Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase
The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-04, Vol.24 (7), p.1711-1714 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | McHardy, Stanton F. Bohmann, Jonathan A. Corbett, Michael R. Campos, Bismarck Tidwell, Michael W. Thompson, Paul Marty Bemben, Chris J. Menchaca, Tony A. Reeves, Tony E. Cantrell, William R. Bauta, William E. Lopez, Ambrosio Maxwell, Donald M. Brecht, Karen M. Sweeney, Richard E. McDonough, John |
| description | The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme. |
| doi_str_mv | 10.1016/j.bmcl.2014.02.049 |
| format | Article |
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New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.02.049</identifier><identifier>PMID: 24630558</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acetylcholinesterase ; Acetylcholinesterase - metabolism ; Cholinesterase Inhibitors - chemical synthesis ; Cholinesterase Inhibitors - chemistry ; Cholinesterase Inhibitors - pharmacology ; Cyclosarin (GF) ; Dose-Response Relationship, Drug ; Drug Design ; GF-inhibited hAChE ; Heteroaryl keto-oximes ; Humans ; Molecular Structure ; Organophosphorus Compounds - chemical synthesis ; Organophosphorus Compounds - chemistry ; Organophosphorus Compounds - pharmacology ; Reactivation ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-04, Vol.24 (7), p.1711-1714</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-94881cec1b87e1adb737e1d3d619b74698d1e2dff1a3848990fff54684f21bc93</citedby><cites>FETCH-LOGICAL-c389t-94881cec1b87e1adb737e1d3d619b74698d1e2dff1a3848990fff54684f21bc93</cites><orcidid>0000-0001-5667-386X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X14001814$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24630558$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McHardy, Stanton F.</creatorcontrib><creatorcontrib>Bohmann, Jonathan A.</creatorcontrib><creatorcontrib>Corbett, Michael R.</creatorcontrib><creatorcontrib>Campos, Bismarck</creatorcontrib><creatorcontrib>Tidwell, Michael W.</creatorcontrib><creatorcontrib>Thompson, Paul Marty</creatorcontrib><creatorcontrib>Bemben, Chris J.</creatorcontrib><creatorcontrib>Menchaca, Tony A.</creatorcontrib><creatorcontrib>Reeves, Tony E.</creatorcontrib><creatorcontrib>Cantrell, William R.</creatorcontrib><creatorcontrib>Bauta, William E.</creatorcontrib><creatorcontrib>Lopez, Ambrosio</creatorcontrib><creatorcontrib>Maxwell, Donald M.</creatorcontrib><creatorcontrib>Brecht, Karen M.</creatorcontrib><creatorcontrib>Sweeney, Richard E.</creatorcontrib><creatorcontrib>McDonough, John</creatorcontrib><title>Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.</description><subject>Acetylcholinesterase</subject><subject>Acetylcholinesterase - metabolism</subject><subject>Cholinesterase Inhibitors - chemical synthesis</subject><subject>Cholinesterase Inhibitors - chemistry</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cyclosarin (GF)</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>GF-inhibited hAChE</subject><subject>Heteroaryl keto-oximes</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>Organophosphorus Compounds - chemical synthesis</subject><subject>Organophosphorus Compounds - chemistry</subject><subject>Organophosphorus Compounds - pharmacology</subject><subject>Reactivation</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFv1DAQhS0EokvhD3BAOXLYhLHjZG2JCyq0IFXiAhI3y7HHxKvEbu1kq-XX49UWjojTG2m-90aaR8hrCg0F2r_bN8NspoYB5Q2wBrh8QjaU97xuOXRPyQZkD7WQ_McFeZHzHgoInD8nF4z3LXSd2JCHj5j9z7Ct8jEsY5nzttLBVmbUSZsFk_-lFx9DFV0V4gGnbZFwv-qyCjodq4QF8we9xJRP0M117cPoB7-grcZ11qHSBpfjZMY4-YC5GHXGl-SZ01PGV496Sb5ff_p29bm-_Xrz5erDbW1aIZdaciGoQUMHsUOq7bBri9rW9lQOO95LYSky6xzVreBCSnDOdbwX3DE6GNlekrfn3LsU79dyXc0-G5wmHTCuWdGOQXFy1v8HSqlgIDgUlJ1Rk2LOCZ26S34u71AU1KkbtVenbtSpGwVMlW6K6c1j_jrMaP9a_pRRgPdnAMtDDh6TysZjMGh9QrMoG_2_8n8DIkKiEw</recordid><startdate>20140401</startdate><enddate>20140401</enddate><creator>McHardy, Stanton F.</creator><creator>Bohmann, Jonathan A.</creator><creator>Corbett, Michael R.</creator><creator>Campos, Bismarck</creator><creator>Tidwell, Michael W.</creator><creator>Thompson, Paul Marty</creator><creator>Bemben, Chris J.