cristallographie aux rayons X</term>
<term>Découverte de médicament</term>
<term>Humains</term>
<term>Indoles</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Lignée cellulaire</term>
<term>Pyrimidines</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</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>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC<sub>50</sub>
 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC<sub>50</sub>
=76.0μM) and comparable to 3TC (EC<sub>50</sub>
=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.</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, Zihui" sort="Chen, Zihui" uniqKey="Chen Z" first="Zihui" last="Chen">Zihui Chen</name>
<name sortKey="Li, Wanzhuo" sort="Li, Wanzhuo" uniqKey="Li W" first="Wanzhuo" last="Li">Wanzhuo Li</name>
<name sortKey="Liu, Huiqing" sort="Liu, Huiqing" uniqKey="Liu H" first="Huiqing" last="Liu">Huiqing Liu</name>
<name sortKey="Liu, Xinhao" sort="Liu, Xinhao" uniqKey="Liu X" first="Xinhao" last="Liu">Xinhao Liu</name>
<name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name>
<name sortKey="Sun, Songkai" sort="Sun, Songkai" uniqKey="Sun S" first="Songkai" last="Sun">Songkai Sun</name>
<name sortKey="Wang, Xueshun" sort="Wang, Xueshun" uniqKey="Wang X" first="Xueshun" last="Wang">Xueshun Wang</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="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name>
</noRegion>
<name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</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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Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.

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