{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T15:59:12Z","timestamp":1793721552699,"version":"4.6.1"},"reference-count":132,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T00:00:00Z","timestamp":1757203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acetylcholinesterase (AChE) has emerged not only as a cholinergic enzyme but also as a modulator of \u03b2-amyloid (A\u03b2) aggregation via its peripheral anionic site (PAS), making it a dual-purpose target in Alzheimer\u2019s disease. While classical AChE inhibitors provide symptomatic relief, they lack efficacy against the amyloidogenic cascade. This review highlights recent advances in multifunctional AChE pharmacophores that inhibit enzymatic activity while simultaneously interfering with A\u03b2 aggregation, oxidative stress, metal dyshomeostasis, and neuroinflammation. Particular emphasis is placed on dual-site inhibitors targeting both catalytic and peripheral domains, multi-target-directed ligands (MTDLs) acting on multiple neurodegenerative pathways, and metal-chelating hybrids that address redox-active metal ions promoting A\u03b2 fibrillization. We also discuss enabling technologies such as AI-assisted drug design, high-resolution structural tools, and human induced pluripotent stem cell (iPSC)-derived neuronal models that support physiologically relevant validation. These insights reflect a paradigm shift towards disease-modifying therapies that bridge molecular pharmacology and pathophysiological relevance.<\/jats:p>","DOI":"10.3390\/ijms26178726","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8726","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Acetylcholinesterase as a Multifunctional Target in Amyloid-Driven Neurodegeneration: From Dual-Site Inhibitors to Anti-Agregation Strategies"],"prefix":"10.3390","volume":"26","author":[{"given":"Weronika","family":"Grabowska","sequence":"first","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-4097","authenticated-orcid":false,"given":"Michal","family":"Bijak","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6646-2203","authenticated-orcid":false,"given":"Rafa\u0142","family":"Szelenberger","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9873-9521","authenticated-orcid":false,"given":"Leslaw","family":"Gorniak","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7566-4205","authenticated-orcid":false,"given":"Marcin","family":"Podogrocki","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2318-6293","authenticated-orcid":false,"given":"Piotr","family":"Harmata","sequence":"additional","affiliation":[{"name":"Faculty of Advanced Technologies and Chemistry, Military University of Technology, 2 gen. 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Neurorestoratology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Chen, Z.R., Huang, J.B., Yang, S.L., and Hong, F.F. (2022). Role of Cholinergic Signaling in Alzheimer\u2019s Disease. Molecules, 27.","DOI":"10.3390\/molecules27061816"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yamashita, K.I., Uehara, T., Taniwaki, Y., Tobimatsu, S., and Kira, J.I. (2022). Long-Term Effect of Acetylcholinesterase Inhibitors on the Dorsal Attention Network of Alzheimer\u2019s Disease Patients: A Pilot Study Using Resting-State Functional Magnetic Resonance Imaging. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.810206"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kim, A.Y., Al Jerdi, S., MacDonald, R., and Triggle, C.R. (2024). Alzheimer\u2019s disease and its treatment-yesterday, today, and tomorrow-PubMed. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1399121"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/S0011-393X(03)00059-6","article-title":"Cholinesterase Inhibitors for the Treatment of Alzheimer\u2019s Disease: Getting On and Staying On","volume":"64","author":"Grossberg","year":"2003","journal-title":"Curr. Ther. Res. Clin. Exp."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108352","DOI":"10.1016\/j.neuropharm.2020.108352","article-title":"Efficacy of acetylcholinesterase inhibitors in Alzheimer\u2019s disease","volume":"190","author":"Marucci","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"927","DOI":"10.2147\/TCRM.S323387","article-title":"Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older People Living with Dementia: A Comprehensive Literature Review","volume":"17","author":"Ruangritchankul","year":"2021","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent advances in Alzheimer\u2019s disease: Mechanisms, clinical trials and new drug development strategies","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Singh, A.A., Khan, F., and Song, M. (2025). Alleviation of Neurological Disorders by Targeting Neurodegenerative-Associated Enzymes: Natural and Synthetic Molecules. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26104707"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"116810","DOI":"10.1016\/j.ejmech.2024.116810","article-title":"Dual-target inhibitors based on acetylcholinesterase: Novel agents for Alzheimer\u2019s disease","volume":"279","author":"Zhao","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"117277","DOI":"10.1016\/j.ejmech.2025.117277","article-title":"Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer\u2019s disease","volume":"286","author":"Azam","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1038\/sj.emboj.7601175","article-title":"Structural insights into substrate traffic and inhibition in acetylcholinesterase","volume":"25","author":"Colletier","year":"2006","journal-title":"EMBO J."},{"key":"ref_15","first-page":"450","article-title":"Acetylcholinesterase: A Versatile Template to Coin Potent Modulators of Multiple Therapeutic Targets","volume":"57","author":"Luque","year":"2024","journal-title":"Acc. Chem. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.1039\/D4RA07951E","article-title":"Discovery of novel acetylcholinesterase inhibitors through AI-powered structure prediction and high-performance computing-enhanced virtual screening","volume":"15","author":"Cecilia","year":"2025","journal-title":"RSC Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.drudis.2021.11.023","article-title":"Enhancing preclinical drug discovery with artificial intelligence","volume":"27","author":"Vijayan","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_18","first-page":"100237","article-title":"Novel small molecule-based acetylcholinesterase (AChE) inhibitors: From biological perspective to recent developments","volume":"12","author":"Sobha","year":"2024","journal-title":"Eur. J. Med. Chem. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"\u017du\u017eek, M.C. (2024). Advances in Cholinesterase Inhibitor Research\u2014An Overview of Preclinical Studies of Selected Organoruthenium(II) Complexes. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25169049"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"de Almeida, R.B.M., Barbosa, D.B., Bomfim, M.R.D., Amparo, J.A.O., Andrade, B.S., Costa, S.L., Campos, J.M., Cruz, J.N., Santos, C.B.R., and Leite, F.H.A. (2023). Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies. Pharmaceuticals, 16.","DOI":"10.3390\/ph16010095"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pourtaher, H., Hasaninejad, A., Zare, S., Tanideh, N., and Iraji, A. (2023). The anti-Alzheimer potential of novel spiroindolin-1,2-diazepine derivatives as targeted cholinesterase inhibitors with modified substituents. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-38236-0"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107066","DOI":"10.1016\/j.ejps.2025.107066","article-title":"Light-mediated activation\/deactivation control and in vitro ADME-Tox profiling of a donepezil-like Dual AChE\/MAO-B Inhibitor","volume":"209","author":"Poggialini","year":"2025","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.1021\/acs.jmedchem.1c00048","article-title":"Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer\u2019s Disease","volume":"64","author":"Rossi","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Huang, L.K., Kuan, Y.C., Lin, H.W., and Hu, C.J. (2023). Clinical trials of new drugs for Alzheimer disease: A 2020\u20132023 update. J. Biomed. Sci., 30.","DOI":"10.1186\/s12929-023-00976-6"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e12465","DOI":"10.1002\/trc2.12465","article-title":"Alzheimer\u2019s disease drug development pipeline: 2024","volume":"10","author":"Cummings","year":"2024","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Romano, J.D., and Tatonetti, N.P. (2019). Informatics and Computational Methods in Natural Product Drug Discovery: A Review and Perspectives. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00368"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Atanasova, M., Dimitrov, I., Ivanov, S., Georgiev, B., Berkov, S., Zheleva-Dimitrova, D., and Doytchinova, I. (2022). Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors. Molecules, 27.","DOI":"10.3390\/molecules27103139"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2174\/1570159X11311030006","article-title":"Acetylcholinesterase Inhibitors: Pharmacology and Toxicology","volume":"11","year":"2013","journal-title":"Curr. Neuropharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.cbi.2008.05.035","article-title":"Acetylcholinesterase: How is structure related to function?","volume":"175","author":"Silman","year":"2008","journal-title":"Chem.-Biol. Interact."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cbi.2010.01.042","article-title":"Acetylcholinesterase: From 3D structure to function","volume":"187","author":"Dvir","year":"2010","journal-title":"Chem.-Biol. Interact."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.2174\/1389557517666170120153930","article-title":"Acetylcholinesterase: A Primary Target for Drugs and Insecticides","volume":"17","author":"Thapa","year":"2017","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6296","DOI":"10.1016\/S0021-9258(17)37371-4","article-title":"Acetylcholinesterase peripheral anionic site degeneracy conferred by amino acid arrays sharing a common core","volume":"269","author":"Barak","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1073\/pnas.0308206100","article-title":"Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation","volume":"101","author":"Bourne","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"23070","DOI":"10.1021\/jp053736x","article-title":"Modeling effects of oxyanion hole on the ester hydrolysis catalyzed by human cholinesterases","volume":"109","author":"Gao","year":"2005","journal-title":"J. Phys. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/pro.5560030204","article-title":"Structure and dynamics of the active site gorge of acetylcholinesterase: Synergistic use of molecular dynamics simulation and X-ray crystallography","volume":"3","author":"Axelsen","year":"1994","journal-title":"Protein Sci. A Publ. Protein Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"29256","DOI":"10.1074\/jbc.M603018200","article-title":"Substrate and product trafficking through the active center gorge of acetylcholinesterase analyzed by crystallography and equilibrium binding","volume":"281","author":"Bourne","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/35067589","article-title":"Acetylcholinesterase\u2014new roles for an old actor","volume":"2","author":"Soreq","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_38","unstructured":"(2025, September 01). FDA Approved Drug Products, Available online: http:\/\/www.accessdata.fda.gov\/scripts\/cder\/drugsatfda\/index.cfm."},{"key":"ref_39","unstructured":"(2025, September 01). EMA Approved Drug Products. Available online: https:\/\/www.ema.europa.eu\/en\/medicines."},{"key":"ref_40","unstructured":"(2018). National Institute for Health and Care Excellence: Guidelines. Dementia: Assessment, Management and Support for People Living with Dementia and Their Carers, National Institute for Health and Care Excellence (NICE)."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3233\/JAD-132690","article-title":"Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"41","author":"Tan","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3233\/JAD-122140","article-title":"A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer\u2019s disease","volume":"35","author":"Prinelli","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1001\/archinternmed.2009.43","article-title":"Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: A population-based cohort study","volume":"169","author":"Gill","year":"2009","journal-title":"Arch. Intern. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Miculas, D.C., Negru, P.A., Bungau, S.G., Behl, T., Hassan, S.S.u., and Tit, D.M. (2022). Pharmacotherapy Evolution in Alzheimer\u2019s Disease: Current Framework and Relevant Directions. Cells, 12.","DOI":"10.3390\/cells12010131"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2174\/1570159X113116660047","article-title":"Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer\u2019s Disease","volume":"12","author":"Fernandez","year":"2014","journal-title":"Curr. Neuropharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Niazi, S.K., Magoola, M., and Mariam, Z. (2024). Innovative Therapeutic Strategies in Alzheimer\u2019s Disease: A Synergistic Approach to Neurodegenerative Disorders. Pharmaceuticals, 17.","DOI":"10.3390\/ph17060741"},{"key":"ref_47","unstructured":"Kumar, A., Gupta, V., and Sharma, S. (2025). Donepezil. StatPearls, StatPearls Publishing LLC."