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Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

Identifieur interne : 000857 ( PubMed/Curation ); précédent : 000856; suivant : 000858

Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

Auteurs : Ting Xiao [République populaire de Chine] ; Jia-Fan Tang [République populaire de Chine] ; Ge Meng [République populaire de Chine] ; Christophe Pannecouque [Belgique] ; Yuan-Yuan Zhu [République populaire de Chine] ; Gen-Yan Liu [République populaire de Chine] ; Zhi-Qiang Xu [République populaire de Chine] ; Feng-Shou Wu [République populaire de Chine] ; Shuang-Xi Gu [République populaire de Chine] ; Fen-Er Chen [République populaire de Chine]

Source :

European journal of medicinal chemistry [ 1768-3254 ] ; 2020.

RBID : pubmed:31767136

Descripteurs français

English descriptors

KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Dose-Response Relationship, Drug, Drug Design, HIV (drug effects), HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (metabolism), Humans, Indazoles (chemistry), Indazoles (pharmacology), Microbial Sensitivity Tests, Molecular Structure, Piperidines (chemical synthesis), Piperidines (chemistry), Piperidines (pharmacology), Pyrimidines (chemical synthesis), Pyrimidines (chemistry), Pyrimidines (pharmacology), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship.
MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemical synthesis : Anti-HIV Agents, Piperidines, Pyrimidines, Reverse Transcriptase Inhibitors.
- chemical , chemistry : Anti-HIV Agents, Indazoles, Piperidines, Pyrimidines, Reverse Transcriptase Inhibitors.
- chemical , metabolism : HIV Reverse Transcriptase.
- chemical , pharmacology : Anti-HIV Agents, Indazoles, Piperidines, Pyrimidines, Reverse Transcriptase Inhibitors.
- drug effects : HIV.
- Dose-Response Relationship, Drug, Drug Design, Humans, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship.

Abstract

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC₅₀ values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC₅₀ = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC₅₀ = 0.077 μM), Y181C (EC₅₀ = 0.11 μM), E138K (EC₅₀ = 0.057 μM), and moderate activity against double mutants RES056 (EC₅₀ = 8.7 μM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.

DOI: 10.1016/j.ejmech.2019.111864
PubMed: 31767136

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<term>Dose-Response Relationship, Drug</term>
<term>Drug Design</term>
<term>HIV (drug effects)</term>
<term>HIV Reverse Transcriptase (antagonists & inhibitors)</term>
<term>HIV Reverse Transcriptase (metabolism)</term>
<term>Humans</term>
<term>Indazoles (chemistry)</term>
<term>Indazoles (pharmacology)</term>
<term>Microbial Sensitivity Tests</term>
<term>Molecular Structure</term>
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<term>Piperidines (chemistry)</term>
<term>Piperidines (pharmacology)</term>
<term>Pyrimidines (chemical synthesis)</term>
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<term>Conception de médicament</term>
<term>Humains</term>
<term>Indazoles ()</term>
<term>Indazoles (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>
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<term>Pipéridines (pharmacologie)</term>
<term>Pipéridines (synthèse chimique)</term>
<term>Pyrimidines ()</term>
<term>Pyrimidines (pharmacologie)</term>
<term>Pyrimidines (synthèse chimique)</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Structure moléculaire</term>
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<term>Relation structure-activité</term>
<term>Structure moléculaire</term>
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<front><div type="abstract" xml:lang="en">A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC<sub>50</sub>
 values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC<sub>50</sub>
 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC<sub>50</sub>
 = 0.077 μM), Y181C (EC<sub>50</sub>
 = 0.11 μM), E138K (EC<sub>50</sub>
 = 0.057 μM), and moderate activity against double mutants RES056 (EC<sub>50</sub>
 = 8.7 μM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.</div>
</front>
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<Title>European journal of medicinal chemistry</Title>
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<ArticleTitle>Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.</ArticleTitle>
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<Abstract><AbstractText>A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC<sub>50</sub>
 values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC<sub>50</sub>
 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC<sub>50</sub>
 = 0.077 μM), Y181C (EC<sub>50</sub>
 = 0.11 μM), E138K (EC<sub>50</sub>
 = 0.057 μM), and moderate activity against double mutants RES056 (EC<sub>50</sub>
 = 8.7 μM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.</AbstractText>
<CopyrightInformation>Copyright © 2019 Elsevier Masson SAS. All rights reserved.</CopyrightInformation>
</Abstract>
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<ForeName>Ting</ForeName>
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<AffiliationInfo><Affiliation>Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China. Electronic address: shuangxigu@163.com.</Affiliation>
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<AffiliationInfo><Affiliation>Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China; Department of Chemistry, Fudan University, Shanghai, 200433, China. Electronic address: rfchen@fudan.edu.cn.</Affiliation>
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<Month>11</Month>
<Day>08</Day>
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<ISSNLinking>0223-5234</ISSNLinking>
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<NameOfSubstance UI="C514824">reverse transcriptase, Human immunodeficiency virus 1</NameOfSubstance>
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<Chemical><RegistryNumber>EC 2.7.7.49</RegistryNumber>
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<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
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<MeshHeading><DescriptorName UI="D018894" MajorTopicYN="N">Reverse Transcriptase Inhibitors</DescriptorName>
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<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName>
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<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">AIDS</Keyword>
<Keyword MajorTopicYN="N">Anti-HIV</Keyword>
<Keyword MajorTopicYN="N">Diaryl ethers</Keyword>
<Keyword MajorTopicYN="N">Indazole analogues</Keyword>
<Keyword MajorTopicYN="N">Molecular hybridization</Keyword>
<Keyword MajorTopicYN="N">NNRTIs</Keyword>
<Keyword MajorTopicYN="N">Piperidin-4-yl-aminopyrimidines</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year>
<Month>10</Month>
<Day>04</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2019</Year>
<Month>10</Month>
<Day>25</Day>
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<PubMedPubDate PubStatus="accepted"><Year>2019</Year>
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<Day>06</Day>
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<Month>11</Month>
<Day>27</Day>
<Hour>6</Hour>
<Minute>0</Minute>
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<ArticleIdList><ArticleId IdType="pubmed">31767136</ArticleId>
<ArticleId IdType="pii">S0223-5234(19)31016-5</ArticleId>
<ArticleId IdType="doi">10.1016/j.ejmech.2019.111864</ArticleId>
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Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

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