{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:31:11Z","timestamp":1774373471397,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T00:00:00Z","timestamp":1578528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/DTP-FTO\/2433\/2014, PTDC\/BIA-MOL\/28607\/2017, POCI-01-0145-FEDER-028607"],"award-info":[{"award-number":["PTDC\/DTP-FTO\/2433\/2014, PTDC\/BIA-MOL\/28607\/2017, POCI-01-0145-FEDER-028607"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/QUI\/00081"],"award-info":[{"award-number":["UID\/QUI\/00081"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["NORTE-01-0145-FEDER-000028"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000028"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar \u03b2-amyloid 1\u201342 (A\u03b242), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA\u2019s) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds 7 and 11 with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicity.<\/jats:p>","DOI":"10.3390\/molecules25020276","type":"journal-article","created":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T04:06:51Z","timestamp":1578629211000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer\u2019s Disease Pathophysiological Hallmarks"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9645-8152","authenticated-orcid":false,"given":"Sofia","family":"Benfeito","sequence":"first","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre 1021\/1055, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0102-0703","authenticated-orcid":false,"given":"Carlos","family":"Fernandes","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre 1021\/1055, 4169-007 Porto, Portugal"}]},{"given":"Santiago","family":"Vilar","sequence":"additional","affiliation":[{"name":"Departmento Qu\u00edmica Org\u00e1nica, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"given":"Eugenio","family":"Uriarte","sequence":"additional","affiliation":[{"name":"Departmento Qu\u00edmica Org\u00e1nica, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Spain"},{"name":"Instituto de Ciencias Qu\u00edmicas Aplicadas, Universidad Autonoma de Chile, Av. Libertador Bernardo O\u2019Higgins, 7500912 Santiago de Chile, Chile"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-2402","authenticated-orcid":false,"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"CIQUP\/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre 1021\/1055, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"364","DOI":"10.2174\/1570159X14666160119094820","article-title":"AChE Inhibition-based Multi-target-directed Ligands, a Novel Pharmacological Approach for the Symptomatic and Disease-modifying Therapy of Alzheimer\u2019s Disease","volume":"14","author":"Wang","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.1016\/j.bmcl.2006.01.067","article-title":"Isoquinoline derivatives as potential acetylcholinesterase inhibitors","volume":"16","author":"Markmee","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1016\/j.bmcl.2015.07.052","article-title":"Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors","volume":"26","author":"Si","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.phrs.2003.11.017","article-title":"Cholinesterase inhibitors: New roles and therapeutic alternatives","volume":"50","author":"Giacobini","year":"2004","journal-title":"Pharmacol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1159\/000107015","article-title":"The Implication of Current Therapeutic Approaches for the Cholinergic Hypothesis of Dementia","volume":"3","author":"Traub","year":"1992","journal-title":"Dement. Geriatr. Cogn."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1016\/j.bmcl.2008.05.039","article-title":"Design, synthesis and evaluation of isaindigotone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors","volume":"18","author":"Pan","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1017\/S1461145705005833","article-title":"Targeting acetylcholinesterase and butyrylcholinesterase in dementia","volume":"9","author":"Lane","year":"2006","journal-title":"Int. J. Neuropsychop."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/ana.410340312","article-title":"Neuroglial cholinesterases in the normal brain and in Alzheimer\u2019s disease: Relationship to plaques, tangles, and patterns of selective vulnerability","volume":"34","author":"Wright","year":"1993","journal-title":"Ann. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrn1035","article-title":"Neurobiology of butyrylcholinesterase","volume":"4","author":"Darvesh","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.arr.2014.03.008","article-title":"Alzheimer\u2019s disease, enzyme targets and drug discovery struggles: From natural products to drug prototypes","volume":"15","author":"Silva","year":"2014","journal-title":"Ageing Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1046\/j.1471-4159.2000.751320.x","article-title":"Abundant Tissue Butyrylcholinesterase and Its Possible Function in the Acetylcholinesterase Knockout Mouse","volume":"75","author":"Li","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1185\/03007990152673800","article-title":"A New Therapeutic Target in Alzheimer\u2019s Disease Treatment: Attention to Butyrylcholinesterase","volume":"17","author":"Greig","year":"2001","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.2174\/0929867321666141106122628","article-title":"Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimer\u2019s Disease","volume":"22","author":"Guzior","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1365-2990.1978.tb00545.x","article-title":"Changes in brain cholinesterases in senile dementia of Alzheimer type","volume":"4","author":"Perry","year":"1978","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/ana.410360506","article-title":"Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia","volume":"36","author":"Mesulam","year":"1994","journal-title":"Ann. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17213","DOI":"10.1073\/pnas.0508575102","article-title":"Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer \u03b2-amyloid peptide in rodent","volume":"102","author":"Greig","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0306-4522(01)00613-3","article-title":"Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine","volume":"110","author":"Mesulam","year":"2002","journal-title":"Neuroscience"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.neuroscience.2012.12.054","article-title":"Butyrylcholinesterase and the cholinergic system","volume":"234","author":"Reid","year":"2013","journal-title":"Neuroscience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8628","DOI":"10.1073\/pnas.0602922103","article-title":"Butyrylcholinesterase attenuates amyloid fibril formation in vitro","volume":"103","author":"Diamant","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jalz.2011.02.011","article-title":"Effects of FDA approved medications for Alzheimer\u2019s disease on clinical progression","volume":"8","author":"Mielke","year":"2012","journal-title":"Alzheimers Dement."