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Kleberg, Jr. and Helen C. Kleberg Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012394","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["AARFD-17-529742"],"award-info":[{"award-number":["AARFD-17-529742"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG071985"],"award-info":[{"award-number":["AG071985"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100025348","name":"Lowe Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100025348","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s (AD) and Parkinson\u2019s (PD) disease are neurodegenerative disorders that are considered to be a significant global health challenge due to their increasing prevalence and profound impact on both individuals and society. These disorders are characterized by the progressive loss of neuronal function, leading to cognitive and motor impairments. A key pathological feature of AD and PD is the abnormal accumulation of misfolded proteins within the brain. In AD, amyloid-beta aggregates into plaques, while tau proteins form neurofibrillary tangles (NFTs). Parkinson\u2019s disease, on the other hand, is marked by the accumulation of \u03b1-synuclein (\u03b1-syn) in the form of Lewy bodies (LBs). These protein aggregates are involved in neuronal dysfunction and neurodegeneration, contributing to disease progression. Research efforts are increasingly focused on identifying small molecules that can simultaneously target multiple pathological processes, offering the potential to not only alleviate symptoms but also modify the progression of neurodegeneration. Herein, a novel group of triazole-based compounds was designed and synthesized to curtail the aggregation of \u03b1-syn and tau proteins, which are closely linked to the physiopathology of PD and AD, respectively. A thioflavin T (ThT) fluorescence assay was used to measure fibril formation and assess the antiaggregation effects of various compounds. To further validate these findings, transmission electron microscopy (TEM) was employed as a direct method to visualize the impact of these compounds on fibril morphology. Inhibition of oligomer formation was evaluated using photoinduced cross-linking of unmodified proteins (PICUP), enabling the detection of early protein aggregation events. During fibril formation assays, three compounds (3e, 4b, 4d) demonstrated superior inhibitory activity as assessed by ThT fluorescence and TEM imaging. Subsequent evaluations, which included tests for antioligomer, anti-inclusion, and disaggregation effects identified compound 4d as the most promising candidate overall.<\/jats:p>","DOI":"10.1021\/acsomega.4c08385","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T05:26:42Z","timestamp":1739338002000},"page":"6721-6734","source":"Crossref","is-referenced-by-count":2,"title":["Inspecting the\nTriazole Scaffold as Powerful Antifibril\nAgents against 2N4R Tau and \u03b1\u2011Synuclein Aggregates"],"prefix":"10.1021","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6339-1190","authenticated-orcid":true,"given":"Ahmed\nA.","family":"Elbatrawy","sequence":"first","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiwo A.","family":"Ademoye","sequence":"additional","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Alnakhala","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital and Harvard Medical School , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arati","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital and Harvard Medical School , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Case Western Reserve University , , , ,","place":["Cleveland, Ohio, United States, 44106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germa\u0301n","family":"Plascencia-Villa","sequence":"additional","affiliation":[{"name":"The University of Texas at San Antonio , , , ,","place":["San Antonio, Texas, United States, 78249"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6547-0172","authenticated-orcid":true,"given":"George","family":"Perry","sequence":"additional","affiliation":[{"name":"The University of Texas at San Antonio , , , ,","place":["San Antonio, Texas, United States, 78249"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Dettmer","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital and Harvard Medical School , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1007-9360","authenticated-orcid":true,"given":"Jessica S.","family":"Fortin","sequence":"additional","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"issue":"7\u20138","key":"2026081811151394400_cit1","doi-asserted-by":"publisher","first-page":"451","DOI":"10.2119\/2007-00100.Irvine","article-title":"Protein aggregation\nin the brain: the molecular basis for Alzheimer\u2019s and Parkinson\u2019s\ndiseases","volume":"14","author":"Irvine","year":"2008","journal-title":"Mol. 