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 : 000F54 ( PubMed/Curation ); précédent : 000F53; suivant : 000F55Fused 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
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000F54
Links to Exploration step
pubmed:25089812Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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.</title>
<author><name sortKey="Wang, Liu" sort="Wang, Liu" uniqKey="Wang L" first="Liu" last="Wang">Liu Wang</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tian, Ye" sort="Tian, Ye" uniqKey="Tian Y" first="Ye" last="Tian">Ye Tian</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chen, Wenmin" sort="Chen, Wenmin" uniqKey="Chen W" first="Wenmin" last="Chen">Wenmin Chen</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Liu, Hong" sort="Liu, Hong" uniqKey="Liu H" first="Hong" last="Liu">Hong 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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Li, Dongyue" sort="Li, Dongyue" uniqKey="Li D" first="Dongyue" last="Li">Dongyue Li</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Liu, Huiqing" sort="Liu, Huiqing" uniqKey="Liu H" first="Huiqing" last="Liu">Huiqing Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute of Pharmacology, School of Medicine, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Institute of Pharmacology, School of Medicine, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</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, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea>
</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, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea>
</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2014">2014</date>
<idno type="RBID">pubmed:25089812</idno>
<idno type="pmid">25089812</idno>
<idno type="doi">10.1016/j.ejmech.2014.07.104</idno>
<idno type="wicri:Area/PubMed/Corpus">000F54</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000F54</idno>
<idno type="wicri:Area/PubMed/Curation">000F54</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000F54</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">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.</title>
<author><name sortKey="Wang, Liu" sort="Wang, Liu" uniqKey="Wang L" first="Liu" last="Wang">Liu Wang</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tian, Ye" sort="Tian, Ye" uniqKey="Tian Y" first="Ye" last="Tian">Ye Tian</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chen, Wenmin" sort="Chen, Wenmin" uniqKey="Chen W" first="Wenmin" last="Chen">Wenmin Chen</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Liu, Hong" sort="Liu, Hong" uniqKey="Liu H" first="Hong" last="Liu">Hong 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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Li, Dongyue" sort="Li, Dongyue" uniqKey="Li D" first="Dongyue" last="Li">Dongyue Li</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Liu, Huiqing" sort="Liu, Huiqing" uniqKey="Liu H" first="Huiqing" last="Liu">Huiqing Liu</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute of Pharmacology, School of Medicine, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Institute of Pharmacology, School of Medicine, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</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, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea>
</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, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea>
</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, 44, West Culture Road, 250012 Jinan, Shandong, PR 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, 44, West Culture Road, 250012 Jinan, Shandong</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">European journal of medicinal chemistry</title>
<idno type="eISSN">1768-3254</idno>
<imprint><date when="2014" type="published">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Drug Design</term>
<term>HIV Reverse Transcriptase (antagonists & inhibitors)</term>
<term>HIV Reverse Transcriptase (chemistry)</term>
<term>HIV Reverse Transcriptase (genetics)</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 (enzymology)</term>
<term>HIV-1 (genetics)</term>
<term>Models, Molecular</term>
<term>Mutation</term>
<term>Nitrogen (chemistry)</term>
<term>Protein Conformation</term>
<term>Pyrimidines (chemistry)</term>
<term>Pyrimidines (pharmacology)</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>Azote ()</term>
<term>Conception de médicament</term>
<term>Conformation des protéines</term>
<term>Inhibiteurs de la transcriptase inverse ()</term>
<term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term>
<term>Modèles moléculaires</term>
<term>Mutation</term>
<term>Pyrimidines ()</term>
<term>Pyrimidines (pharmacologie)</term>
<term>Relation structure-activité</term>
<term>Transcriptase inverse du VIH ()</term>
<term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term>
<term>Transcriptase inverse du VIH (génétique)</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="chemistry" xml:lang="en"><term>HIV Reverse Transcriptase</term>
<term>Nitrogen</term>
<term>Pyrimidines</term>
<term>Reverse Transcriptase Inhibitors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>HIV Reverse Transcriptase</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="genetics" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de la transcriptase inverse</term>
