Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Identifieur interne : 002A64 ( Main/Exploration ); précédent : 002A63; suivant : 002A65Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Auteurs : Andrea Spallarossa [Italie] ; Sara Cesarini ; Angelo Ranise ; Olga Bruno ; Silvia Schenone ; Paolo La Colla ; Gabriella Collu ; Giuseppina Sanna ; Barbara Secci ; Roberta LoddoSource :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2009.
Descripteurs français
- KwdFr :
- Concentration inhibitrice 50, Conception de médicament, Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Inhibiteurs de la transcriptase inverse (synthèse chimique), Modèles moléculaires, Nucléosides (), Relation structure-activité, Résistance virale aux médicaments, Thiocarbamates (), Thiocarbamates (pharmacologie), Thiocarbamates (synthèse chimique), 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) (enzymologie), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (physiologie).
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- enzymologie : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- pharmacologie : Inhibiteurs de la transcriptase inverse, Thiocarbamates.
- physiologie : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- synthèse chimique : Inhibiteurs de la transcriptase inverse, Thiocarbamates.
- Concentration inhibitrice 50, Conception de médicament, Inhibiteurs de la transcriptase inverse, Modèles moléculaires, Nucléosides, Relation structure-activité, Résistance virale aux médicaments, Thiocarbamates, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Drug Design, Drug Resistance, Viral, HIV Reverse Transcriptase (antagonists & inhibitors), HIV-1 (drug effects), HIV-1 (enzymology), HIV-1 (physiology), Inhibitory Concentration 50, Models, Molecular, 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 , antagonists & inhibitors : HIV Reverse Transcriptase.
- 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.
- physiology : HIV-1.
- Drug Design, Drug Resistance, Viral, Inhibitory Concentration 50, Models, Molecular, Structure-Activity Relationship.
Abstract
The structure-activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl) substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC(50)=1.3 microM) with good potency against the K103R mutant (EC(50)=4.8 microM). Docking simulations helped to rationalize the SARs.
DOI: 10.1016/j.ejmech.2008.09.024
PubMed: 18954921
Affiliations:
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type 1) (enzymologie)</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="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="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></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" 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scheme="MESH" xml:lang="fr"><term>Concentration inhibitrice 50</term><term>Conception de médicament</term><term>Inhibiteurs de la transcriptase inverse</term><term>Modèles moléculaires</term><term>Nucléosides</term><term>Relation structure-activité</term><term>Résistance virale aux médicaments</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">The structure-activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl) substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC(50)=1.3 microM) with good potency against the K103R mutant (EC(50)=4.8 microM). Docking simulations helped to rationalize the SARs.</div></front></TEI><affiliations><list><country><li>Italie</li></country></list><tree><noCountry><name sortKey="Bruno, Olga" sort="Bruno, Olga" uniqKey="Bruno O" first="Olga" last="Bruno">Olga Bruno</name><name sortKey="Cesarini, Sara" sort="Cesarini, Sara" uniqKey="Cesarini S" first="Sara" last="Cesarini">Sara Cesarini</name><name sortKey="Collu, Gabriella" sort="Collu, Gabriella" uniqKey="Collu G" first="Gabriella" last="Collu">Gabriella Collu</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="Schenone, Silvia" sort="Schenone, Silvia" uniqKey="Schenone S" first="Silvia" last="Schenone">Silvia Schenone</name><name sortKey="Secci, Barbara" sort="Secci, Barbara" uniqKey="Secci B" first="Barbara" last="Secci">Barbara Secci</name></noCountry><country name="Italie"><noRegion><name sortKey="Spallarossa, Andrea" sort="Spallarossa, Andrea" uniqKey="Spallarossa A" first="Andrea" last="Spallarossa">Andrea Spallarossa</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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