Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent
A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure–activity relationship (SAR) was investigated based on in vitro and in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin...
Gespeichert in:
| Veröffentlicht in: | European journal of medicinal chemistry 2011-04, Vol.46 (4), p.1027-1039 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1039 |
|---|---|
| container_issue | 4 |
| container_start_page | 1027 |
| container_title | European journal of medicinal chemistry |
| container_volume | 46 |
| creator | Im, Weon Bin Choi, Sun Ho Park, Ju-Young Choi, Sung Hak Finn, John Yoon, Sung-Hwa |
| description | A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure–activity relationship (SAR) was investigated based on
in vitro and
in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0
μg/mL, and against
Haemophilus influenzae (Hi) from 2.0 to 8.0
μg/mL. Compared to linezolid, only four compounds (
11,
12,
21 and
29) showed higher
in vitro antibacterial activities and better
in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound
11 (DA-7157), which exerted a potency that was enhanced by 2–8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound
42 exhibited excellent aqueous solubility (>50
mg/mL in DW) and good pharmacokinetic profiles, along with better
in vivo efficacy than linezolid. This compound
42 is currently undergoing clinical trials with the brand name Torezolid.
A series of novel substituted pyridyl phenyl oxazolidinone analogues were prepared and evaluated. The phosphate prodrug of compound
11 exhibited excellent aqueous solubility and potent activity.
[Display omitted]
►Torezolid is a 5-hydroxymethyl-oxazolidinone derivative. ►Torezolid is very active for Gram-positive infection. ►Torezolid phosphate can be developed as po and iv formulations. |
| doi_str_mv | 10.1016/j.ejmech.2011.01.014 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_855201957</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0223523411000225</els_id><sourcerecordid>855201957</sourcerecordid><originalsourceid>FETCH-LOGICAL-c457t-7c5b3bc071677eb354b7eeb535ab280058298235d0926aa8cf48f4886045b0e3</originalsourceid><addsrcrecordid>eNp9kMtKxDAUhoMoOl7eQKQbcdUx1142goxXEFzoPiTpqZOhbTTpDFOf3tQZdSf8kEW-k_znQ-iU4CnBJLtcTGHRgplPKSZkisfwHTQheVakjAq-iyaYUpYKyvgBOgxhgTEWGcb76IASWlImsgl6ubHBuBX4IXF10jsPn66xVaJCopIuXjSJSOdD5d16aKGfD03q1uqbsZ3rIFFdb7UyPXirmkS9Qdcfo71aNQFOtucRer27fZ09pE_P94-z66fUcJH3aW6EZtrgnGR5DpoJrnMALZhQmhaxa0HLIrascEkzpQpT8yKmyDAXGgM7QhebZ9-9-1hC6GUbd4GmUR24ZZCFEFFNKfJI8g1pvAvBQy3fvW2VHyTBcpQpF3IjU44yJR7D49jZ9oOlbqH6HfqxF4HzLaCCUU3tVWds-ONYmZWMiMhdbTiINlYWvAzGQmegsh5MLytn_2_yBVdblE4</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>855201957</pqid></control><display><type>article</type><title>Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Im, Weon Bin ; Choi, Sun Ho ; Park, Ju-Young ; Choi, Sung Hak ; Finn, John ; Yoon, Sung-Hwa</creator><creatorcontrib>Im, Weon Bin ; Choi, Sun Ho ; Park, Ju-Young ; Choi, Sung Hak ; Finn, John ; Yoon, Sung-Hwa</creatorcontrib><description>A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure–activity relationship (SAR) was investigated based on
in vitro and
in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0
μg/mL, and against
Haemophilus influenzae (Hi) from 2.0 to 8.0
μg/mL. Compared to linezolid, only four compounds (
11,
12,
21 and
29) showed higher
in vitro antibacterial activities and better
in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound
11 (DA-7157), which exerted a potency that was enhanced by 2–8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound
42 exhibited excellent aqueous solubility (>50
mg/mL in DW) and good pharmacokinetic profiles, along with better
in vivo efficacy than linezolid. This compound
42 is currently undergoing clinical trials with the brand name Torezolid.
A series of novel substituted pyridyl phenyl oxazolidinone analogues were prepared and evaluated. The phosphate prodrug of compound
11 exhibited excellent aqueous solubility and potent activity.
