{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:20:00Z","timestamp":1790302800668,"version":"4.1.0"},"reference-count":47,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100018546","name":"Postdoctoral Innovation Project of Shandong Province","doi-asserted-by":"publisher","award":["SDCX-ZG-202400076"],"award-info":[{"award-number":["SDCX-ZG-202400076"]}],"id":[{"id":"10.13039\/501100018546","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2025,8]]},"DOI":"10.1016\/j.ejmech.2025.117660","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T02:48:59Z","timestamp":1745290139000},"page":"117660","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":5,"special_numbering":"C","title":["Design, synthesis, and structure-activity relationship of 5,7- dimethylbenzo[d]thiazoles as novel Kv7.2\/7.3 activators with antiepileptic effects"],"prefix":"10.1016","volume":"292","author":[{"given":"Denggao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"KeWei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejmech.2025.117660_bib1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/j.0013-9580.2005.66104.x","article-title":"Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE) and the international Bureau for Epilepsy (IBE)","volume":"46","author":"Fisher","year":"2005","journal-title":"Epilepsia"},{"key":"10.1016\/j.ejmech.2025.117660_bib2","year":"2024"},{"key":"10.1016\/j.ejmech.2025.117660_bib3","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1212\/WNL.0000000000003509","article-title":"Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies","volume":"88","author":"Fiest","year":"2017","journal-title":"Neurology"},{"key":"10.1016\/j.ejmech.2025.117660_bib4","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1212\/WNL.0000000000011839","article-title":"Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis","volume":"96","author":"Sultana","year":"2021","journal-title":"Neurology"},{"key":"10.1016\/j.ejmech.2025.117660_bib5","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/35036198","article-title":"Neuronal KCNQ potassium channels: physiology and role in disease","volume":"1","author":"Jentsch","year":"2000","journal-title":"Nat. Rev. Neurosci."},{"key":"10.1016\/j.ejmech.2025.117660_bib6","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1146\/annurev-pharmtox-010617-052912","article-title":"KCNQ-Encoded potassium channels as therapeutic targets","volume":"58","author":"Barrese","year":"2018","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"10.1016\/j.ejmech.2025.117660_bib7","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1007\/s00424-014-1655-3","article-title":"Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain","volume":"467","author":"Mathie","year":"2015","journal-title":"Pfl\u00fcgers Archiv"},{"key":"10.1016\/j.ejmech.2025.117660_bib8","doi-asserted-by":"crossref","first-page":"11340","DOI":"10.1021\/acs.jmedchem.2c00911","article-title":"Beyond retigabine: design, synthesis, and pharmacological characterization of a potent and chemically stable neuronal Kv7 Channel activator with anticonvulsant activity","volume":"65","author":"Musella","year":"2022","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.117660_bib9","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1111\/epi.12200","article-title":"Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation","volume":"54","author":"Kato","year":"2013","journal-title":"Epilepsia"},{"key":"10.1016\/j.ejmech.2025.117660_bib10","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/epi4.12353","article-title":"A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy","volume":"4","author":"Lauritano","year":"2019","journal-title":"Epilepsia Open"},{"key":"10.1016\/j.ejmech.2025.117660_bib11","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1159\/000496422","article-title":"Suppression of KCNQ\/M potassium channel in Dorsal root ganglia neurons contributes to the development of osteoarthritic pain","volume":"103","author":"Zhang","year":"2019","journal-title":"Pharmacology"},{"key":"10.1016\/j.ejmech.2025.117660_bib12","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1001\/jamaneurol.2020.4300","article-title":"Effect of ezogabine on cortical and spinal motor neuron excitability in amyotrophic lateral sclerosis: a randomized clinical trial","volume":"78","author":"Wainger","year":"2021","journal-title":"JAMA Neurol."},{"key":"10.1016\/j.ejmech.2025.117660_bib13","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/s41380-018-0283-2","article-title":"Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder","volume":"25","author":"Tan","year":"2020","journal-title":"Mol. Psychiatr."