Structural Requirements for Antibacterial Activity and $\beta$-Lactamase Stability of 7$\beta$-Arylmalonylamino-7$\alpha$-Methoxy-1-Oxacephems
Replacement of a sulphur atom by an oxygen at the 1-position of the cephem nucleus generally resulted in fourfold to sixteenfold increase of antibacterial activity in each pair of the structural congeners. However, the increased antibacterial activity caused by the replacement was accompanied by ins...
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| Veröffentlicht in: | Philosophical transactions of the Royal Society of London. Series B, Biological sciences Biological sciences, 1980-05, Vol.289 (1036), p.231-237 |
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| container_title | Philosophical transactions of the Royal Society of London. Series B, Biological sciences |
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| creator | Yoshida, T. |
| description | Replacement of a sulphur atom by an oxygen at the 1-position of the cephem nucleus generally resulted in fourfold to sixteenfold
increase of antibacterial activity in each pair of the structural congeners. However, the increased antibacterial activity
caused by the replacement was accompanied by instability to $\beta$-lactamase to some extent, which was due
presumably to the increased chemical reactivity of the $\beta$-lactam ring system. The aim of the research
effort is to confer $\beta$-lactamase stability and expand the Gram-negative spectrum. Two types of substituents
have been demonstrated to protect 1-oxacephem from enzymic hydrolysis and their protecting effects were specifically related
to the types of $\beta$-lactamases derived from Gram-negative bacteria: the 7$\beta$-malonylamino
function is specific to cephalosporinase and the 7$\alpha$-methoxy group to penicillinase. The complementary
effect of these substituents was clearly demonstrated. This line of studies led us to prepare the clinical candidate 6059-S,
which possessed widely expanded antibacterial spectra against Gram-negative bacteria including indole-positive Proteus, Enterobacter,
Sarratia marcescens, Pseudomonas aeruginosa and Bacteroides fragilis. |
| doi_str_mv | 10.1098/rstb.1980.0041 |
| format | Article |
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increase of antibacterial activity in each pair of the structural congeners. However, the increased antibacterial activity
caused by the replacement was accompanied by instability to $\beta$-lactamase to some extent, which was due
presumably to the increased chemical reactivity of the $\beta$-lactam ring system. The aim of the research
effort is to confer $\beta$-lactamase stability and expand the Gram-negative spectrum. Two types of substituents
have been demonstrated to protect 1-oxacephem from enzymic hydrolysis and their protecting effects were specifically related
to the types of $\beta$-lactamases derived from Gram-negative bacteria: the 7$\beta$-malonylamino
function is specific to cephalosporinase and the 7$\alpha$-methoxy group to penicillinase. The complementary
effect of these substituents was clearly demonstrated. This line of studies led us to prepare the clinical candidate 6059-S,
which possessed widely expanded antibacterial spectra against Gram-negative bacteria including indole-positive Proteus, Enterobacter,
Sarratia marcescens, Pseudomonas aeruginosa and Bacteroides fragilis.</description><identifier>ISSN: 0962-8436</identifier><identifier>ISSN: 0080-4622</identifier><identifier>EISSN: 1471-2970</identifier><identifier>EISSN: 2054-0280</identifier><identifier>DOI: 10.1098/rstb.1980.0041</identifier><identifier>PMID: 6109319</identifier><language>eng</language><publisher>London: The Royal Society</publisher><subject>Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - metabolism ; Anti-Bacterial Agents - pharmacology ; Antibacterials ; Bacteria - drug effects ; beta-Lactamases - metabolism ; Cephalosporins ; Cephalosporins - chemical synthesis ; Cephamycins - chemical synthesis ; Cephamycins - metabolism ; Cephamycins - pharmacology ; Chemical Phenomena ; Chemistry ; Congeners ; Drug Stability ; Enterobacter ; Enzymes ; Gram negative bacteria ; Hydrolysis ; Klebsiella ; Oxygen ; Structure-Activity Relationship ; Sulfur</subject><ispartof>Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 1980-05, Vol.289 (1036), p.231-237</ispartof><rights>Copyright 1980 The Royal Society</rights><rights>Scanned images copyright © 2017, Royal Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-735c4c68fe9ba9f7f42019cb1bf0e0eb2634ad3c848e0205285e85eb414060fa3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2395380$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2395380$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,776,780,799,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/6109319$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoshida, T.