},{"key":"ref_48","unstructured":"Kalola, U.K., Patel, P., and Nguyen, H. (2025). Galantamine. StatPearls, StatPearls Publishing LLC."},{"key":"ref_49","unstructured":"Patel, P.H., and Gupta, V. (2025). Rivastigmine. StatPearls, StatPearls Publishing LLC."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e30788","DOI":"10.1016\/j.heliyon.2024.e30788","article-title":"A comprehensive review on the progress and challenges of tetrahydroisoquinoline derivatives as a promising therapeutic agent to treat Alzheimer\u2019s disease","volume":"10","author":"Thangeswaran","year":"2024","journal-title":"Heliyon"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4909","DOI":"10.1021\/acs.jmedchem.1c02150","article-title":"Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer\u2019s Disease","volume":"65","author":"Codony","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Zag\u00f3rska, A., and Jaromin, A. (2020). Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer\u2032s Disease Therapy. Molecules, 25.","DOI":"10.3390\/molecules25153337"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6032","DOI":"10.2174\/0109298673264076230921065945","article-title":"Recent Advancements in the Treatment of Alzheimer\u2019s Disease: A Multitarget-directed Ligand Approach","volume":"31","author":"Kumar","year":"2024","journal-title":"Curr. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"115253","DOI":"10.1016\/j.ejmech.2023.115253","article-title":"Development of the \u201chidden\u201d multi-target-directed ligands by AChE\/BuChE for the treatment of Alzheimer\u2019s disease","volume":"251","author":"Chen","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.neuropharm.2019.05.025","article-title":"New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer\u2019s disease","volume":"155","author":"Zueva","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1006\/jmbi.1997.1245","article-title":"Acetylcholinesterase promotes the aggregation of amyloid-\u03b2-peptide fragments by forming a complex with the growing fibrils","volume":"272","author":"Alvarez","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Kumar, N., Kumar, V., Anand, P., Kumar, V., Dwivedi, A.R., and Kumar, V. (2022). Advancements in the development of multi-target directed ligands for the treatment of Alzheimer\u2019s disease. Bioorganic Med. Chem., 61.","DOI":"10.1016\/j.bmc.2022.116742"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"19764","DOI":"10.1039\/D2RA03081K","article-title":"Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase","volume":"12","author":"Obaid","year":"2022","journal-title":"RSC Adv."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s10822-019-00202-2","article-title":"Discovery of new multifunctional selective acetylcholinesterase inhibitors: Structure-based virtual screening and biological evaluation","volume":"33","author":"Jiang","year":"2019","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"28827","DOI":"10.1039\/D0RA05172A","article-title":"Aryldiazoquinoline based multifunctional small molecules for modulating A\u03b242 aggregation and cholinesterase activity related to Alzheimer\u2019s disease","volume":"10","author":"Rana","year":"2020","journal-title":"RSC Adv."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2270781","DOI":"10.1080\/14756366.2023.2270781","article-title":"Latest advances in dual inhibitors of acetylcholinesterase and monoamine oxidase B against Alzheimer\u2019s disease","volume":"38","author":"Zou","year":"2023","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"116131","DOI":"10.1016\/j.ejmech.2024.116131","article-title":"Design, synthesis, and pharmacological evaluation of indole-piperidine amides as Blood\u2212brain barrier permeable dual cholinesterase and \u03b2-secretase inhibitors","volume":"266","author":"Banoo","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7483","DOI":"10.1021\/acs.jmedchem.1c00160","article-title":"Discovery of Novel Tacrine\u2013Pyrimidone Hybrids as Potent Dual AChE\/GSK-3 Inhibitors for the Treatment of Alzheimer\u2019s Disease","volume":"64","author":"Yao","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1021\/acschemneuro.8b00376","article-title":"Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer\u2019s Disease","volume":"10","author":"Hu","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"114503","DOI":"10.1016\/j.ejmech.2022.114503","article-title":"Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4\/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer\u2019s disease","volume":"238","author":"Liu","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Asim, A., Jastrz\u0119bski, M.K., and Kaczor, A.A. (2025). Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase-B for the Treatment of Alzheimer\u2019s Disease. Molecules, 30.","DOI":"10.3390\/molecules30142975"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e18325","DOI":"10.1590\/s2175-97902019000418325","article-title":"Donepezil: A review of the recent structural modifications and their impact on anti-Alzheimer activity","volume":"56","author":"Mohsin","year":"2020","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s40263-024-01093-0","article-title":"Targeting Biometals in Alzheimer\u2019s Disease with Metal Chelating Agents Including Coumarin Derivatives","volume":"38","year":"2024","journal-title":"CNS Drugs"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Leuci, R., Brunetti, L., Laghezza, A., Loiodice, F., Tortorella, P., and Piemontese, L. (2020). Importance of Biometals as Targets in Medicinal Chemistry: An Overview about the Role of Zinc (II) Chelating Agents. Appl. Sci., 10.","DOI":"10.3390\/app10124118"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Sharma, A., Pachauri, V., and Flora, S.J.S. (2018). Advances in Multi-Functional Ligands and the Need for Metal-Related Pharmacology for the Management of Alzheimer Disease. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01247"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.ccr.2012.03.013","article-title":"Copper, zinc and iron in neurodegenerative diseases (Alzheimer\u2019s, Parkinson\u2019s and prion diseases)","volume":"256","author":"Kozlowski","year":"2012","journal-title":"Coord. Chem. Rev."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Krasnovskaya, O., Spector, D., Zlobin, A., Pavlov, K., Gorelkin, P., Erofeev, A., Beloglazkina, E., and Majouga, A. (2020). Metals in Imaging of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239190"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2174\/0929867324666170330092304","article-title":"Hydroxypyridinone Derivatives: A Fascinating Class of Chelators with Therapeutic Applications-An Update","volume":"25","author":"Chaves","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J., and Reddy, P.H. (2022). Phosphorylated Tau in Alzheimer\u2019s Disease and Other Tauopathies. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112841"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Ivanov, S.M., Atanasova, M., Dimitrov, I., and Doytchinova, I.A. (2020). Cellular polyamines condense hyperphosphorylated Tau, triggering Alzheimer\u2019s disease. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-67119-x"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Natale, G.D., Sabatino, G., Sciacca, M.F.M., Tosto, R., Milardi, D., and Pappalardo, G. (2022). A\u03b2 and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer\u2019s Disease?. Molecules, 27.","DOI":"10.3390\/molecules27165066"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Kumar, H.M.S., Herrmann, L., and Tsogoeva, S.B. (2020). Structural hybridization as a facile approach to new drug candidates. Bioorganic Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.127514"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5100904","DOI":"10.1155\/2022\/5100904","article-title":"Bioactive Compounds and Their Derivatives: An Insight into Prospective Phytotherapeutic Approach against Alzheimer\u2019s Disease","volume":"2022","author":"Islam","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Yang, H., Zeng, F., Luo, Y., Zheng, C., Ran, C., and Yang, J. (2022). Curcumin Scaffold as a Multifunctional Tool for Alzheimer\u2019s Disease Research-PubMed. Molecules, 27.","DOI":"10.3390\/molecules27123879"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Roy, A., Khan, A., Ahmad, I., Alghamdi, S., Rajab, B.S., Babalghith, A.O., Alshahrani, M.Y., Islam, S., and Islam, M.R. (2022). Flavonoids a Bioactive Compound from Medicinal Plants and Its Therapeutic Applications. BioMed Res. Int., 2022.","DOI":"10.1155\/2022\/5445291"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"184","DOI":"10.3390\/ddc3010011","article-title":"Plant-Derived Natural Products: A Source for Drug Discovery and Development","volume":"3","author":"Chaachouay","year":"2024","journal-title":"Drugs Drug Candidates"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Cichon, N., Grabowska, W., Gorniak, L., Stela, M., Harmata, P., Ceremuga, M., and Bijak, M. (2024). Mechanistic and Therapeutic Insights into Flavonoid-Based Inhibition of Acetylcholinesterase: Implications for Neurodegenerative Diseases. Nutrients, 17.","DOI":"10.3390\/nu17010078"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Huang, W., Wang, Y., Tian, W., Cui, X., Tu, P., Li, J., Shi, S., and Liu, X. (2022). Biosynthesis Investigations of Terpenoid, Alkaloid, and Flavonoid Antimicrobial Agents Derived from Medicinal Plants. Antibiotics, 11.","DOI":"10.3390\/antibiotics11101380"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1016\/j.bmc.2017.02.049","article-title":"Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property","volume":"25","author":"Liu","year":"2017","journal-title":"Bioorganic Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"116070","DOI":"10.1016\/j.ejmech.2023.116070","article-title":"Curcumin hybrid molecules for the treatment of Alzheimer\u2019s disease: Structure and pharmacological activities","volume":"265","author":"Zang","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Stavrakov, G., Philipova, I., Lukarski, A., Atanasova, M., Zheleva, D., Zhivkova, Z.D., Ivanov, S., Atanasova, T., Konstantinov, S., and Doytchinova, I. (2020). Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors. Molecules, 25.","DOI":"10.3390\/molecules25153341"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Singh, Y.P., Prasad, S., and Kumar, H. (2024). Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer\u2019s Disease. Chem. Biol. Drug Des., 104.","DOI":"10.1111\/cbdd.70004"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Simeonova, R., Zheleva, D., Valkova, I., Stavrakov, G., Philipova, I., Atanasova, M., and Doytchinova, I. (2021). A Novel Galantamine-Curcumin Hybrid as a Potential Multi-Target Agent against Neurodegenerative Disorders. Molecules, 26.","DOI":"10.3390\/molecules26071865"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.2174\/092986710793205426","article-title":"Prodrug design to improve pharmacokinetic and drug delivery properties: Challenges to the discovery scientists","volume":"17","author":"Jana","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrd2468","article-title":"Prodrugs: Design and clinical applications","volume":"7","author":"Rautio","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Choudhary, D., Goykar, H., Kalyane, D., Sreeharsha, N., and Tekade, R.K. (2020). Prodrug design for improving the biopharmaceutical properties of therapeutic drugs. The Future of Pharmaceutical Product Development and Research, Elsevier.","DOI":"10.1016\/B978-0-12-814455-8.00006-2"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Jornada, D.H., Fernandes, G.F.d.S., Chiba, D.E., Melo, T.R.F.d., Santos, J.L.d., and Chung, M.C. (2016). The Prodrug Approach: A Successful Tool for Improving Drug Solubility. Molecules, 21.","DOI":"10.3390\/molecules21010042"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1039\/D4MD00788C","article-title":"Prodrugs and their activation mechanisms for brain drug delivery","volume":"16","author":"Lillethorup","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Zeiadeh, I., Najjar, A., and Karaman, R. (2018). Strategies for Enhancing the Permeation of CNS-Active Drugs through the Blood-Brain Barrier: A Review. Molecules, 23.","DOI":"10.3390\/molecules23061289"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e202300681","DOI":"10.1002\/anie.202300681","article-title":"Rational Design in Photopharmacology with Molecular Photoswitches","volume":"62","author":"Kobauri","year":"2023","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/cptc.202000119","article-title":"Photopharmacology on Acetylcholinesterase: Novel Photoswitchable Inhibitors with Improved Pharmacological Profiles","volume":"5","author":"Scheiner","year":"2020","journal-title":"ChemPhotoChem"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1021\/cn500016p","article-title":"Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of \u03b2-Amyloid Aggregation","volume":"5","author":"Chen","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.fmre.2024.04.021","article-title":"Role of artificial intelligence in revolutionizing drug discovery","volume":"5","author":"Rehman","year":"2025","journal-title":"Fundam. Res."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Reynoso-Garc\u00eda, M.F., Nicol\u00e1s-\u00c1lvarez, D.E., Tenorio-Barajas, A.Y., and Reyes-Chaparro, A. (2025). Structural Bioinformatics Applied to Acetylcholinesterase Enzyme Inhibition. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26083781"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.1021\/acs.jmedchem.4c01257","article-title":"Artificial Intelligence in Natural Product Drug Discovery: Current Applications and Future Perspectives","volume":"68","author":"Gangwal","year":"2025","journal-title":"J. Med. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1177\/0394632015588765","article-title":"Current insights into computer-aided immunotherapeutic design strategies","volume":"28","author":"Cai","year":"2015","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1039\/D4SC06762B","article-title":"Multi-target-directed therapeutic strategies for Alzheimer\u2019s disease: Controlling amyloid-\u03b2 aggregation, metal ion homeostasis, and enzyme inhibition","volume":"16","author":"Yoo","year":"2025","journal-title":"Chem. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Giorgetti, S., Greco, C., Tortora, P., and Aprile, F.A. (2018). Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201808.0155.v1"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e202400277","DOI":"10.1002\/chem.202400277","article-title":"Aggregation Mechanisms and Molecular Structures of Amyloid-\u03b2 in Alzheimer\u2019s Disease","volume":"30","author":"Niu","year":"2024","journal-title":"Chem.\u2013A Eur. J."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Makhaeva, G.F., Kovaleva, N.V., Rudakova, E.V., Boltneva, N.P., Lushchekina, S.V., Astakhova, T.Y., Timokhina, E.N., Serebryakova, O.G., Shchepochkin, A.V., and Averkov, M.A. (2023). Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit \u03b2-amyloid self-aggregation: Potential therapeutic agents for Alzheimer\u2019s disease. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1219980"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ejmech.2018.05.057","article-title":"Rational design of carbamate-based dual binding site and central AChE inhibitors by a \u201cbiooxidisable\u201d prodrug approach: Synthesis, in vitro evaluation and docking studies","volume":"155","author":"Gembus","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/ardp.201500117","article-title":"Multiple Ligands Targeting Cholinesterases and \u03b2-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore","volume":"348","author":"Bajda","year":"2015","journal-title":"Arch. Pharm."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4784","DOI":"10.1016\/j.bmc.2014.06.057","article-title":"Syntheses of coumarin\u2013tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, A\u03b2 aggregation, and \u03b2-secretase","volume":"22","author":"Sun","year":"2014","journal-title":"Bioorganic Med. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Gupta, S., and Mohan, C.G. (2014). Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening. BioMed Res. Int., 2014.","DOI":"10.1155\/2014\/291214"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e202300461","DOI":"10.1002\/slct.202300461","article-title":"Enhancing the Therapeutic Effect in Alzheimer\u2019s Disease Drugs: The role of Polypharmacology and Cholinesterase inhibitors","volume":"8","author":"Martins","year":"2023","journal-title":"ChemistrySelect"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-60761-244-5_3","article-title":"X-ray crystallography in drug discovery","volume":"Volume 572","author":"Carvalho","year":"2009","journal-title":"Methods in Molecular Biology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1080\/17460441.2023.2246881","article-title":"The current role and evolution of X-ray crystallography in drug discovery and development","volume":"18","author":"Bijak","year":"2023","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s41745-017-0026-4","article-title":"X-Ray Crystallography and its Role in Understanding the Physicochemical Properties of Pharmaceutical Cocrystals","volume":"97","author":"Aitipamula","year":"2017","journal-title":"J. Indian Inst. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"127524","DOI":"10.1016\/j.bmcl.2020.127524","article-title":"Cryo-EM as a powerful tool for drug discovery","volume":"30","author":"Drie","year":"2020","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1111\/jnc.15245","article-title":"Cryo-electron microscopy of cholinesterases, present and future","volume":"158","author":"Leung","year":"2020","journal-title":"J. Neurochem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1080\/10408347.2014.881250","article-title":"Surface plasmon resonance (SPR) biosensors in pharmaceutical analysis","volume":"45","author":"Olaru","year":"2015","journal-title":"Crit. Rev. Anal. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"100414","DOI":"10.1016\/j.chphi.2023.100414","article-title":"Optimizing drug discovery: Surface plasmon resonance techniques and their multifaceted applications","volume":"8","author":"Acharya","year":"2024","journal-title":"Chem. Phys. Impact"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"123063","DOI":"10.1016\/j.ijpharm.2023.123063","article-title":"Isothermal titration calorimetry (ITC) as a promising tool in pharmaceutical nanotechnology","volume":"641","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0079-6468(08)70097-3","article-title":"7 Isothermal titration calorimetry in drug discovery","volume":"38","author":"Ward","year":"2001","journal-title":"Prog. Med. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ymeth.2024.03.007","article-title":"Isothermal titration calorimetry and surface plasmon resonance methods to probe protein-protein interactions","volume":"225","author":"Upadhyay","year":"2024","journal-title":"Methods"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Siavashy, S., Soltani, M., Rahimi, S., Hosseinali, M., Guilandokht, Z., and Raahemifar, K. (2024). Recent advancements in microfluidic-based biosensors for detection of genes and proteins: Applications and techniques. Biosens. Bioelectron. X, 19.","DOI":"10.1016\/j.biosx.2024.100489"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1080\/10717544.2022.2069878","article-title":"Merits and advances of microfluidics in the pharmaceutical field: Design technologies and future prospects","volume":"29","author":"Maged","year":"2022","journal-title":"Drug Deliv."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-0716-4530-7_1","article-title":"Cell-Based Assays Using Derived Human-Induced Pluripotent Cells in Drug Discovery and Development","volume":"Volume 2924","author":"Ross","year":"2025","journal-title":"Methods in Molecular Biology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41392-024-01809-0","article-title":"Induced pluripotent stem cells (iPSCs): Molecular mechanisms of induction and applications","volume":"9","author":"Cerneckis","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41392-023-01481-w","article-title":"The blood\u2013brain barrier: Structure, regulation and drug delivery","volume":"8","author":"Wu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2472555218799713","article-title":"Screening Strategies and Methods for Better Off-Target Liability Prediction and Identification of Small-Molecule Pharmaceuticals","volume":"24","author":"Vleet","year":"2019","journal-title":"SLAS Discov."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2133\/dmpk.DMPK-10-RV-062","article-title":"Mechanisms of Drug Toxicity and Relevance to Pharmaceutical Development","volume":"26","author":"Guengerich","year":"2011","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Crucitti, D., P\u00e9rez M\u00edguez, C., D\u00edaz Arias, J.\u00c1., Fernandez Prada, D.B., and Mosquera Orgueira, A. (2024). De novo drug design through artificial intelligence: An introduction. Front. Hematol., 3.","DOI":"10.3389\/frhem.2024.1305741"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Mouchlis, V.D., Afantitis, A., Serra, A., Fratello, M., Papadiamantis, A.G., Aidinis, V., Lynch, I., Greco, D., and Melagraki, G. (2021). Advances in De Novo Drug Design: From Conventional to Machine Learning Methods. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041676"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jsps.2011.04.001","article-title":"Nanoparticles: Emerging carriers for drug delivery","volume":"19","author":"Mudshinge","year":"2011","journal-title":"Saudi Pharm. J."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Dhiman, N., Awasthi, R., Sharma, B., Kharkwal, H., and Kulkarni, G.T. (2021). Lipid Nanoparticles as Carriers for Bioactive Delivery. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.580118"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.3390\/cancers5031020","article-title":"Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?","volume":"5","author":"Wauthoz","year":"2013","journal-title":"Cancers"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8726\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:41:36Z","timestamp":1760035296000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8726"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,7]]},"references-count":132,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178726"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178726","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,7]]}}}