Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine
Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimet...
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| Veröffentlicht in: | Journal of medicinal chemistry 1996-06, Vol.39 (12), p.2427-2431 |
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| container_issue | 12 |
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| container_title | Journal of medicinal chemistry |
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| creator | Danel, Krzysztof Larsen, Erik Pedersen, Erik B Vestergaard, Bent F Nielsen, Claus |
| description | Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6-(arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl)-α,β-d-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2‘,3‘-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N -substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent. |
| doi_str_mv | 10.1021/jm9600499 |
| format | Article |
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Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6-(arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl)-α,β-d-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2‘,3‘-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N -substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm9600499</identifier><identifier>PMID: 8691437</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Alkylation ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - pharmacology ; Antiviral Agents - toxicity ; Biological and medical sciences ; Cell Division - drug effects ; Drug Design ; HIV-1 - drug effects ; HIV-1 - physiology ; human immunodeficiency virus 1 ; Humans ; Magnetic Resonance Spectroscopy ; Medical sciences ; Molecular Structure ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; T-Lymphocytes - drug effects ; T-Lymphocytes - virology ; Thymine - analogs & derivatives ; Thymine - pharmacology ; Uracil - analogs & derivatives ; Uracil - chemical synthesis ; Uracil - pharmacology ; Uracil - toxicity ; Virus Replication - drug effects</subject><ispartof>Journal of medicinal chemistry, 1996-06, Vol.39 (12), p.2427-2431</ispartof><rights>Copyright © 1996 American Chemical Society</rights><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a408t-a903a42fa65452324a83a050fd8a2374fc415ded3c75ad681eaf9e78df63c7053</citedby><cites>FETCH-LOGICAL-a408t-a903a42fa65452324a83a050fd8a2374fc415ded3c75ad681eaf9e78df63c7053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm9600499$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm9600499$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3116439$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8691437$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Danel, Krzysztof</creatorcontrib><creatorcontrib>Larsen, Erik</creatorcontrib><creatorcontrib>Pedersen, Erik B</creatorcontrib><creatorcontrib>Vestergaard, Bent F</creatorcontrib><creatorcontrib>Nielsen, Claus</creatorcontrib><title>Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6-(arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl)-α,β-d-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2‘,3‘-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N -substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent.</description><subject>Alkylation</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - toxicity</subject><subject>Biological and medical sciences</subject><subject>Cell Division - drug effects</subject><subject>Drug Design</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - physiology</subject><subject>human immunodeficiency virus 1</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - virology</subject><subject>Thymine - analogs & derivatives</subject><subject>Thymine - pharmacology</subject><subject>Uracil - analogs & derivatives</subject><subject>Uracil - chemical synthesis</subject><subject>Uracil - pharmacology</subject><subject>Uracil - toxicity</subject><subject>Virus Replication - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkUuLFDEUhYMoYzu68AcItVCZXkTzqlTVsmd89MCgAz2KKBKuVSk7bSppk9Qw5ca_bppueuXmHrjn43A5F6GnlLyihNHXm6GRhIimuYdmtGQEi5qI-2hGCGOYScYfokcxbgghnDJ-gk5q2VDBqxn6u5pcWutoYgGuK6590i4VC5cMXl5-xrRYtMncmjQVvi8--FttC4nPtfsz2TFAa2xmwfqfo447guJvZwwvpy74u0mndZ7zIetkv2OJz7Zr7Sab1sbP824wTj9GD3qwUT856Cn69O7tzcUSX318f3mxuMIgSJ0wNISDYD3IUpSMMwE1B1KSvquB8Ur0raBlpzveViV0sqYa-kZXddfLvCIlP0Uv97nb4H_nY5MaTGy1teC0H6OipRRSCJrB-R5sg48x6F5tgxkgTIoStStbHcvO7LND6Phj0N2RPLSb_ecHH2ILtg_gWhOPGKdUCr6LwXvMxKTvjjaEX0pWvCrVzfVKrb6esy_yTaN45l_seWij2vgx5A_E_5z3Dz8voQo</recordid><startdate>19960607</startdate><enddate>19960607</enddate><creator>Danel, Krzysztof</creator><creator>Larsen, Erik</creator><creator>Pedersen, Erik B</creator><creator>Vestergaard, Bent F</creator><creator>Nielsen, Claus</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>19960607</creationdate><title>Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine</title><author>Danel, Krzysztof ; Larsen, Erik ; Pedersen, Erik B ; Vestergaard, Bent F ; Nielsen, Claus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a408t-a903a42fa65452324a83a050fd8a2374fc415ded3c75ad681eaf9e78df63c7053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Alkylation</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - toxicity</topic><topic>Biological and medical sciences</topic><topic>Cell Division - drug effects</topic><topic>Drug Design</topic><topic>HIV-1 - drug effects</topic><topic>HIV-1 - physiology</topic><topic>human immunodeficiency virus 1</topic><topic>Humans</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - virology</topic><topic>Thymine - analogs & derivatives</topic><topic>Thymine - pharmacology</topic><topic>Uracil - analogs & derivatives</topic><topic>Uracil - chemical synthesis</topic><topic>Uracil - pharmacology</topic><topic>Uracil - toxicity</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Danel, Krzysztof</creatorcontrib><creatorcontrib>Larsen, Erik</creatorcontrib><creatorcontrib>Pedersen, Erik B</creatorcontrib><creatorcontrib>Vestergaard, Bent F</creatorcontrib><creatorcontrib>Nielsen, Claus</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Danel, Krzysztof</au><au>Larsen, Erik</au><au>Pedersen, Erik B</au><au>Vestergaard, Bent F</au><au>Nielsen, Claus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1996-06-07</date><risdate>1996</risdate><volume>39</volume><issue>12</issue><spage>2427</spage><epage>2431</epage><pages>2427-2431</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6-(arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl)-α,β-d-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2‘,3‘-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N -substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8691437</pmid><doi>10.1021/jm9600499</doi><tpages>5</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1996-06, Vol.39 (12), p.2427-2431 |
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| language | eng |
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| subjects | Alkylation Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - pharmacology Antiviral Agents - toxicity Biological and medical sciences Cell Division - drug effects Drug Design HIV-1 - drug effects HIV-1 - physiology human immunodeficiency virus 1 Humans Magnetic Resonance Spectroscopy Medical sciences Molecular Structure Pharmacology. Drug treatments Structure-Activity Relationship T-Lymphocytes - drug effects T-Lymphocytes - virology Thymine - analogs & derivatives Thymine - pharmacology Uracil - analogs & derivatives Uracil - chemical synthesis Uracil - pharmacology Uracil - toxicity Virus Replication - drug effects |
| title | Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine |
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