{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:01:45Z","timestamp":1789603305617,"version":"build-2803163510"},"reference-count":20,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2019M3A9A8066500"],"award-info":[{"award-number":["NRF-2019M3A9A8066500"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1A6A1A03042854"],"award-info":[{"award-number":["NRF-2020R1A6A1A03042854"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2021R1A2C2007159"],"award-info":[{"award-number":["NRF-2021R1A2C2007159"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2020-0-01343"],"award-info":[{"award-number":["2020-0-01343"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC50 = 9.7 nM), as well as neuroprotective effects against A\u03b2-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (&gt;1000 fold) and JNK2 (\u221210 fold).<\/jats:p>","DOI":"10.3390\/ijms222011084","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T22:42:18Z","timestamp":1634251338000},"page":"11084","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Discovery of a Potent and Selective JNK3 Inhibitor with Neuroprotective Effect Against Amyloid \u03b2-Induced Neurotoxicity in Primary Rat Neurons"],"prefix":"10.3390","volume":"22","author":[{"given":"Joonhong","family":"Jun","sequence":"first","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Korea"},{"name":"Center for Proteinopathy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihyun","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Korea"},{"name":"Center for Proteinopathy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Korea"},{"name":"Center for Proteinopathy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyungwoo","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Korea"},{"name":"Center for Proteinopathy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Korea"},{"name":"Center for Proteinopathy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunwook","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Korea"},{"name":"Center for Proteinopathy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Mi","family":"Hah","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Korea"},{"name":"Center for Proteinopathy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0092-8674(00)00116-1","article-title":"Signal Transduction by the JNK Group of MAP Kinases","volume":"103","author":"Davis","year":"2000","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/369156a0","article-title":"The stress-activated protein kinase subfamily of c-Jun kinases","volume":"369","author":"Kyriakis","year":"1994","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.bbapap.2009.11.002","article-title":"c-Jun N-terminal kinase (JNK) signaling: Recent advances and challenges","volume":"1804","author":"Bogoyevitch","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)\u2013Proteins Proteom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.neuroscience.2009.04.014","article-title":"Specific activities of individual c-Jun N-terminal kinases in the brain","volume":"161","author":"Haeusgen","year":"2009","journal-title":"Neuroscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ceb.2007.02.001","article-title":"The JNK signal transduction pathway","volume":"19","author":"Weston","year":"2007","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.nbd.2008.12.014","article-title":"JNK regulates APP cleavage and degradation in a model of Alzheimer\u2019s disease","volume":"33","author":"Colombo","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3233\/JAD-2011-110320","article-title":"JNK plays a key role in tau hyperphosphorylation in Alzheimer\u2019s disease models","volume":"26","author":"Ploia","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/ana.24361","article-title":"Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe\/PS1dE9 mice","volume":"77","author":"Zhou","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1177\/1933719115600553","article-title":"Bentamapimod (JNK inhibitor AS602801) induces regression of endometriotic lesions in animal models","volume":"23","author":"Palmer","year":"2016","journal-title":"Reprod. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/j.bmcl.2011.12.027","article-title":"Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg","volume":"22","author":"Krenitsky","year":"2012","journal-title":"Med. Chem. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"633","DOI":"10.3233\/JAD-2011-091567","article-title":"JNK3 as a Therapeutic Target for Neurodegenerative Diseases","volume":"24","author":"Antoniou","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1016\/j.bmc.2013.02.021","article-title":"Syntheses and biological evaluation of 1-heteroaryl-2-aryl-1 H -benzimidazole derivatives as c-Jun N-terminal kinase inhibitors with neuroprotective effects","volume":"21","author":"Kim","year":"2013","journal-title":"Bioorganic Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1021\/acs.jmedchem.5b00466","article-title":"Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1\/2","volume":"58","author":"Ward","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4780","DOI":"10.1166\/jnn.2009.1087","article-title":"New Synthesis of Nanosized Niobium Oxides and Lithium Niobate Particles and Their Characterization by XPS Analysis","volume":"9","author":"Aufray","year":"2009","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_15","unstructured":"Dean, D., Naylor, K., Takle, A., Kenneth, A., and Wilson, D.M. (2003). (PCT WO 03\/022833)."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1055\/s-0033-1338853","article-title":"Chemoselective Reactions of 4,6-Dichloro-2-(methylsulfonyl)pyrimidine and Related Electrophiles with Amines","volume":"45","author":"Baiazitov","year":"2013","journal-title":"Synthesis"},{"key":"ref_17","unstructured":"Smith, M.B., and March, J. (2007). Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley-Interscience. [6th ed.]."},{"key":"ref_18","unstructured":"We used Reaction Biology Corp. Kinase HotSpotSM service (Reaction Biology Corp. Malvern, PA) for screening of 35b."},{"key":"ref_19","first-page":"12","article-title":"Targeting tau hyperphosphorylation via kinase inhibition- Strategy to address Alzheimers\u2019 disease","volume":"20","author":"Naqvi","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3233\/ADR-190135","article-title":"Curcumin Downregulates GSK3 and Cdk5 in Scopolamine-Induced Alzheimer\u2019s Disease Rats Abrogating A\u03b240\/42 and Tau Hyperphosphorylation","volume":"3","author":"Das","year":"2019","journal-title":"J. Alzheimer\u2019s Dis. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11084\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:14:42Z","timestamp":1760166882000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,14]]},"references-count":20,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222011084"],"URL":"https:\/\/doi.org\/10.3390\/ijms222011084","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,14]]}}}