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Neurol"},{"key":"2026081811151394400_cit3","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s40035-017-0077-5","article-title":"Protein\nmisfolding in neurodegenerative diseases: implications\nand strategies","volume":"6","author":"Sweeney","year":"2017","journal-title":"Transl Neurodegener"},{"issue":"3","key":"2026081811151394400_cit4","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1080\/13506129.2018.1503593","article-title":"Hereditary\ntransthyretin amyloidosis:\nbaseline characteristics of patients in the NEURO-TTR trial","volume":"25","author":"Waddington-Cruz","year":"2018","journal-title":"Amyloid"},{"issue":"3","key":"2026081811151394400_cit5","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/1531-8249(199903)45:3&lt;358::AID-ANA12&gt;3.0.CO;2-X","article-title":"Tangles and plaques in nondemented\naging and \u2033preclinical\u2033\nAlzheimer\u2019s disease","volume":"45","author":"Price","year":"1999","journal-title":"Ann. 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J. Mol. Sci."},{"issue":"22","key":"2026081811151394400_cit21","doi-asserted-by":"publisher","first-page":"20102","DOI":"10.1021\/acsomega.3c02668","article-title":"5-Nitro-1,2-benzothiazol-3-amine\nand N-Ethyl-1-[(ethylcarbamoyl)\u00ad(5-nitro-1,2-benzothiazol-3-yl)\u00adamino]\u00adformamide\nModulate alpha-Synuclein and Tau Aggregation","volume":"8","author":"Ramirez","year":"2023","journal-title":"ACS Omega"},{"issue":"21","key":"2026081811151394400_cit22","doi-asserted-by":"publisher","first-page":"3913","DOI":"10.1021\/acschemneuro.3c00464","article-title":"Evaluation\nof N- and\nO-Linked Indole Triazines for a Dual Effect on alpha-Synuclein and\nTau Aggregation","volume":"14","author":"Ramirez","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"2026081811151394400_cit23","doi-asserted-by":"publisher","DOI":"10.1016\/j.rechem.2023.100938","article-title":"Discovery\nof 4-aminoindole carboxamide derivatives to curtail alpha-synuclein\nand tau isoform 2N4R oligomer formation","volume":"5","author":"Ramirez","year":"2023","journal-title":"Results\nChem."},{"key":"2026081811151394400_cit24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2024.117613","article-title":"Discovery of small\nmolecule benzothiazole and indole derivatives tackling tau 2N4R and\nalpha-synuclein fibrils","volume":"100","author":"Elbatrawy","year":"2024","journal-title":"Bioorg. Med. Chem."},{"key":"2026081811151394400_cit25","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.bioorg.2017.01.010","article-title":"Medicinal\nattributes of 1,2,3-triazoles:\nCurrent developments","volume":"71","author":"Dheer","year":"2017","journal-title":"Bioorg Chem."},{"issue":"14","key":"2026081811151394400_cit26","doi-asserted-by":"publisher","first-page":"3380","DOI":"10.1021\/jm070467l","article-title":"Quick assembly\nof 1,4-diphenyltriazoles as probes targeting beta-amyloid aggregates\nin Alzheimer\u2019s disease","volume":"50","author":"Qu","year":"2007","journal-title":"J. Med. Chem."},{"key":"2026081811151394400_cit27","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.ejmech.2017.02.057","article-title":"Identification of\ndibenzyl imidazolidine and triazole\nacetamide derivatives through virtual screening targeting amyloid\nbeta aggregation and neurotoxicity in PC12 cells","volume":"130","author":"Das","year":"2017","journal-title":"Eur. J. Med. Chem."},{"issue":"17","key":"2026081811151394400_cit28","doi-asserted-by":"publisher","first-page":"7710","DOI":"10.1073\/pnas.0910723107","article-title":"EGCG remodels mature\nalpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity","volume":"107","author":"Bieschke","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"2026081811151394400_cit29","doi-asserted-by":"publisher","first-page":"12579","DOI":"10.1038\/s41598-020-69429-6","article-title":"EGCG impedes\nhuman Tau aggregation and interacts with Tau","volume":"10","author":"Sonawane","year":"2020","journal-title":"Sci. Rep"},{"key":"2026081811151394400_cit30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2023.123194","article-title":"EGCG attenuates\nalpha-synuclein protofibril-membrane interactions and disrupts