},{"key":"10.1016\/j.ejmech.2025.117660_bib14","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nrd3561","article-title":"Ezogabine (retigabine)","volume":"10","author":"Stafstrom","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"10.1016\/j.ejmech.2025.117660_bib15","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1021\/acs.jmedchem.0c02252","article-title":"Discovery of HN37 as a potent and chemically stable antiepileptic drug candidate","volume":"64","author":"Zhang","year":"2021","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.117660_bib16","doi-asserted-by":"crossref","first-page":"7989","DOI":"10.1021\/acsomega.1c07103","article-title":"Modifications of the triaminoaryl metabophore of flupirtine and retigabine aimed at avoiding quinone diimine formation","volume":"7","author":"Wurm","year":"2022","journal-title":"ACS Omega"},{"key":"10.1016\/j.ejmech.2025.117660_bib17","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1002\/cmdc.201900112","article-title":"Sulfide analogues of flupirtine and retigabine with nanomolar K(V) 7.2\/K(V) 7.3 channel opening activity","volume":"14","author":"Bock","year":"2019","journal-title":"ChemMedChem"},{"key":"10.1016\/j.ejmech.2025.117660_bib18","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1021\/acs.chemrestox.8b00313","article-title":"An investigation into retigabine (ezogabine) associated dyspigmentation in rat eyes by MALDI imaging mass spectrometry","volume":"32","author":"Groseclose","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.ejmech.2025.117660_bib19","year":"2024"},{"key":"10.1016\/j.ejmech.2025.117660_bib20","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1080\/17512433.2024.2337012","article-title":"A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy","volume":"17","author":"Lattanzi","year":"2024","journal-title":"Expet Rev. Clin. Pharmacol."},{"key":"10.1016\/j.ejmech.2025.117660_bib21","doi-asserted-by":"crossref","first-page":"2","DOI":"10.17925\/USN.2022.18.1.2","article-title":"XEN1101: a novel potassium channel modulator for the potential treatment of focal epilepsy in adults","volume":"18","author":"Wang","year":"2022","journal-title":"touch REVIEWS in Neurology"},{"key":"10.1016\/j.ejmech.2025.117660_bib22","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1111\/epi.18092","article-title":"Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity","volume":"65","author":"Wang","year":"2024","journal-title":"Epilepsia"},{"key":"10.1016\/j.ejmech.2025.117660_bib23","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1016\/j.bmcl.2018.05.019","article-title":"Design, synthesis and evaluation of novel N-phenylbutanamide derivatives as KCNQ openers for the treatment of epilepsy","volume":"28","author":"Yang","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"10.1016\/j.ejmech.2025.117660_bib24","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1021\/acs.orglett.0c00994","article-title":"K2S as sulfur source and DMSO as carbon source for the synthesis of 2-Unsubstituted benzothiazoles","volume":"22","author":"Zhu","year":"2020","journal-title":"Org. Lett."},{"key":"10.1016\/j.ejmech.2025.117660_bib25","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1089\/adt.2004.2.525","article-title":"Validation of an atomic absorption rubidium ion efflux assay for KCNQ\/M-channels using the ion channel reader 8000","volume":"2","author":"Wang","year":"2004","journal-title":"Assay Drug Dev. Technol."},{"key":"10.1016\/j.ejmech.2025.117660_bib26","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.ejmech.2011.01.010","article-title":"Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7\/KCNQ potassium channel activators","volume":"46","author":"Qi","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.117660_bib27","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/cn200065b","article-title":"Discovery, synthesis, and structure activity relationship of a series of N-Aryl- bicyclo[2.2.1]heptane-2-carboxamides: characterization of ML213 as a novel KCNQ2 and KCNQ4 potassium channel opener","volume":"2","author":"Yu","year":"2011","journal-title":"ACS Chem. Neurosci."},{"key":"10.1016\/j.ejmech.2025.117660_bib28","doi-asserted-by":"crossref","first-page":"14360","DOI":"10.1021\/acsomega.9b02221","article-title":"Evolving concept of activity cliffs","volume":"4","author":"Stumpfe","year":"2019","journal-title":"ACS Omega"},{"key":"10.1016\/j.ejmech.2025.117660_bib29","doi-asserted-by":"crossref","first-page":"8116","DOI":"10.1038\/ncomms9116","article-title":"Atomic basis for therapeutic activation of neuronal potassium channels","volume":"6","author":"Kim","year":"2015","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejmech.2025.117660_bib30","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.nurt.2006.11.009","article-title":"Discovery of antiepileptic drugs","volume":"4","author":"Smith","year":"2007","journal-title":"Neurotherapeutics"},{"key":"10.1016\/j.ejmech.2025.117660_bib31","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbrc.2024.149947","article-title":"A mutation in the cardiac KV7.1 channel possibly disrupts interaction with Yotiao protein","volume":"714","author":"Li","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.ejmech.2025.117660_bib32","first-page":"81","article-title":"Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy, drug healthc","volume":"4","author":"Ciliberto","year":"2012","journal-title":"Patient Saf"},{"key":"10.1016\/j.ejmech.2025.117660_bib33","first-page":"53","article-title":"Calculating oral LD(50) of 1,2-dichloropropane on BALB\/cA-nu mice by improved Kohl's method, Chin","volume":"37","author":"Rong","year":"2019","journal-title":"J. Ind. Hyg. Occup. Dis."