Discovery of nitropyridine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors via a structure-based core refining approach.
Identifieur interne : 001662 ( Main/Exploration ); précédent : 001661; suivant : 001663Discovery of nitropyridine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors via a structure-based core refining approach.
Auteurs : Jun Wang [République populaire de Chine] ; Peng Zhan [République populaire de Chine] ; Zhenyu 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 :
- Découverte de médicament, Humains, Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Lignée cellulaire, Pyridines (), Pyridines (pharmacologie), Relation structure-activité, Réplication virale (), Simulation de docking moléculaire, Spectrométrie de masse ESI, Spectroscopie par résonance magnétique, Structure moléculaire, Tests de sensibilité microbienne, Transcriptase inverse du VIH (antagonistes et inhibiteurs), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (physiologie).
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- pharmacologie : Inhibiteurs de la transcriptase inverse, Pyridines.
- physiologie : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- Découverte de médicament, Humains, Inhibiteurs de la transcriptase inverse, Lignée cellulaire, Pyridines, Relation structure-activité, Réplication virale, Simulation de docking moléculaire, Spectrométrie de masse ESI, Spectroscopie par résonance magnétique, Structure moléculaire, Tests de sensibilité microbienne, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Cell Line, Drug Discovery, HIV Reverse Transcriptase (antagonists & inhibitors), HIV-1 (drug effects), HIV-1 (physiology), Humans, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Pyridines (chemistry), Pyridines (pharmacology), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemistry : Pyridines, Reverse Transcriptase Inhibitors.
- drug effects : HIV-1, Virus Replication.
- chemical , pharmacology : Pyridines, Reverse Transcriptase Inhibitors.
- physiology : HIV-1.
- Cell Line, Drug Discovery, Humans, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship.
Abstract
As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1 activity in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1 IIIB. Most notably, the compound 7b was identified as the most promising candidate in inhibiting HIV-1 replication with an EC50 value of 0.056 μM and a selective index (SI) of 1251, which were much better than those of NVP (EC₅₀ = 0.23 μM) and DLV (EC₅₀ = 0.51 μM). Some other compounds, 7k, 7c, 7j and 7e, were also endowed with a favorable anti-HIV-1 potency (EC₅₀ = 0.034, 0.11, 0.11 and 0.16 μM, respectively). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.
DOI: 10.1016/j.ejmech.2014.02.047
PubMed: 24602795
Affiliations:
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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><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Li, Zhenyu" sort="Li, Zhenyu" uniqKey="Li Z" first="Zhenyu" last="Li">Zhenyu 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><wicri:noRegion>Shandong</wicri:noRegion></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 Ji'nan, 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 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></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><wicri:noRegion>B-3000 Leuven</wicri:noRegion></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><wicri:noRegion>B-3000 Leuven</wicri:noRegion></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><wicri:noRegion>Shandong</wicri:noRegion></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>Cell Line</term><term>Drug Discovery</term><term>HIV Reverse Transcriptase (antagonists & inhibitors)</term><term>HIV-1 (drug effects)</term><term>HIV-1 (physiology)</term><term>Humans</term><term>Magnetic Resonance Spectroscopy</term><term>Microbial Sensitivity Tests</term><term>Molecular Docking Simulation</term><term>Molecular Structure</term><term>Pyridines (chemistry)</term><term>Pyridines (pharmacology)</term><term>Reverse Transcriptase Inhibitors (chemistry)</term><term>Reverse Transcriptase Inhibitors (pharmacology)</term><term>Spectrometry, Mass, Electrospray Ionization</term><term>Structure-Activity Relationship</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Découverte de médicament</term><term>Humains</term><term>Inhibiteurs de la transcriptase inverse ()</term><term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term><term>Lignée cellulaire</term><term>Pyridines ()</term><term>Pyridines (pharmacologie)</term><term>Relation structure-activité</term><term>Réplication virale ()</term><term>Simulation de docking moléculaire</term><term>Spectrométrie de masse ESI</term><term>Spectroscopie par résonance magnétique</term><term>Structure moléculaire</term><term>Tests de sensibilité microbienne</term><term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (physiologie)</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>Pyridines</term><term>Reverse Transcriptase Inhibitors</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><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de la transcriptase inverse</term><term>Pyridines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Pyridines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>HIV-1</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Drug Discovery</term><term>Humans</term><term>Magnetic Resonance Spectroscopy</term><term>Microbial Sensitivity Tests</term><term>Molecular Docking Simulation</term><term>Molecular Structure</term><term>Spectrometry, Mass, Electrospray Ionization</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Découverte de médicament</term><term>Humains</term><term>Inhibiteurs de la transcriptase inverse</term><term>Lignée cellulaire</term><term>Pyridines</term><term>Relation structure-activité</term><term>Réplication virale</term><term>Simulation de docking moléculaire</term><term>Spectrométrie de masse ESI</term><term>Spectroscopie par résonance magnétique</term><term>Structure moléculaire</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">As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1 activity in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1 IIIB. Most notably, the compound 7b was identified as the most promising candidate in inhibiting HIV-1 replication with an EC50 value of 0.056 μM and a selective index (SI) of 1251, which were much better than those of NVP (EC₅₀ = 0.23 μM) and DLV (EC₅₀ = 0.51 μM). Some other compounds, 7k, 7c, 7j and 7e, were also endowed with a favorable anti-HIV-1 potency (EC₅₀ = 0.034, 0.11, 0.11 and 0.16 μM, respectively). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.</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, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name></noRegion><name sortKey="Li, Zhenyu" sort="Li, Zhenyu" uniqKey="Li Z" first="Zhenyu" last="Li">Zhenyu Li</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="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>Pour manipuler ce document sous Unix (Dilib)
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