Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.
Identifieur interne : 000D46 ( Ncbi/Curation ); précédent : 000D45; suivant : 000D47Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.
Auteurs : Naoyuki Masuda [Japon] ; Osamu Yamamoto ; Masahiro Fujii ; Tetsuro Ohgami ; Jiro Fujiyasu ; Toru Kontani ; Ayako Moritomo ; Masaya Orita ; Hiroyuki Kurihara ; Hironobu Koga ; Shunji Kageyama ; Mitsuaki Ohta ; Hiroshi Inoue ; Toshifumi Hatta ; Masafumi Shintani ; Hiroshi Suzuki ; Kenji Sudo ; Yasuaki Shimizu ; Eiichi Kodama ; Masao Matsuoka ; Masatoshi Fujiwara ; Tomoyuki Yokota ; Shiro Shigeta ; Masanori BabaSource :
- Bioorganic & medicinal chemistry [ 0968-0896 ] ; 2005.
Descripteurs français
- KwdFr :
- Humains, Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Inhibiteurs de la transcriptase inverse (synthèse chimique), Lignée cellulaire, Relation structure-activité, Spectrométrie de masse FAB, Spectroscopie par résonance magnétique, Sulfonamides (), Sulfonamides (pharmacologie), Sulfonamides (synthèse chimique), Tests de sensibilité microbienne, VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- pharmacologie : Inhibiteurs de la transcriptase inverse, Sulfonamides.
- synthèse chimique : Inhibiteurs de la transcriptase inverse, Sulfonamides.
- Humains, Inhibiteurs de la transcriptase inverse, Lignée cellulaire, Relation structure-activité, Spectrométrie de masse FAB, Spectroscopie par résonance magnétique, Sulfonamides, Tests de sensibilité microbienne, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Cell Line, HIV-1 (drug effects), Humans, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Spectrometry, Mass, Fast Atom Bombardment, Structure-Activity Relationship, Sulfonamides (chemical synthesis), Sulfonamides (chemistry), Sulfonamides (pharmacology).
- MESH :
- chemical , chemical synthesis : Reverse Transcriptase Inhibitors, Sulfonamides.
- chemical , chemistry : Reverse Transcriptase Inhibitors, Sulfonamides.
- drug effects : HIV-1.
- chemical , pharmacology : Reverse Transcriptase Inhibitors, Sulfonamides.
- Cell Line, Humans, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Spectrometry, Mass, Fast Atom Bombardment, Structure-Activity Relationship.
Abstract
In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 10l and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 microM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 microM, respectively.
DOI: 10.1016/j.bmc.2004.11.045
PubMed: 15670903
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<term>HIV-1 (drug effects)</term>
<term>Humans</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Microbial Sensitivity Tests</term>
<term>Reverse Transcriptase Inhibitors (chemical synthesis)</term>
<term>Reverse Transcriptase Inhibitors (chemistry)</term>
<term>Reverse Transcriptase Inhibitors (pharmacology)</term>
<term>Spectrometry, Mass, Fast Atom Bombardment</term>
<term>Structure-Activity Relationship</term>
<term>Sulfonamides (chemical synthesis)</term>
<term>Sulfonamides (chemistry)</term>
<term>Sulfonamides (pharmacology)</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>Humains</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>
<term>Lignée cellulaire</term>
<term>Relation structure-activité</term>
<term>Spectrométrie de masse FAB</term>
<term>Spectroscopie par résonance magnétique</term>
<term>Sulfonamides ()</term>
<term>Sulfonamides (pharmacologie)</term>
<term>Sulfonamides (synthèse chimique)</term>
<term>Tests de sensibilité microbienne</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
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<term>Sulfonamides</term>
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<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Reverse Transcriptase Inhibitors</term>
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<term>Spectrometry, Mass, Fast Atom Bombardment</term>
<term>Structure-Activity Relationship</term>
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<term>Inhibiteurs de la transcriptase inverse</term>
<term>Lignée cellulaire</term>
<term>Relation structure-activité</term>
<term>Spectrométrie de masse FAB</term>
<term>Spectroscopie par résonance magnétique</term>
<term>Sulfonamides</term>
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<front><div type="abstract" xml:lang="en">In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 10l and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 microM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 microM, respectively.</div>
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