the\nprotofibril","volume":"230","author":"Yang","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"issue":"5","key":"2026081811151394400_cit31","doi-asserted-by":"publisher","first-page":"767","DOI":"10.3390\/biom11050767","article-title":"Green Tea\nEpigallocatechin-3-gallate\n(EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative\nDiseases","volume":"11","author":"Goncalves","year":"2021","journal-title":"Biomolecules"},{"issue":"10","key":"2026081811151394400_cit32","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1021\/acschemneuro.3c00162","article-title":"Mechanistic Insights into Polyphenols\u2019\nAggregation Inhibition of alpha-Synuclein and Related Peptides","volume":"14","author":"Martins","year":"2023","journal-title":"ACS Chem. Neurosci."},{"issue":"4","key":"2026081811151394400_cit33","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1016\/j.jmb.2008.11.006","article-title":"Molecular mechanism\nof thioflavin-T binding to the surface of beta-rich peptide self-assemblies","volume":"385","author":"Biancalana","year":"2009","journal-title":"J. Mol. Biol."},{"issue":"1","key":"2026081811151394400_cit34","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13024-023-00651-2","article-title":"Misfolded\nprotein oligomers: mechanisms of formation, cytotoxic effects, and\npharmacological approaches against protein misfolding diseases","volume":"19","author":"Rinauro","year":"2024","journal-title":"Mol. Neurodegener"},{"key":"2026081811151394400_cit35","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.ijbiomac.2021.03.113","article-title":"The role of\namyloid\noligomers in neurodegenerative pathologies","volume":"181","author":"Wells","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"issue":"24","key":"2026081811151394400_cit36","doi-asserted-by":"publisher","first-page":"4351","DOI":"10.1021\/acschemneuro.0c00598","article-title":"Epigallocatechin\nGallate Destabilizes\nalpha-Synuclein Fibril by Disrupting the E46-K80 Salt-Bridge and Inter-protofibril\nInterface","volume":"11","author":"Yao","year":"2020","journal-title":"ACS Chem. Neurosci."},{"issue":"15","key":"2026081811151394400_cit37","doi-asserted-by":"publisher","first-page":"5193","DOI":"10.3390\/ijms21155193","article-title":"Rapid Alpha-Synuclein Toxicity in a Neural Cell Model\nand Its Rescue by a Stearoyl-CoA Desaturase Inhibitor","volume":"21","author":"Terry-Kantor","year":"2020","journal-title":"Int. J. Mol. Sci."},{"issue":"41","key":"2026081811151394400_cit38","doi-asserted-by":"publisher","first-page":"20760","DOI":"10.1073\/pnas.1903216116","article-title":"Cell models of lipid-rich\nalpha-synuclein aggregation validate known modifiers of alpha-synuclein\nbiology and identify stearoyl-CoA desaturase","volume":"116","author":"Imberdis","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081811151394400_cit39","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2022.133574","article-title":"Anti-fibrillization\neffects of sulfonamide derivatives on alpha-synuclein and hyperphosphorylated\ntau isoform 1N4R","volume":"1267","author":"Fortin","year":"2022","journal-title":"J. Mol. Struct."},{"issue":"1","key":"2026081811151394400_cit40","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1074\/mcp.O114.044412","article-title":"Protein interaction\nmodule-assisted function X (PIMAX) approach to producing challenging\nproteins including hyperphosphorylated tau and active CDK5\/p25 kinase\ncomplex","volume":"14","author":"Sui","year":"2015","journal-title":"Mol. Cell Proteomics"},{"issue":"1","key":"2026081811151394400_cit41","doi-asserted-by":"publisher","first-page":"16551","DOI":"10.1038\/s41598-020-73680-2","article-title":"Hyperphosphorylated\ntau aggregation and cytotoxicity modulators screen identified prescription\ndrugs linked to Alzheimer\u2019s disease and cognitive functions","volume":"10","author":"Liu","year":"2020","journal-title":"Sci. Rep"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.4c08385","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/10\/7\/6721\/40792601\/ao4c08385.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/10\/7\/6721\/40792601\/ao4c08385.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:41:16Z","timestamp":1787074876000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/10\/7\/6721\/3652047\/Inspecting-the-Triazole-Scaffold-as-Powerful"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,12]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,2,12]]},"published-print":{"date-parts":[[2025,2,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.4c08385","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,12]]}}}