</creator><creator>Menchaca, Tony A.</creator><creator>Reeves, Tony E.</creator><creator>Cantrell, William R.</creator><creator>Bauta, William E.</creator><creator>Lopez, Ambrosio</creator><creator>Maxwell, Donald M.</creator><creator>Brecht, Karen M.</creator><creator>Sweeney, Richard E.</creator><creator>McDonough, John</creator><general>Elsevier Ltd</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><orcidid>https://orcid.org/0000-0001-5667-386X</orcidid></search><sort><creationdate>20140401</creationdate><title>Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase</title><author>McHardy, Stanton F. ; Bohmann, Jonathan A. ; Corbett, Michael R. ; Campos, Bismarck ; Tidwell, Michael W. ; Thompson, Paul Marty ; Bemben, Chris J. ; Menchaca, Tony A. ; Reeves, Tony E. ; Cantrell, William R. ; Bauta, William E. ; Lopez, Ambrosio ; Maxwell, Donald M. ; Brecht, Karen M. ; Sweeney, Richard E. ; McDonough, John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-94881cec1b87e1adb737e1d3d619b74698d1e2dff1a3848990fff54684f21bc93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acetylcholinesterase</topic><topic>Acetylcholinesterase - metabolism</topic><topic>Cholinesterase Inhibitors - chemical synthesis</topic><topic>Cholinesterase Inhibitors - chemistry</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cyclosarin (GF)</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>GF-inhibited hAChE</topic><topic>Heteroaryl keto-oximes</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>Organophosphorus Compounds - chemical synthesis</topic><topic>Organophosphorus Compounds - chemistry</topic><topic>Organophosphorus Compounds - pharmacology</topic><topic>Reactivation</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McHardy, Stanton F.</creatorcontrib><creatorcontrib>Bohmann, Jonathan A.</creatorcontrib><creatorcontrib>Corbett, Michael R.</creatorcontrib><creatorcontrib>Campos, Bismarck</creatorcontrib><creatorcontrib>Tidwell, Michael W.</creatorcontrib><creatorcontrib>Thompson, Paul Marty</creatorcontrib><creatorcontrib>Bemben, Chris J.</creatorcontrib><creatorcontrib>Menchaca, Tony A.</creatorcontrib><creatorcontrib>Reeves, Tony E.</creatorcontrib><creatorcontrib>Cantrell, William R.</creatorcontrib><creatorcontrib>Bauta, William E.</creatorcontrib><creatorcontrib>Lopez, Ambrosio</creatorcontrib><creatorcontrib>Maxwell, Donald M.</creatorcontrib><creatorcontrib>Brecht, Karen M.</creatorcontrib><creatorcontrib>Sweeney, Richard E.</creatorcontrib><creatorcontrib>McDonough, John</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><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>McHardy, Stanton F.</au><au>Bohmann, Jonathan A.</au><au>Corbett, Michael R.</au><au>Campos, Bismarck</au><au>Tidwell, Michael W.</au><au>Thompson, Paul Marty</au><au>Bemben, Chris J.</au><au>Menchaca, Tony A.</au><au>Reeves, Tony E.</au><au>Cantrell, William R.</au><au>Bauta, William E.</au><au>Lopez, Ambrosio</au><au>Maxwell, Donald M.</au><au>Brecht, Karen M.</au><au>Sweeney, Richard E.</au><au>McDonough, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2014-04-01</date><risdate>2014</risdate><volume>24</volume><issue>7</issue><spage>1711</spage><epage>1714</epage><pages>1711-1714</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24630558</pmid><doi>10.1016/j.bmcl.2014.02.049</doi><tpages>4</tpages><orcidid>https://orcid.org/0000-0001-5667-386X</orcidid></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2014-04, Vol.24 (7), p.1711-1714 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Acetylcholinesterase Acetylcholinesterase - metabolism Cholinesterase Inhibitors - chemical synthesis Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - pharmacology Cyclosarin (GF) Dose-Response Relationship, Drug Drug Design GF-inhibited hAChE Heteroaryl keto-oximes Humans Molecular Structure Organophosphorus Compounds - chemical synthesis Organophosphorus Compounds - chemistry Organophosphorus Compounds - pharmacology Reactivation Structure-Activity Relationship |
| title | Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase |
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