Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Parallel synthesis, molecular modelling and structure-activity relationship studies on O-[2-(hetero)arylethyl]-N-phenylthiocarbamates.
Identifieur interne : 002F83 ( Main/Exploration ); précédent : 002F82; suivant : 002F84Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Parallel synthesis, molecular modelling and structure-activity relationship studies on O-[2-(hetero)arylethyl]-N-phenylthiocarbamates.
Auteurs : Sara Cesarini [Italie] ; Andrea Spallarossa ; Angelo Ranise ; Paola Fossa ; Paolo La Colla ; Giuseppina Sanna ; Gabriella Collu ; Roberta LoddoSource :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2008.
Descripteurs français
- KwdFr :
- Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Inhibiteurs de la transcriptase inverse (synthèse chimique), Modèles moléculaires, Mutation (génétique), Nucléosides (), RNA-directed DNA polymerase (génétique), RNA-directed DNA polymerase (métabolisme), Relation structure-activité, Structure moléculaire, Thiocarbamates (), Thiocarbamates (pharmacologie), Thiocarbamates (synthèse chimique), 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 :
- enzymologie : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- génétique : Mutation, RNA-directed DNA polymerase, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- métabolisme : RNA-directed DNA polymerase.
- pharmacologie : Inhibiteurs de la transcriptase inverse, Thiocarbamates.
- synthèse chimique : Inhibiteurs de la transcriptase inverse, Thiocarbamates.
- Inhibiteurs de la transcriptase inverse, Modèles moléculaires, Nucléosides, Relation structure-activité, Structure moléculaire, Thiocarbamates, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- HIV-1 (drug effects), HIV-1 (enzymology), HIV-1 (genetics), Models, Molecular, Molecular Structure, Mutation (genetics), Nucleosides (chemistry), RNA-Directed DNA Polymerase (genetics), RNA-Directed DNA Polymerase (metabolism), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship, Thiocarbamates (chemical synthesis), Thiocarbamates (chemistry), Thiocarbamates (pharmacology).
- MESH :
- chemical , chemical synthesis : Reverse Transcriptase Inhibitors, Thiocarbamates.
- chemical , chemistry : Nucleosides, Reverse Transcriptase Inhibitors, Thiocarbamates.
- drug effects : HIV-1.
- enzymology : HIV-1.
- genetics : HIV-1, Mutation, RNA-Directed DNA Polymerase.
- chemical , metabolism : RNA-Directed DNA Polymerase.
- chemical , pharmacology : Reverse Transcriptase Inhibitors, Thiocarbamates.
- Models, Molecular, Molecular Structure, Structure-Activity Relationship.
Abstract
In order to expand the structure-activity relationship (SAR) studies on Thiocarbamates (TCs), a recently discovered class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 38 analogues of the lead O-[2-(2-pyridyl)ethyl]-N-phenylthiocarbamate 1 were prepared by parallel solution-phase synthesis. The SAR strategy was focused on the variation (mono- and disubstitution) of the N-phenyl ring and the replacement of the 2-pyridyl with 4-pyridyl, 2-thienyl and phenyl rings. The majority of the new TCs proved to prevent the wild-type HIV-1 multiplication in MT-4 cell culture and the most potent congeners displayed an EC(50) value of 100 nM. Two TCs were active also at micromolar concentrations against the Y181C- and/or K103N/Y181C-resistant mutants. Docking simulations helped to rationalize the SARs.
DOI: 10.1016/j.bmc.2007.12.050
PubMed: 18226532
Affiliations:
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Part 1: Parallel synthesis, molecular modelling and structure-activity relationship studies on O-[2-(hetero)arylethyl]-N-phenylthiocarbamates.</title><author><name sortKey="Cesarini, Sara" sort="Cesarini, Sara" uniqKey="Cesarini S" first="Sara" last="Cesarini">Sara Cesarini</name><affiliation wicri:level="1"><nlm:affiliation>Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. sara.cesarini@unige.it</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova</wicri:regionArea><wicri:noRegion>I-16132 Genova</wicri:noRegion></affiliation></author><author><name sortKey="Spallarossa, Andrea" sort="Spallarossa, Andrea" uniqKey="Spallarossa A" first="Andrea" last="Spallarossa">Andrea Spallarossa</name></author><author><name sortKey="Ranise, Angelo" sort="Ranise, Angelo" uniqKey="Ranise A" first="Angelo" last="Ranise">Angelo Ranise</name></author><author><name sortKey="Fossa, Paola" sort="Fossa, Paola" uniqKey="Fossa P" first="Paola" last="Fossa">Paola Fossa</name></author><author><name sortKey="La Colla, Paolo" sort="La Colla, Paolo" uniqKey="La Colla P" first="Paolo" last="La Colla">Paolo La Colla</name></author><author><name sortKey="Sanna, Giuseppina" sort="Sanna, Giuseppina" uniqKey="Sanna G" first="Giuseppina" last="Sanna">Giuseppina Sanna</name></author><author><name sortKey="Collu, Gabriella" sort="Collu, Gabriella" uniqKey="Collu G" first="Gabriella" last="Collu">Gabriella Collu</name></author><author><name