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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.

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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.

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.

RBID : pubmed:25089812

Descripteurs français

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

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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>
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<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>
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   |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.
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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.

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.

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