<term>Pyrimidines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Pyrimidines</term>
<term>Reverse Transcriptase Inhibitors</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Drug Design</term>
<term>Models, Molecular</term>
<term>Mutation</term>
<term>Protein Conformation</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Azote</term>
<term>Conception de médicament</term>
<term>Conformation des protéines</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Modèles moléculaires</term>
<term>Mutation</term>
<term>Pyrimidines</term>
<term>Relation structure-activité</term>
<term>Transcriptase inverse du VIH</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<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>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25089812</PMID>
<DateCompleted><Year>2015</Year>
<Month>06</Month>
<Day>02</Day>
</DateCompleted>
<DateRevised><Year>2014</Year>
<Month>09</Month>
<Day>11</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1768-3254</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>85</Volume>
<PubDate><Year>2014</Year>
<Month>Oct</Month>
<Day>06</Day>
</PubDate>
</JournalIssue>
<Title>European journal of medicinal chemistry</Title>
<ISOAbbreviation>Eur J Med Chem</ISOAbbreviation>
</Journal>
<ArticleTitle>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.</ArticleTitle>
<Pagination><MedlinePgn>293-303</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ejmech.2014.07.104</ELocationID>
<ELocationID EIdType="pii" ValidYN="Y">S0223-5234(14)00719-3</ELocationID>
<Abstract><AbstractText>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. </AbstractText>
<CopyrightInformation>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Liu</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tian</LastName>
<ForeName>Ye</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>Wenmin</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Liu</LastName>
<ForeName>Hong</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhan</LastName>
<ForeName>Peng</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Li</LastName>
<ForeName>Dongyue</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Liu</LastName>
<ForeName>Huiqing</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Institute of Pharmacology, School of Medicine, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>De Clercq</LastName>
<ForeName>Erik</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pannecouque</LastName>
<ForeName>Christophe</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Liu</LastName>
<ForeName>Xinyong</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2014</Year>
<Month>07</Month>
<Day>30</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>France</Country>
<MedlineTA>Eur J Med Chem</MedlineTA>
<NlmUniqueID>0420510</NlmUniqueID>
<ISSNLinking>0223-5234</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011743">Pyrimidines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D018894">Reverse Transcriptase Inhibitors</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.7.49</RegistryNumber>
<NameOfSubstance UI="D054303">HIV Reverse Transcriptase</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>N762921K75</RegistryNumber>
<NameOfSubstance UI="D009584">Nitrogen</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D015195" MajorTopicYN="Y">Drug Design</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D054303" MajorTopicYN="N">HIV Reverse Transcriptase</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015497" MajorTopicYN="N">HIV-1</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009584" MajorTopicYN="N">Nitrogen</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011743" MajorTopicYN="N">Pyrimidines</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018894" MajorTopicYN="N">Reverse Transcriptase Inhibitors</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Bridgehead nitrogen heterocycle</Keyword>
<Keyword MajorTopicYN="N">DAPY</Keyword>
<Keyword MajorTopicYN="N">Molecular modeling</Keyword>
<Keyword MajorTopicYN="N">Structure–activity relationships</Keyword>
<Keyword MajorTopicYN="N">[1,2,4]Triazolo[1,5-a]pyrimidine</Keyword>
<Keyword MajorTopicYN="N">anti-HIV activities</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year>
<Month>01</Month>
<Day>11</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2014</Year>
<Month>07</Month>
<Day>28</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2014</Year>
<Month>07</Month>
<Day>29</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2014</Year>
<Month>8</Month>
<Day>5</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2014</Year>
<Month>8</Month>
<Day>5</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2015</Year>
<Month>6</Month>
<Day>3</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">25089812</ArticleId>
<ArticleId IdType="pii">S0223-5234(14)00719-3</ArticleId>
<ArticleId IdType="doi">10.1016/j.ejmech.2014.07.104</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/PubMed/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000F54 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd -nk 000F54 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= SrasV1 |flux= PubMed |étape= Curation |type= RBID |clé= pubmed:25089812 |texte= 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. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Curation/RBID.i -Sk "pubmed:25089812" \ | HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd \ | NlmPubMed2Wicri -a SrasV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |