Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Parallel synthesis, molecular modelling and structure-activity relationship studies on analogues of O-(2-phenylethyl)-N-phenylthiocarbamate.
Identifieur interne : 002F82 ( Main/Exploration ); précédent : 002F81; suivant : 002F83Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Parallel synthesis, molecular modelling and structure-activity relationship studies on analogues of O-(2-phenylethyl)-N-phenylthiocarbamate.
Auteurs : Sara Cesarini [Italie] ; Andrea Spallarossa ; Angelo Ranise ; Olga Bruno ; Paolo La Colla ; Barbara Secci ; 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, Nucléosides (), 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).
- MESH :
- enzymologie : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- 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), Models, Molecular, Molecular Structure, Nucleosides (chemistry), 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.
- chemical , pharmacology : Reverse Transcriptase Inhibitors, Thiocarbamates.
- Models, Molecular, Molecular Structure, Structure-Activity Relationship.
Abstract
To acquire further insight into the structure-activity relationship (SAR) of the thiocarbamates (TCs) described in the preceding work, 57 analogues of the lead compound O-(2-phenylethyl)-N-phenylthiocarbamate I were prepared by parallel solution-phase synthesis. We varied the 2-phenylethyl moiety (mono-substitution on the phenyl ring and modification of the ethyl linker), keeping constant the N-phenyl ring substitutions which have given the best results in the previous series. Most of the new TCs inhibited wild-type HIV-1 at micro- and nanomolar concentrations in MT-4 cell-based assays. Some TCs were also active at micromolar concentrations against the Y181C and/or K103N/Y181C resistant mutants. The SARs were rationalized by docking simulations.
DOI: 10.1016/j.bmc.2007.12.046
PubMed: 18226533
Affiliations:
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Le document en format XML
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<term>HIV-1 (enzymology)</term>
<term>Models, Molecular</term>
<term>Molecular Structure</term>
<term>Nucleosides (chemistry)</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>
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<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>Nucléosides ()</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>
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<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Reverse Transcriptase Inhibitors</term>
<term>Thiocarbamates</term>
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<term>Reverse Transcriptase Inhibitors</term>
<term>Thiocarbamates</term>
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<front><div type="abstract" xml:lang="en">To acquire further insight into the structure-activity relationship (SAR) of the thiocarbamates (TCs) described in the preceding work, 57 analogues of the lead compound O-(2-phenylethyl)-N-phenylthiocarbamate I were prepared by parallel solution-phase synthesis. We varied the 2-phenylethyl moiety (mono-substitution on the phenyl ring and modification of the ethyl linker), keeping constant the N-phenyl ring substitutions which have given the best results in the previous series. Most of the new TCs inhibited wild-type HIV-1 at micro- and nanomolar concentrations in MT-4 cell-based assays. Some TCs were also active at micromolar concentrations against the Y181C and/or K103N/Y181C resistant mutants. The SARs were rationalized by docking simulations.</div>
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