{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:56:15Z","timestamp":1790362575213,"version":"4.1.0"},"reference-count":26,"publisher":"American Chemical Society (ACS)","issue":"4","license":[{"start":{"date-parts":[[2015,1,28]],"date-time":"2015-01-28T00:00:00Z","timestamp":1422403200000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["R21NS072086"],"award-info":[{"award-number":["R21NS072086"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["U01 NS058046"],"award-info":[{"award-number":["U01 NS058046"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,2,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP\u2013hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP\u2013hBChE conjugate.<\/jats:p>","DOI":"10.1021\/jm401650z","type":"journal-article","created":{"date-parts":[[2014,1,28]],"date-time":"2014-01-28T17:08:36Z","timestamp":1390928916000},"page":"1378-1389","source":"Crossref","is-referenced-by-count":82,"title":["Imidazole Aldoximes Effective\nin Assisting Butyrylcholinesterase\nCatalysis of Organophosphate Detoxification"],"prefix":"10.1021","volume":"57","author":[{"given":"Rakesh K.","family":"Sit","sequence":"first","affiliation":[{"name":"The Scripps Research Institute , , , ,","place":["La Jolla, California, United States, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valery V.","family":"Fokin","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , ,","place":["La Jolla, California, United States, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Amitai","sequence":"additional","affiliation":[{"name":"Israel Institute for Biological Research , , ,","place":["Ness Ziona, Israel, 74100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Barry","family":"Sharpless","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , ,","place":["La Jolla, California, United States, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palmer","family":"Taylor","sequence":"additional","affiliation":[{"name":"University of California at San Diego , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoran","family":"Radic\u0301","sequence":"additional","affiliation":[{"name":"University of California at San Diego , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,1,28]]},"reference":[{"key":"2026090114544563700_cit1","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1038\/nm1013-1194","article-title":"Syrian gas\nattack reinforces need for better anti-sarin drugs","volume":"19","author":"Dolgin","year":"2013","journal-title":"Nat. Med."},{"key":"2026090114544563700_cit2","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.cbi.2013.09.015","article-title":"Limitations and challenges in treatment\nof acute chemical warfare agent poisoning","volume":"206","author":"Thiermann","year":"2013","journal-title":"Chem.-Biol.\nInteract."},{"key":"2026090114544563700_cit3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3109\/15376516.2010.529190","article-title":"The oxime\npro-2-PAM provides minimal protection against the CNS effects of the\nnerve agents sarin, cyclosarin, and VX in guinea pigs","volume":"21","author":"Shih","year":"2011","journal-title":"Toxicol. Mech. Methods"},{"key":"2026090114544563700_cit4","first-page":"363","article-title":"In vitro and in\nvivo characterization of recombinant human butyrylcholinesterase (Protexia)\nas a potential nerve agent bioscavenger","volume":"157\u2013158","author":"Cerasoli","year":"2005","journal-title":"Chem.-Biol.\nInteract."},{"key":"2026090114544563700_cit5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.tox.2006.11.066","article-title":"Stoichiometric\nand catalytic scavengers as protection\nagainst nerve agent toxicity: A mini review","volume":"233","author":"Lenz","year":"2007","journal-title":"Toxicology"},{"key":"2026090114544563700_cit6","first-page":"nihms5095","article-title":"Large scale purification\nof butyrylcholinesterase from human plasma suitable for injection\ninto monkeys; a potential new therapeutic for protection against cocaine\nand nerve agent toxicity","volume":"3","author":"Lockridge","year":"2005","journal-title":"Journal of Medical\nChemical, Biological and Radiological Defense"},{"key":"2026090114544563700_cit7","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1081\/CLT-200026967","article-title":"The effects\nof fresh frozen plasma on cholinesterase levels and outcomes in patients\nwith organophosphate poisoning","volume":"42","author":"Gu\u0308ven","year":"2004","journal-title":"J. Toxicol.\nClin. Toxicol."},{"key":"2026090114544563700_cit8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3109\/15563650.2011.568944","article-title":"Post-exposure therapy\nwith human butyrylcholinesterase following percutaneous VX challenge\nin guinea pigs","volume":"49","author":"Mumford","year":"2011","journal-title":"Clin. Toxicol."},{"key":"2026090114544563700_cit9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/0006-3002(55)90040-8","article-title":"A powerful reactivator\nof alkylphosphate-inhibited\nacetylcholinesterase","volume":"18","author":"Wilson","year":"1955","journal-title":"Biochim. Biophys. Acta"},{"key":"2026090114544563700_cit10","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.cbi.2010.02.023","article-title":"Pseudo-catalytic\nscavenging: Searching for a suitable reactivator of phosphorylated\nbutyrylcholinesterase","volume":"187","author":"Kovarik","year":"2010","journal-title":"Chem.