Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides
A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia—with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6629-6635 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Rennison, David Conole, Daniel Tingle, Malcolm D. Yang, Junpeng Eason, Charles T. Brimble, Margaret A. |
| description | A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia—with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1–20; compound 6 metHb%=74.1±2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10–16) and cyclic (17–20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30–32, sulfoxide 33, sulfone 34 and sulfonamides 35–36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity. |
| doi_str_mv | 10.1016/j.bmcl.2013.10.046 |
| format | Article |
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It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1–20; compound 6 metHb%=74.1±2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10–16) and cyclic (17–20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30–32, sulfoxide 33, sulfone 34 and sulfonamides 35–36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.10.046</identifier><identifier>PMID: 24210502</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Erythrocytes - drug effects ; Erythrocytes - metabolism ; Humans ; hydrophobicity ; Methemoglobin ; Methemoglobin - chemistry ; Methemoglobin - drug effects ; Methemoglobin - metabolism ; Methemoglobinemia ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; oximes ; para-Aminopropiophenone (PAPP) ; Pest Control ; Propiophenones - chemical synthesis ; Propiophenones - chemistry ; Propiophenones - pharmacology ; Rat toxicant ; Rodenticide ; rodenticides ; Rodenticides - chemical synthesis ; Rodenticides - chemistry ; Rodenticides - pharmacology ; sulfonamides ; toxicity</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-12, Vol.23 (24), p.6629-6635</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-72445d676b239a280c42060bc544e4e9e665dead0b7bd1c39ed912ad0b05db393</citedby><cites>FETCH-LOGICAL-c413t-72445d676b239a280c42060bc544e4e9e665dead0b7bd1c39ed912ad0b05db393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2013.10.046$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24210502$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rennison, David</creatorcontrib><creatorcontrib>Conole, Daniel</creatorcontrib><creatorcontrib>Tingle, Malcolm D.</creatorcontrib><creatorcontrib>Yang, Junpeng</creatorcontrib><creatorcontrib>Eason, Charles T.</creatorcontrib><creatorcontrib>Brimble, Margaret A.</creatorcontrib><title>Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia—with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1–20; compound 6 metHb%=74.1±2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10–16) and cyclic (17–20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30–32, sulfoxide 33, sulfone 34 and sulfonamides 35–36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.</description><subject>Animals</subject><subject>Erythrocytes - drug effects</subject><subject>Erythrocytes - metabolism</subject><subject>Humans</subject><subject>hydrophobicity</subject><subject>Methemoglobin</subject><subject>Methemoglobin - chemistry</subject><subject>Methemoglobin - drug effects</subject><subject>Methemoglobin - metabolism</subject><subject>Methemoglobinemia</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>oximes</subject><subject>para-Aminopropiophenone (PAPP)</subject><subject>Pest Control</subject><subject>Propiophenones - chemical synthesis</subject><subject>Propiophenones - chemistry</subject><subject>Propiophenones - pharmacology</subject><subject>Rat toxicant</subject><subject>Rodenticide</subject><subject>rodenticides</subject><subject>Rodenticides - chemical synthesis</subject><subject>Rodenticides - chemistry</subject><subject>Rodenticides - pharmacology</subject><subject>sulfonamides</subject><subject>toxicity</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9r3DAQxUVpaTZpv0APrY-9eDuSZXkNuZSl-QOBHtJAb0KWZr1aLMmV7EDol6-M0xxzEm_0mzePR8gnClsKVHw7bTunhy0DWuXBFrh4QzaUC15WHOq3ZAOtgHLX8t9n5DylEwDlwPl7csY4o1AD25C_909-OmKyqVDeFA6zcKEfQmc9OqtK682sre-LMYYR42QxFeGQYTWEfl7FqKIqlbM-LJAN4xF98FiY7Nt7NIVKxXF2Ko9iMOgnq23--0DeHdSQ8OPze0Eern782t-Udz-vb_ff70rNaTWVDeO8NqIRHataxXagOQMBna45R44tClEbVAa6pjNUVy2alrJFQ226qq0uyNfVN6f7kyNP0tmkcRhyoDAnSWuAZkcbsaBsRXUMKUU8yDFap-KTpCCX0uVJLqXLpfRllkvPS5-f_efOoXlZ-d9yBr6swEEFqfpok3y4zw75Lq2Y2C0WlyuBuYdHi1EmbdFrNDainqQJ9rUE_wBZdJ88</recordid><startdate>20131215</startdate><enddate>20131215</enddate><creator>Rennison, David</creator><creator>Conole, Daniel</creator><creator>Tingle, Malcolm D.</creator><creator>Yang, Junpeng</creator><creator>Eason, Charles T.</creator><creator>Brimble, Margaret A.</creator><general>Elsevier Ltd</general><scope>FBQ</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20131215</creationdate><title>Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides</title><author>Rennison, David ; Conole, Daniel ; Tingle, Malcolm D. ; Yang, Junpeng ; Eason, Charles T. ; Brimble, Margaret A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c413t-72445d676b239a280c42060bc544e4e9e665dead0b7bd1c39ed912ad0b05db393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Erythrocytes - drug effects</topic><topic>Erythrocytes - metabolism</topic><topic>Humans</topic><topic>hydrophobicity</topic><topic>Methemoglobin</topic><topic>Methemoglobin - chemistry</topic><topic>Methemoglobin - drug effects</topic><topic>Methemoglobin - metabolism</topic><topic>Methemoglobinemia</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>oximes</topic><topic>para-Aminopropiophenone (PAPP)</topic><topic>Pest Control</topic><topic>Propiophenones - chemical synthesis</topic><topic>Propiophenones - chemistry</topic><topic>Propiophenones - pharmacology</topic><topic>Rat toxicant</topic><topic>Rodenticide</topic><topic>rodenticides</topic><topic>Rodenticides - chemical synthesis</topic><topic>Rodenticides - chemistry</topic><topic>Rodenticides - pharmacology</topic><topic>sulfonamides</topic><topic>toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rennison, David</creatorcontrib><creatorcontrib>Conole, Daniel</creatorcontrib><creatorcontrib>Tingle, Malcolm D.</creatorcontrib><creatorcontrib>Yang, Junpeng</creatorcontrib><creatorcontrib>Eason, Charles T.</creatorcontrib><creatorcontrib>Brimble, Margaret A.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rennison, David</au><au>Conole, Daniel</au><au>Tingle, Malcolm D.</au><au>Yang, Junpeng</au><au>Eason, Charles T.</au><au>Brimble, Margaret A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-12-15</date><risdate>2013</risdate><volume>23</volume><issue>24</issue><spage>6629</spage><epage>6635</epage><pages>6629-6635</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia—with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1–20; compound 6 metHb%=74.1±2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10–16) and cyclic (17–20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30–32, sulfoxide 33, sulfone 34 and sulfonamides 35–36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24210502</pmid><doi>10.1016/j.bmcl.2013.10.046</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Erythrocytes - drug effects Erythrocytes - metabolism Humans hydrophobicity Methemoglobin Methemoglobin - chemistry Methemoglobin - drug effects Methemoglobin - metabolism Methemoglobinemia Microsomes, Liver - drug effects Microsomes, Liver - metabolism oximes para-Aminopropiophenone (PAPP) Pest Control Propiophenones - chemical synthesis Propiophenones - chemistry Propiophenones - pharmacology Rat toxicant Rodenticide rodenticides Rodenticides - chemical synthesis Rodenticides - chemistry Rodenticides - pharmacology sulfonamides toxicity |
| title | Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides |
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