Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 2: discovery of novel [1,2,4]Triazolo[1,5-a]pyrimidines using a structure-guided core-refining approach.
Identifieur interne : 001648 ( Main/Exploration ); précédent : 001647; suivant : 001649Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 2: discovery of novel [1,2,4]Triazolo[1,5-a]pyrimidines using a structure-guided core-refining approach.
Auteurs : Liu Wang [République populaire de Chine] ; Ye Tian [République populaire de Chine] ; Wenmin Chen [République populaire de Chine] ; Hong Liu [République populaire de Chine] ; Peng Zhan [République populaire de Chine] ; Dongyue Li [République populaire de Chine] ; Huiqing Liu [République populaire de Chine] ; Erik De Clercq [Belgique] ; Christophe Pannecouque [Belgique] ; Xinyong Liu [République populaire de Chine]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2014.
Descripteurs français
- KwdFr :
- Azote (), Conception de médicament, Conformation des protéines, Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Modèles moléculaires, Mutation, Pyrimidines (), Pyrimidines (pharmacologie), Relation structure-activité, Transcriptase inverse du VIH (), Transcriptase inverse du VIH (antagonistes et inhibiteurs), Transcriptase inverse du VIH (génétique), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (enzymologie), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique).
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- enzymologie : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- génétique : Transcriptase inverse du VIH, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- pharmacologie : Inhibiteurs de la transcriptase inverse, Pyrimidines.
- Azote, Conception de médicament, Conformation des protéines, Inhibiteurs de la transcriptase inverse, Modèles moléculaires, Mutation, Pyrimidines, Relation structure-activité, Transcriptase inverse du VIH, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Drug Design, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (chemistry), HIV Reverse Transcriptase (genetics), HIV-1 (drug effects), HIV-1 (enzymology), HIV-1 (genetics), Models, Molecular, Mutation, Nitrogen (chemistry), Protein Conformation, Pyrimidines (chemistry), Pyrimidines (pharmacology), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship.
- MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemistry : HIV Reverse Transcriptase, Nitrogen, Pyrimidines, Reverse Transcriptase Inhibitors.
- chemical , genetics : HIV Reverse Transcriptase.
- drug effects : HIV-1.
- enzymology : HIV-1.
- genetics : HIV-1.
- chemical , pharmacology : Pyrimidines, Reverse Transcriptase Inhibitors.
- Drug Design, Models, Molecular, Mutation, Protein Conformation, Structure-Activity Relationship.
Abstract
Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were rationally designed via structure-based core refining approach, synthesized through the readily accessible synthetic methods and evaluated for their anti-HIV activities in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against the wild-type HIV-1 IIIB. Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC50 values of 0.02 μM and 7.6 μM, respectively, which were much better than or similar to nevirapine (NVP, EC50 = 0.15 μM, 2.9 μM) and delavirdine (DLV, EC50 = 0.07 μM, >36 μM). Besides, some other compounds, 5b, 7c, 7e, 7f, and 7m, were also endowed with favorable anti-HIV-1 potency (EC50 = 0.07, 0.05, 0.05, 0.07, and 0.05 μM, respectively), which were better than or similar to those of NVP and DLV, suggesting a high potential to further develop this type of bridgehead nitrogen heterocycle as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. The selected compound, 7i, was found moderately inhibitory towards RT (IC50 = 0.39 μM), which was higher than for ETV (IC50 = 0.56 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were detailed in this manuscript.
DOI: 10.1016/j.ejmech.2014.07.104
PubMed: 25089812
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en">Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were rationally designed via structure-based core refining approach, synthesized through the readily accessible synthetic methods and evaluated for their anti-HIV activities in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against the wild-type HIV-1 IIIB. Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC50 values of 0.02 μM and 7.6 μM, respectively, which were much better than or similar to nevirapine (NVP, EC50 = 0.15 μM, 2.9 μM) and delavirdine (DLV, EC50 = 0.07 μM, >36 μM). Besides, some other compounds, 5b, 7c, 7e, 7f, and 7m, were also endowed with favorable anti-HIV-1 potency (EC50 = 0.07, 0.05, 0.05, 0.07, and 0.05 μM, respectively), which were better than or similar to those of NVP and DLV, suggesting a high potential to further develop this type of bridgehead nitrogen heterocycle as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. The selected compound, 7i, was found moderately inhibitory towards RT (IC50 = 0.39 μM), which was higher than for ETV (IC50 = 0.56 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were detailed in this manuscript. </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="Wang, Liu" sort="Wang, Liu" uniqKey="Wang L" first="Liu" last="Wang">Liu Wang</name>
</noRegion>
<name sortKey="Chen, Wenmin" sort="Chen, Wenmin" uniqKey="Chen W" first="Wenmin" last="Chen">Wenmin Chen</name>
<name sortKey="Li, Dongyue" sort="Li, Dongyue" uniqKey="Li D" first="Dongyue" last="Li">Dongyue Li</name>
<name sortKey="Liu, Hong" sort="Liu, Hong" uniqKey="Liu H" first="Hong" last="Liu">Hong Liu</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="Tian, Ye" sort="Tian, Ye" uniqKey="Tian Y" first="Ye" last="Tian">Ye Tian</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>
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