-Biol. Interact."},{"key":"2026090114544563700_cit11","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1042\/BJ20121612","article-title":"Catalytic\ndetoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase\nassisted with non-pyridinium oximes","volume":"450","author":"Radic\u0301","year":"2013","journal-title":"Biochem.\nJ."},{"key":"2026090114544563700_cit12","doi-asserted-by":"crossref","first-page":"19422","DOI":"10.1074\/jbc.M111.230656","article-title":"New structural scaffolds for centrally\nacting oxime reactivators of phosphylated cholinesterases","volume":"286","author":"Sit","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2026090114544563700_cit13","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/jps.2600610433","article-title":"Structure-activity relationships\nin reactivators of organophosphorus-inhibited acetylcholinesterase.\n5. 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Chem."},{"key":"2026090114544563700_cit16","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1021\/jm00379a026","article-title":"Reactivators of\norganophosphorus-inhibited acetylcholinesterase. 1. Imidazole oxime\nderivatives","volume":"28","author":"Herrador","year":"1985","journal-title":"J. Med. Chem."},{"key":"2026090114544563700_cit17","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1021\/jm00108a020","article-title":"Quaternary salts of 2-[(Hydroxyimino)methyl]imidazole.\n5. Structure-activity relationships for side-chain nitro-, sulfone-,\namino-, and aminosulfonyl-substituted analogues for therapy against\nanticholinesterase intoxication","volume":"34","author":"Koolpe","year":"1991","journal-title":"J. Med. Chem."},{"key":"2026090114544563700_cit18","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1021\/jm00108a019","article-title":"Quaternary salts\nof 2-[(hydroxyimino)methyl]imidazole.\n4. Effect of various side-chain substituents on therapeutic activity\nagainst anticholinesterase intoxication","volume":"34","author":"Goff","year":"1991","journal-title":"J.\nMed. Chem."},{"key":"2026090114544563700_cit19","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s002040050504","article-title":"Quinuclidinium-imidazolium\ncompounds: Synthesis, mode of interaction with acetylcholinesterase\nand effect upon Soman intoxicated mice","volume":"72","author":"Simeon-Rudolf","year":"1998","journal-title":"Arch.\nToxicol."},{"key":"2026090114544563700_cit20","article-title":"Pyridinium,\nimidazolium, and quinuclidinium oximes: Synthesis, interaction with\nnative and phosphorylated cholinesterases, and antidotes against organophosphorus\ncompounds","volume":"2","author":"Primoz\u030cic\u0301","year":"2004","journal-title":"Journal of Medical Chemical, Biological\nand Radiological Defense"},{"key":"2026090114544563700_cit21","first-page":"171","article-title":"Pyridinium, imidazolium and quinuclidinium\ncompounds:\nToxicity and antidotal effects against the nerve agents tabun and\nsoman","volume":"57","author":"Reiner","year":"2006","journal-title":"Arh. Hig. Rada Toksikol."},{"key":"2026090114544563700_cit22","doi-asserted-by":"crossref","first-page":"e67446","DOI":"10.1371\/journal.pone.0067446","article-title":"Gene transfer\nof mutant mouse cholinesterase provides high lifetime expression and\nreduced cocaine responses with no evident toxicity","volume":"8","author":"Geng","year":"2013","journal-title":"PLoS One"},{"key":"2026090114544563700_cit23","doi-asserted-by":"crossref","first-page":"29718","DOI":"10.1074\/jbc.M111.264739","article-title":"Oxime-assisted acetylcholinesterase catalytic scavengers\nof organophosphates that resist aging","volume":"286","author":"Cochran","year":"2011","journal-title":"J. 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Pharmacol."},{"key":"2026090114544563700_cit26","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1021\/bi036191a","article-title":"Mutant cholinesterases possessing\nenhanced capacity for reactivation of their phosphonylated conjugates","volume":"43","author":"Kovarik","year":"2004","journal-title":"Biochemistry"}],"container-title":["Journal of\nMedicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm401650z","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/4\/1378\/12868939\/jm401650z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/4\/1378\/12868939\/jm401650z.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:54:54Z","timestamp":1788288894000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/4\/1378\/1300251\/Imidazole-Aldoximes-Effective-in-Assisting"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,28]]},"references-count":26,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2014,1,28]]},"published-print":{"date-parts":[[2014,2,27]]}},"URL":"https:\/\/doi.org\/10.1021\/jm401650z","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,28]]}}}