</creatorcontrib><title>Structural Requirements for Antibacterial Activity and $\beta$-Lactamase Stability of 7$\beta$-Arylmalonylamino-7$\alpha$-Methoxy-1-Oxacephems</title><title>Philosophical transactions of the Royal Society of London. Series B, Biological sciences</title><addtitle>Phil. Trans. R. Soc. Lond. B</addtitle><addtitle>Philos Trans R Soc Lond B Biol Sci</addtitle><description>Replacement of a sulphur atom by an oxygen at the 1-position of the cephem nucleus generally resulted in fourfold to sixteenfold
increase of antibacterial activity in each pair of the structural congeners. However, the increased antibacterial activity
caused by the replacement was accompanied by instability to $\beta$-lactamase to some extent, which was due
presumably to the increased chemical reactivity of the $\beta$-lactam ring system. The aim of the research
effort is to confer $\beta$-lactamase stability and expand the Gram-negative spectrum. Two types of substituents
have been demonstrated to protect 1-oxacephem from enzymic hydrolysis and their protecting effects were specifically related
to the types of $\beta$-lactamases derived from Gram-negative bacteria: the 7$\beta$-malonylamino
function is specific to cephalosporinase and the 7$\alpha$-methoxy group to penicillinase. The complementary
effect of these substituents was clearly demonstrated. This line of studies led us to prepare the clinical candidate 6059-S,
which possessed widely expanded antibacterial spectra against Gram-negative bacteria including indole-positive Proteus, Enterobacter,
Sarratia marcescens, Pseudomonas aeruginosa and Bacteroides fragilis.</description><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - metabolism</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibacterials</subject><subject>Bacteria - drug effects</subject><subject>beta-Lactamases - metabolism</subject><subject>Cephalosporins</subject><subject>Cephalosporins - chemical synthesis</subject><subject>Cephamycins - chemical synthesis</subject><subject>Cephamycins - metabolism</subject><subject>Cephamycins - pharmacology</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Congeners</subject><subject>Drug Stability</subject><subject>Enterobacter</subject><subject>Enzymes</subject><subject>Gram negative bacteria</subject><subject>Hydrolysis</subject><subject>Klebsiella</subject><subject>Oxygen</subject><subject>Structure-Activity Relationship</subject><subject>Sulfur</subject><issn>0962-8436</issn><issn>0080-4622</issn><issn>1471-2970</issn><issn>2054-0280</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1980</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kk1r2zAYx83Y6NJu15028KHs5uyRJdvSaWRlb5BRaLrbQMiKvCjIlivJXd0Psc88OckKYaxgMOL3f5H0KEleIZgjYPSd86GeI0ZhDkDQk2SGSIWynFXwNJkBK_OMElw-T0693wIAKypykpyU0YsRmyW_V8ENMgxOmPRK3QzaqVZ1waeNdemiC7oWMiinI17IoG91GFPRrdPzH7UK4jxbRixa4VW6CqLWZuK2Sau_fOFG0wpju9GIVnc2i0SYfhPRNxU29m7MUHZ5J6TqN6r1L5JnjTBevTz8z5Lvnz5eX3zJlpefv14slpkkVRGyCheSyJI2itWCNVVDckBM1qhuQIGq8xITscaSEqoghyKnhYpfTRCBEhqBz5K3-9ze2ZtB-cBb7aUyRnTKDp5XBYl3ilgUzvdC6az3TjW8d7oVbuQI-DQAPg2ATwPg0wCi4c0heahbtX6QH248crznzo7xhFZqFUa-tYPr4vL_qf4x19Xq-gNiJbvNKdMIcMmBYgRVTlHJ73W_i5sEPAq49n5QfCc7rvm39fW-deuDdQ9HyTErMIWIYY83-ufmV3w5_Gh3cdHHuKlx15XjKfH9o5apX9ouxCd4ZOTNYAzv1w3-AzYB6xU</recordid><startdate>19800516</startdate><enddate>19800516</enddate><creator>Yoshida, T.