[Display omitted]
►Torezolid is a 5-hydroxymethyl-oxazolidinone derivative. ►Torezolid is very active for Gram-positive infection. ►Torezolid phosphate can be developed as po and iv formulations.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2011.01.014</identifier><identifier>PMID: 21292356</identifier><identifier>CODEN: EJMCA5</identifier><language>eng</language><publisher>Kidlington: Elsevier Masson SAS</publisher><subject>Animals ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - metabolism ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - pharmacology ; Antibacterial activity ; Antibacterial agents ; Antibiotics ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Bacteria - drug effects ; Biological and medical sciences ; DA-7867 ; Drug Discovery ; Male ; Medical sciences ; Mice ; Microbial Sensitivity Tests ; Models, Molecular ; Molecular Conformation ; Oxazolidinone ; Oxazolidinones - chemistry ; Oxazolidinones - metabolism ; Oxazolidinones - pharmacokinetics ; Oxazolidinones - pharmacology ; Pharmacology. Drug treatments ; Prodrug ; Prodrugs - chemistry ; Prodrugs - metabolism ; Pyridine ; Solubility ; Tetrazoles - chemistry ; Tetrazoles - metabolism ; Tetrazoles - pharmacokinetics ; Tetrazoles - pharmacology</subject><ispartof>European journal of medicinal chemistry, 2011-04, Vol.46 (4), p.1027-1039</ispartof><rights>2011 Elsevier Masson SAS</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c457t-7c5b3bc071677eb354b7eeb535ab280058298235d0926aa8cf48f4886045b0e3</citedby><cites>FETCH-LOGICAL-c457t-7c5b3bc071677eb354b7eeb535ab280058298235d0926aa8cf48f4886045b0e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523411000225$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23969315$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21292356$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Im, Weon Bin</creatorcontrib><creatorcontrib>Choi, Sun Ho</creatorcontrib><creatorcontrib>Park, Ju-Young</creatorcontrib><creatorcontrib>Choi, Sung Hak</creatorcontrib><creatorcontrib>Finn, John</creatorcontrib><creatorcontrib>Yoon, Sung-Hwa</creatorcontrib><title>Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure–activity relationship (SAR) was investigated based on
in vitro and
in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0
μg/mL, and against
Haemophilus influenzae (Hi) from 2.0 to 8.0
μg/mL. Compared to linezolid, only four compounds (
11,
12,
21 and
29) showed higher
in vitro antibacterial activities and better
in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound
11 (DA-7157), which exerted a potency that was enhanced by 2–8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound
42 exhibited excellent aqueous solubility (>50
mg/mL in DW) and good pharmacokinetic profiles, along with better
in vivo efficacy than linezolid. This compound
42 is currently undergoing clinical trials with the brand name Torezolid.
A series of novel substituted pyridyl phenyl oxazolidinone analogues were prepared and evaluated. The phosphate prodrug of compound
11 exhibited excellent aqueous solubility and potent activity.
[Display omitted]
►Torezolid is a 5-hydroxymethyl-oxazolidinone derivative. ►Torezolid is very active for Gram-positive infection. ►Torezolid phosphate can be developed as po and iv formulations.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - metabolism</subject><subject>Anti-Bacterial Agents - pharmacokinetics</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibacterial activity</subject><subject>Antibacterial agents</subject><subject>Antibiotics</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Bacteria - drug effects</subject><subject>Biological and medical sciences</subject><subject>DA-7867</subject><subject>Drug Discovery</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Oxazolidinone</subject><subject>Oxazolidinones - chemistry</subject><subject>Oxazolidinones - metabolism</subject><subject>Oxazolidinones - pharmacokinetics</subject><subject>Oxazolidinones - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrug</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - metabolism</subject><subject>Pyridine</subject><subject>Solubility</subject><subject>Tetrazoles - chemistry</subject><subject>Tetrazoles - metabolism</subject><subject>Tetrazoles - pharmacokinetics</subject><subject>Tetrazoles - pharmacology</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtKxDAUhoMoOl7eQKQbcdUx1142goxXEFzoPiTpqZOhbTTpDFOf3tQZdSf8kEW-k_znQ-iU4CnBJLtcTGHRgplPKSZkisfwHTQheVakjAq-iyaYUpYKyvgBOgxhgTEWGcb76IASWlImsgl6ubHBuBX4IXF10jsPn66xVaJCopIuXjSJSOdD5d16aKGfD03q1uqbsZ3rIFFdb7UyPXirmkS9Qdcfo71aNQFOtucRer27fZ09pE_P94-z66fUcJH3aW6EZtrgnGR5DpoJrnMALZhQmhaxa0HLIrascEkzpQpT8yKmyDAXGgM7QhebZ9-9-1hC6GUbd4GmUR24ZZCFEFFNKfJI8g1pvAvBQy3fvW2VHyTBcpQpF3IjU44yJR7D49jZ9oOlbqH6HfqxF4HzLaCCUU3tVWds-ONYmZWMiMhdbTiINlYWvAzGQmegsh5MLytn_2_yBVdblE4</recordid><startdate>20110401</startdate><enddate>20110401</enddate><creator>Im, Weon Bin</creator><creator>Choi, Sun Ho</creator><creator>Park, Ju-Young</creator><creator>Choi, Sung Hak</creator><creator>Finn, John</creator><creator>Yoon, Sung-Hwa</creator><general>Elsevier Masson SAS</general><general>Elsevier</general><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>7X8</scope></search><sort><creationdate>20110401</creationdate><title>Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent</title><author>Im, Weon Bin ; Choi, Sun Ho ; Park, Ju-Young ; Choi, Sung Hak ; Finn, John ; Yoon, Sung-Hwa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-7c5b3bc071677eb354b7eeb535ab280058298235d0926aa8cf48f4886045b0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - metabolism</topic><topic>Anti-Bacterial Agents - pharmacokinetics</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antibacterial activity</topic><topic>Antibacterial agents</topic><topic>Antibiotics</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Bacteria - drug effects</topic><topic>Biological and medical sciences</topic><topic>DA-7867</topic><topic>Drug Discovery</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Microbial Sensitivity Tests</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Oxazolidinone</topic><topic>Oxazolidinones - chemistry</topic><topic>Oxazolidinones - metabolism</topic><topic>Oxazolidinones - pharmacokinetics</topic><topic>Oxazolidinones - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrug</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - metabolism</topic><topic>Pyridine</topic><topic>Solubility</topic><topic>Tetrazoles - chemistry</topic><topic>Tetrazoles - metabolism</topic><topic>Tetrazoles - pharmacokinetics</topic><topic>Tetrazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Im, Weon Bin</creatorcontrib><creatorcontrib>Choi, Sun Ho</creatorcontrib><creatorcontrib>Park, Ju-Young</creatorcontrib><creatorcontrib>Choi, Sung Hak</creatorcontrib><creatorcontrib>Finn, John</creatorcontrib><creatorcontrib>Yoon, Sung-Hwa</creatorcontrib><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>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Im, Weon Bin</au><au>Choi, Sun Ho</au><au>Park, Ju-Young</au><au>Choi, Sung Hak</au><au>Finn, John</au><au>Yoon, Sung-Hwa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2011-04-01</date><risdate>2011</risdate><volume>46</volume><issue>4</issue><spage>1027</spage><epage>1039</epage><pages>1027-1039</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><coden>EJMCA5</coden><abstract>A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure–activity relationship (SAR) was investigated based on
in vitro and
in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0
μg/mL, and against
Haemophilus influenzae (Hi) from 2.0 to 8.0
μg/mL. Compared to linezolid, only four compounds (
11,
12,
21 and
29) showed higher
in vitro antibacterial activities and better
in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound
11 (DA-7157), which exerted a potency that was enhanced by 2–8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound
42 exhibited excellent aqueous solubility (>50
mg/mL in DW) and good pharmacokinetic profiles, along with better
in vivo efficacy than linezolid. This compound
42 is currently undergoing clinical trials with the brand name Torezolid.
A series of novel substituted pyridyl phenyl oxazolidinone analogues were prepared and evaluated. The phosphate prodrug of compound
11 exhibited excellent aqueous solubility and potent activity.
[Display omitted]
►Torezolid is a 5-hydroxymethyl-oxazolidinone derivative. ►Torezolid is very active for Gram-positive infection. ►Torezolid phosphate can be developed as po and iv formulations.</abstract><cop>Kidlington</cop><pub>Elsevier Masson SAS</pub><pmid>21292356</pmid><doi>10.1016/j.ejmech.2011.01.014</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0223-5234 |
| ispartof | European journal of medicinal chemistry, 2011-04, Vol.46 (4), p.1027-1039 |
| issn | 0223-5234 1768-3254 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_855201957 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - metabolism Anti-Bacterial Agents - pharmacokinetics Anti-Bacterial Agents - pharmacology Antibacterial activity Antibacterial agents Antibiotics Antibiotics. Antiinfectious agents. Antiparasitic agents Bacteria - drug effects Biological and medical sciences DA-7867 Drug Discovery Male Medical sciences Mice Microbial Sensitivity Tests Models, Molecular Molecular Conformation Oxazolidinone Oxazolidinones - chemistry Oxazolidinones - metabolism Oxazolidinones - pharmacokinetics Oxazolidinones - pharmacology Pharmacology. Drug treatments Prodrug Prodrugs - chemistry Prodrugs - metabolism Pyridine Solubility Tetrazoles - chemistry Tetrazoles - metabolism Tetrazoles - pharmacokinetics Tetrazoles - pharmacology |
| title | Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T15%3A00%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20torezolid%20as%20a%20novel%205-hydroxymethyl-oxazolidinone%20antibacterial%20agent&rft.jtitle=European%20journal%20of%20medicinal%20chemistry&rft.au=Im,%20Weon%20Bin&rft.date=2011-04-01&rft.volume=46&rft.issue=4&rft.spage=1027&rft.epage=1039&rft.pages=1027-1039&rft.issn=0223-5234&rft.eissn=1768-3254&rft.coden=EJMCA5&rft_id=info:doi/10.1016/j.ejmech.2011.01.014&rft_dat=%3Cproquest_cross%3E855201957%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=855201957&rft_id=info:pmid/21292356&rft_els_id=S0223523411000225&rfr_iscdi=true |