sortKey="Loddo, Roberta" sort="Loddo, Roberta" uniqKey="Loddo R" first="Roberta" last="Loddo">Roberta Loddo</name></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="eISSN">1464-3391</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>HIV-1 (drug effects)</term><term>HIV-1 (enzymology)</term><term>HIV-1 (genetics)</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Mutation (genetics)</term><term>Nucleosides (chemistry)</term><term>RNA-Directed DNA Polymerase (genetics)</term><term>RNA-Directed DNA Polymerase (metabolism)</term><term>Reverse Transcriptase Inhibitors (chemical synthesis)</term><term>Reverse Transcriptase Inhibitors (chemistry)</term><term>Reverse Transcriptase Inhibitors (pharmacology)</term><term>Structure-Activity Relationship</term><term>Thiocarbamates (chemical synthesis)</term><term>Thiocarbamates (chemistry)</term><term>Thiocarbamates (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Inhibiteurs de la transcriptase inverse ()</term><term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term><term>Inhibiteurs de la transcriptase inverse (synthèse chimique)</term><term>Modèles moléculaires</term><term>Mutation (génétique)</term><term>Nucléosides ()</term><term>RNA-directed DNA polymerase (génétique)</term><term>RNA-directed DNA polymerase (métabolisme)</term><term>Relation structure-activité</term><term>Structure moléculaire</term><term>Thiocarbamates ()</term><term>Thiocarbamates (pharmacologie)</term><term>Thiocarbamates (synthèse chimique)</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="chemical synthesis" xml:lang="en"><term>Reverse Transcriptase Inhibitors</term><term>Thiocarbamates</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Nucleosides</term><term>Reverse Transcriptase Inhibitors</term><term>Thiocarbamates</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><term>Mutation</term><term>RNA-Directed DNA Polymerase</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Mutation</term><term>RNA-directed DNA polymerase</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>RNA-Directed DNA Polymerase</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>RNA-directed DNA polymerase</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de la transcriptase inverse</term><term>Thiocarbamates</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Reverse Transcriptase Inhibitors</term><term>Thiocarbamates</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Inhibiteurs de la transcriptase inverse</term><term>Thiocarbamates</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Models, Molecular</term><term>Molecular Structure</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Inhibiteurs de la transcriptase inverse</term><term>Modèles moléculaires</term><term>Nucléosides</term><term>Relation structure-activité</term><term>Structure moléculaire</term><term>Thiocarbamates</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In order to expand the structure-activity relationship (SAR) studies on Thiocarbamates (TCs), a recently discovered class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 38 analogues of the lead O-[2-(2-pyridyl)ethyl]-N-phenylthiocarbamate 1 were prepared by parallel solution-phase synthesis. The SAR strategy was focused on the variation (mono- and disubstitution) of the N-phenyl ring and the replacement of the 2-pyridyl with 4-pyridyl, 2-thienyl and phenyl rings. The majority of the new TCs proved to prevent the wild-type HIV-1 multiplication in MT-4 cell culture and the most potent congeners displayed an EC(50) value of 100 nM. Two TCs were active also at micromolar concentrations against the Y181C- and/or K103N/Y181C-resistant mutants. Docking simulations helped to rationalize the SARs.</div></front></TEI><affiliations><list><country><li>Italie</li></country></list><tree><noCountry><name sortKey="Collu, Gabriella" sort="Collu, Gabriella" uniqKey="Collu G" first="Gabriella" last="Collu">Gabriella Collu</name><name sortKey="Fossa, Paola" sort="Fossa, Paola" uniqKey="Fossa P" first="Paola" last="Fossa">Paola Fossa</name><name sortKey="La Colla, Paolo" sort="La Colla, Paolo" uniqKey="La Colla P" first="Paolo" last="La Colla">Paolo La Colla</name><name sortKey="Loddo, Roberta" sort="Loddo, Roberta" uniqKey="Loddo R" first="Roberta" last="Loddo">Roberta Loddo</name><name sortKey="Ranise, Angelo" sort="Ranise, Angelo" uniqKey="Ranise A" first="Angelo" last="Ranise">Angelo Ranise</name><name sortKey="Sanna, Giuseppina" sort="Sanna, Giuseppina" uniqKey="Sanna G" first="Giuseppina" last="Sanna">Giuseppina Sanna</name><name sortKey="Spallarossa, Andrea" sort="Spallarossa, Andrea" uniqKey="Spallarossa A" first="Andrea" last="Spallarossa">Andrea Spallarossa</name></noCountry><country name="Italie"><noRegion><name sortKey="Cesarini, Sara" sort="Cesarini, Sara" uniqKey="Cesarini S" first="Sara" last="Cesarini">Sara Cesarini</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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