</creator><general>The Royal Society</general><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>19800516</creationdate><title>Structural Requirements for Antibacterial Activity and $\beta$-Lactamase Stability of 7$\beta$-Arylmalonylamino-7$\alpha$-Methoxy-1-Oxacephems</title><author>Yoshida, T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-735c4c68fe9ba9f7f42019cb1bf0e0eb2634ad3c848e0205285e85eb414060fa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1980</creationdate><topic>Anti-Bacterial Agents - chemical synthesis</topic><topic>Anti-Bacterial Agents - metabolism</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antibacterials</topic><topic>Bacteria - drug effects</topic><topic>beta-Lactamases - metabolism</topic><topic>Cephalosporins</topic><topic>Cephalosporins - chemical synthesis</topic><topic>Cephamycins - chemical synthesis</topic><topic>Cephamycins - metabolism</topic><topic>Cephamycins - pharmacology</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Congeners</topic><topic>Drug Stability</topic><topic>Enterobacter</topic><topic>Enzymes</topic><topic>Gram negative bacteria</topic><topic>Hydrolysis</topic><topic>Klebsiella</topic><topic>Oxygen</topic><topic>Structure-Activity Relationship</topic><topic>Sulfur</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yoshida, T.</creatorcontrib><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>Philosophical transactions of the Royal Society of London. Series B, Biological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yoshida, T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Requirements for Antibacterial Activity and $\beta$-Lactamase Stability of 7$\beta$-Arylmalonylamino-7$\alpha$-Methoxy-1-Oxacephems</atitle><jtitle>Philosophical transactions of the Royal Society of London. Series B, Biological sciences</jtitle><stitle>Phil. Trans. R. Soc. Lond. B</stitle><addtitle>Philos Trans R Soc Lond B Biol Sci</addtitle><date>1980-05-16</date><risdate>1980</risdate><volume>289</volume><issue>1036</issue><spage>231</spage><epage>237</epage><pages>231-237</pages><issn>0962-8436</issn><issn>0080-4622</issn><eissn>1471-2970</eissn><eissn>2054-0280</eissn><abstract>Replacement of a sulphur atom by an oxygen at the 1-position of the cephem nucleus generally resulted in fourfold to sixteenfold
increase of antibacterial activity in each pair of the structural congeners. However, the increased antibacterial activity
caused by the replacement was accompanied by instability to $\beta$-lactamase to some extent, which was due
presumably to the increased chemical reactivity of the $\beta$-lactam ring system. The aim of the research
effort is to confer $\beta$-lactamase stability and expand the Gram-negative spectrum. Two types of substituents
have been demonstrated to protect 1-oxacephem from enzymic hydrolysis and their protecting effects were specifically related
to the types of $\beta$-lactamases derived from Gram-negative bacteria: the 7$\beta$-malonylamino
function is specific to cephalosporinase and the 7$\alpha$-methoxy group to penicillinase. The complementary
effect of these substituents was clearly demonstrated. This line of studies led us to prepare the clinical candidate 6059-S,
which possessed widely expanded antibacterial spectra against Gram-negative bacteria including indole-positive Proteus, Enterobacter,
Sarratia marcescens, Pseudomonas aeruginosa and Bacteroides fragilis.</abstract><cop>London</cop><pub>The Royal Society</pub><pmid>6109319</pmid><doi>10.1098/rstb.1980.0041</doi><tpages>7</tpages></addata></record> |
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| identifier | ISSN: 0962-8436 |
| ispartof | Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 1980-05, Vol.289 (1036), p.231-237 |
| issn | 0962-8436 0080-4622 1471-2970 2054-0280 |
| language | eng |
| recordid | cdi_royalsociety_journals_10_1098_rstb_1980_0041 |
| source | Jstor Complete Legacy; MEDLINE |
| subjects | Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - metabolism Anti-Bacterial Agents - pharmacology Antibacterials Bacteria - drug effects beta-Lactamases - metabolism Cephalosporins Cephalosporins - chemical synthesis Cephamycins - chemical synthesis Cephamycins - metabolism Cephamycins - pharmacology Chemical Phenomena Chemistry Congeners Drug Stability Enterobacter Enzymes Gram negative bacteria Hydrolysis Klebsiella Oxygen Structure-Activity Relationship Sulfur |
| title | Structural Requirements for Antibacterial Activity and $\beta$-Lactamase Stability of 7$\beta$-Arylmalonylamino-7$\alpha$-Methoxy-1-Oxacephems |
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