},{"key":"10.1016\/j.ejmech.2025.117660_bib34","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1111\/j.1528-1167.2011.03365.x","article-title":"The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy","volume":"53","author":"Gunthorpe","year":"2012","journal-title":"Epilepsia"},{"key":"10.1016\/j.ejmech.2025.117660_bib35","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41422-020-00410-8","article-title":"Molecular basis for ligand activation of the human KCNQ2 channel","volume":"31","author":"Li","year":"2021","journal-title":"Cell Res."},{"key":"10.1016\/j.ejmech.2025.117660_bib36","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.neuron.2021.10.029","article-title":"Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel","volume":"110","author":"Zheng","year":"2022","journal-title":"Neuron"},{"key":"10.1016\/j.ejmech.2025.117660_bib37","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1021\/acs.jmedchem.9b00796","article-title":"Synthesis and pharmacological characterization of conformationally restricted retigabine analogues as novel neuronal Kv7 channel activators","volume":"63","author":"Ostacolo","year":"2020","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.117660_bib38","doi-asserted-by":"crossref","first-page":"9154","DOI":"10.1096\/fj.201802848RR","article-title":"Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy","volume":"33","author":"Zhang","year":"2019","journal-title":"FASEB J."},{"key":"10.1016\/j.ejmech.2025.117660_bib39","doi-asserted-by":"crossref","first-page":"16282","DOI":"10.1021\/acs.jmedchem.1c01579","article-title":"Photosensitive and photoswitchable TRPA1 agonists optically control pain through channel desensitization","volume":"64","author":"Qiao","year":"2021","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.117660_bib40","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuropharm.2021.108884","article-title":"The novel dual-mechanism Kv7 potassium channel\/TSPO receptor activator GRT-X is more effective than the Kv7 channel opener retigabine in the 6-Hz refractory seizure mouse model","volume":"203","author":"Bloms-Funke","year":"2022","journal-title":"Neuropharmacology"},{"key":"10.1016\/j.ejmech.2025.117660_bib41","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1021\/acs.jmedchem.0c02252","article-title":"Discovery of HN37 as a potent and chemically stable antiepileptic drug candidate","volume":"64","author":"Zhang","year":"2021","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.117660_bib42","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1111\/epi.16617","article-title":"Collaborative Cross mice reveal extreme epilepsy phenotypes and genetic loci for seizure susceptibility","volume":"61","author":"Gu","year":"2020","journal-title":"Epilepsia"},{"key":"10.1016\/j.ejmech.2025.117660_bib43","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1111\/epi.17190","article-title":"Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects","volume":"63","author":"Nagib","year":"2022","journal-title":"Epilepsia"},{"key":"10.1016\/j.ejmech.2025.117660_bib44","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.yebeh.2019.02.029","article-title":"PTZ-induced seizures in mice require a revised Racine scale","volume":"95","author":"Van Erum","year":"2019","journal-title":"Epilepsy Behav."},{"key":"10.1016\/j.ejmech.2025.117660_bib45","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J. Comput. Aided Mol. Des."},{"key":"10.1016\/j.ejmech.2025.117660_bib46","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel procedure for modeling ligand\/receptor induced fit effects","volume":"49","author":"Sherman","year":"2006","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.117660_bib47","doi-asserted-by":"crossref","first-page":"D370","DOI":"10.1093\/nar\/gkr703","article-title":"OPM database and PPM web server: resources for positioning of proteins in membranes","volume":"40","author":"Lomize","year":"2012","journal-title":"Nucleic Acids Res."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523425004258?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523425004258?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T08:48:04Z","timestamp":1753865284000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523425004258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":47,"alternative-id":["S0223523425004258"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2025.117660","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Design, synthesis, and structure-activity relationship of 5,7- dimethylbenzo[d]thiazoles as novel Kv7.2\/7.3 activators with antiepileptic effects","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2025.117660","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"117660"}}