},{"key":"ref_21","first-page":"22","article-title":"Revisiting the Role of Acetylcholinesterase in Alzheimer\u2019s Disease: Cross-Talk with P-tau and \u03b2-Amyloid","volume":"4","author":"Small","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/978-3-7091-6139-5_17","article-title":"Long-term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer\u2019 disease","volume":"62","author":"Giacobini","year":"2002","journal-title":"J. Neural. Transm. Suppl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1136\/bmj.331.7512.321","article-title":"Cholinesterase inhibitors for patients with Alzheimer\u2019s disease: Systematic review of randomised clinical trials","volume":"331","author":"Kaduszkiewicz","year":"2005","journal-title":"Br. Med. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8501693","DOI":"10.1155\/2016\/8501693","article-title":"Current Research Therapeutic Strategies for Alzheimer\u2019s Disease Treatment","volume":"2016","author":"Folch","year":"2016","journal-title":"Neural Plast."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kritis, A.A., Stamoula, E.G., Paniskaki, K.A., and Vavilis, T.D. (2015). Researching glutamate-induced cytotoxicity in different cell lines: A comparative\/collective analysis\/study. Front. Cell. Neurosci., 9.","DOI":"10.3389\/fncel.2015.00091"},{"key":"ref_26","first-page":"376","article-title":"Oxidative stress in neurodegenerative diseases","volume":"7","author":"Chen","year":"2012","journal-title":"Neural Regen. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.neuron.2014.05.004","article-title":"The intersection of amyloid beta and tau at synapses in Alzheimer\u2019s disease","volume":"82","author":"Hyman","year":"2014","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18295","DOI":"10.1074\/jbc.271.31.18295","article-title":"Amyloid \u03b2-Protein and the Genetics of Alzheimer\u2019s Disease","volume":"271","author":"Selkoe","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"523","DOI":"10.2307\/3579270","article-title":"Fenton Chemistry: An Introduction","volume":"145","author":"Wardman","year":"1996","journal-title":"Radiat. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s12264-010-0813-7","article-title":"Excitotoxicity effects of glutamate on human neuroblastoma SH-SY5Y cells via oxidative damage","volume":"26","author":"Sun","year":"2010","journal-title":"Neurosci. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.3233\/JAD-160763","article-title":"Role of Glutamate and NMDA Receptors in Alzheimer\u2019s Disease","volume":"57","author":"Wang","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.ejmech.2019.01.055","article-title":"Fine-tuning the neuroprotective and blood-brain barrier permeability profile of multi-target agents designed to prevent progressive mitochondrial dysfunction","volume":"167","author":"Benfeito","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7084","DOI":"10.1021\/acs.jmedchem.7b00741","article-title":"Development of a Mitochondriotropic Antioxidant Based on Caffeic Acid: Proof of Concept on Cellular and Mitochondrial Oxidative Stress Models","volume":"60","author":"Teixeira","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cbi.2012.08.005","article-title":"A step toward the reactivation of aged cholinesterases-Crystal structure of ligands binding to aged human butyrylcholinesterase","volume":"203","author":"Wandhammer","year":"2013","journal-title":"Chem. Biol. Interact."},{"key":"ref_36","unstructured":"Schr\u00f6dinger (2017, August 30). Schr\u00f6dinger Schr\u00f6dinger Suite 2017-2. Available online: http:\/\/www.schrodinger.com\/."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.bioorg.2016.06.002","article-title":"Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR)","volume":"67","author":"Bacalhau","year":"2016","journal-title":"Bioorg. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"41141","DOI":"10.1074\/jbc.M210241200","article-title":"Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products","volume":"278","author":"Nicolet","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/BF03033178","article-title":"Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists","volume":"5","author":"Presgraves","year":"2003","journal-title":"Neurotox. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Krishtal, J., Bragina, O., Metsla, K., Palumaa, P., and T\u00f5ugu, V. (2017). In situ fibrillizing amyloid-beta 1-42 induces neurite degeneration and apoptosis of differentiated SH-SY5Y cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186636"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1021\/acs.bioconjchem.8b00151","article-title":"Development of a PEGylated-Based Platform for Efficient Delivery of Dietary Antioxidants Across the Blood\u2013Brain Barrier","volume":"29","author":"Fernandes","year":"2018","journal-title":"Bioconj. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0002-9440(10)64857-2","article-title":"Oxidative damage and cancer","volume":"160","author":"Oberley","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1080\/10715760500176866","article-title":"Rac1-NADPH oxidase-regulated generation of reactive oxygen species mediates glutamate-induced apoptosis in SH-SY5Y human neuroblastoma cells","volume":"39","author":"Nikolova","year":"2005","journal-title":"Free Radic. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9941","DOI":"10.1038\/s41598-017-10212-5","article-title":"Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors","volume":"7","author":"Chakraborty","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"39557","DOI":"10.1021\/acsami.8b17224","article-title":"PEGylated PLGA Nanoparticles as a Smart Carrier to Increase the Cellular Uptake of a Coumarin-Based Monoamine Oxidase B Inhibitor","volume":"10","author":"Fernandes","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/2\/276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:19:21Z","timestamp":1760361561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/2\/276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,9]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["molecules25020276"],"URL":"https:\/\/doi.org\/10.3390\/molecules25020276","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,9]]}}}