{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:58:59Z","timestamp":1785560339410,"version":"3.56.0"},"reference-count":72,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003336","name":"Bulgarian National Science Fund","doi-asserted-by":"crossref","award":["KP-06-N63\/11"],"award-info":[{"award-number":["KP-06-N63\/11"]}],"id":[{"id":"10.13039\/501100003336","id-type":"DOI","asserted-by":"crossref"}]},{"award":["KP-06-N63\/11"],"award-info":[{"award-number":["KP-06-N63\/11"]}],"id":[{"id":"https:\/\/ror.org\/05eg49r29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a multifactorial neurodegenerative disorder that requires therapeutic agents capable of targeting multiple pathological pathways. In this study, a series of cannabidiol (CBD)-like hydrazone derivatives (3a\u2013i) was synthesized and characterized by NMR, HRMS, and single-crystal X-ray diffraction for compound 3i. In silico ADME analysis predicted favorable drug-like properties, including compliance with Lipinski\u2019s Rule of Five, oral bioavailability, and blood\u2013brain barrier permeability. The compounds were evaluated for cholinesterase inhibition, antioxidant activity, cytotoxicity in neuronal cell lines, and binding interactions with human butyrylcholinesterase (hBChE) by molecular docking. Biological evaluation revealed a marked preference for BChE over acetylcholinesterase (AChE). Compound 3f was the most potent BChE inhibitor (IC50 = 1.67 \u00b1 0.11 \u03bcM), while compounds 3b and 3f demonstrated high selectivity toward BChE. Antioxidant assays (DPPH, ABTS, FRAP, and FTC) indicated moderate, mechanism-dependent activity. Compounds 3b and 3e showed the strongest ABTS radical-scavenging effects, whereas compounds 3b and 3f provided the greatest protection against lipid peroxidation, surpassing CBD under the tested conditions. Several derivatives, particularly 3a, 3b, 3f, 3h, and 3i, exhibited favorable safety profiles in SH-SY5Y and Neuro-2a cells. Molecular docking supported the experimental findings. Overall, compounds 3b and 3f emerged as promising multifunctional leads for the development of multitarget-directed anti-Alzheimer agents.<\/jats:p>","DOI":"10.3390\/molecules31152657","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:32:13Z","timestamp":1785403933000},"page":"2657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, In Silico and In Vitro Pharmacological Profiling of Cannabidiol-like Synthetic Analogues as Multi-Target Anti-Alzheimer\u2019s Agents"],"prefix":"10.3390","volume":"31","author":[{"given":"Boris P.","family":"Stoyanov","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7255-7965","authenticated-orcid":false,"given":"Borislav","family":"Georgiev","sequence":"additional","affiliation":[{"name":"Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6859-9369","authenticated-orcid":false,"given":"Denitsa","family":"Stefanova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Tzankova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Kalcheva-Yovkova","sequence":"additional","affiliation":[{"name":"Faculty of Computer Systems and Technologies, Technical University\u2013Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8781-2866","authenticated-orcid":false,"given":"Nikolay","family":"Vassilev","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miroslav","family":"Rangelov","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7195-195X","authenticated-orcid":false,"given":"Nadezhda","family":"Todorova","sequence":"additional","affiliation":[{"name":"Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1952-9903","authenticated-orcid":false,"given":"Dimitrina","family":"Zheleva-Dimitrova","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8765-6536","authenticated-orcid":false,"given":"Boris","family":"Shivachev","sequence":"additional","affiliation":[{"name":"Institute of Mineralogy and Crystallography \u201cAcad. Ivan Kostov\u201d, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6415-7336","authenticated-orcid":false,"given":"Violina T.","family":"Angelova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bertoni, G., Ristori, S., and Monti, D. (2026). Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications. Cells, 15.","DOI":"10.3390\/cells15080657"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"111375","DOI":"10.1016\/j.pnpbp.2025.111375","article-title":"Neuroadaptation in neurodegenerative diseases: Compensatory mechanisms and therapeutic approaches","volume":"139","author":"Kopalli","year":"2025","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1002\/med.70047","article-title":"Multi-Targeting Ligands as Prospective Therapeutics for Alzheimer\u2019s Disease, a Prevalent Neurodegenerative Disorder: Mechanistic Insights, Emerging Targets and Drug Discovery Campaigns","volume":"46","author":"Thakur","year":"2026","journal-title":"Med. Res. Rev."},{"key":"ref_5","unstructured":"Padda, I.S., and Parmar, M. (2024). Aducanumab. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in early Alzheimer\u2019s disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_7","unstructured":"Sims, J.R. (2023). Donanemab in Early Symptomatic Alzheimer\u2019s Disease: Efficacy Results from TRAILBLAZER-ALZ 2. Proceedings of the Alzheimer\u2019s Association International Conference, Alzheimer\u2019s Disease Association."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1001\/jama.2023.11704","article-title":"Donanemab for Alzheimer disease\u2014Who benefits and who is harmed?","volume":"330","author":"Manly","year":"2023","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1080\/14737175.2025.2546868","article-title":"Donanemab for Alzheimer\u2019s disease: From preclinical research to the clinical application","volume":"25","author":"Dodel","year":"2025","journal-title":"Expert Rev. Neurother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1001\/jamaneurol.2022.0315","article-title":"Cost-effectiveness of aducanumab and donanemab for early Alzheimer disease in the US","volume":"79","author":"Ross","year":"2022","journal-title":"JAMA Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3174\/ajnr.A8469","article-title":"Alzheimer disease anti-amyloid immunotherapies: Imaging recommendations and practice considerations for monitoring of amyloid-related imaging abnormalities","volume":"46","author":"Cogswell","year":"2025","journal-title":"Am. J. Neuroradiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107152","DOI":"10.1016\/j.bioorg.2024.107152","article-title":"A comprehensive review of multi-target directed ligands in the treatment of Alzheimer\u2019s disease","volume":"144","author":"Pathak","year":"2024","journal-title":"Bioorganic Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1177\/25424823241284464","article-title":"A systematic study of molecular targets of cannabidiol in Alzheimer\u2019s disease","volume":"8","author":"Patil","year":"2024","journal-title":"J. Alzheimer\u2019s Dis. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1089\/can.2016.0034","article-title":"An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies","volume":"2","author":"Iffland","year":"2017","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tian, L., Zhang, B., Yang, X., Zhai, X., Gao, Y., Zhang, Y., Xie, X., Zhang, D., and Liang, C. (2026). Potential Therapeutic Strategy for Neurodegenerative Disorders: Insights from Natural Cannabis Compounds and Analogues. Biomedical Imaging in Neurodegeneration, Springer.","DOI":"10.1007\/978-3-031-95878-6_11"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dagla, I., Gkikas, F., Gikas, E., and Tsarbopoulos, A. (2026). Targeting Amyloid Beta Aggregation and Neuroinflammation in Alzheimer\u2019s Disease: Advances and Future Directions. Cells, 15.","DOI":"10.3390\/cells15030295"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1007\/s11011-026-01894-w","article-title":"Cannabidiol attenuates tau hyperphosphorylation and cognitive deficits in an experimental model of Alzheimer\u2019s disease and is associated with restoration of PP2A expression","volume":"41","author":"Sura","year":"2026","journal-title":"Metab. Brain Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"104051","DOI":"10.1016\/j.redox.2026.104051","article-title":"The Dual Roles of Natural Cannabidiol in Combating Oxidative Stress and Inflammation: A Potential Intestinal Guardian","volume":"91","author":"Lv","year":"2026","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jorgovan, M., Maksimovi\u0107, T., B\u0103tr\u00eena, O., \u0218oica, C., Mioc, A., and Mioc, M. (2026). The Therapeutic Crossroad Between Mitochondria and Cannabidiol: A Mini-Review. Biology, 15.","DOI":"10.3390\/biology15060510"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1002\/bcp.70430","article-title":"Cannabinoids and drug\u2013drug pharmacokinetic interactions: Deciphering the risks","volume":"92","author":"Papakyriakopoulou","year":"2026","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1124\/dmd.123.001435","article-title":"Advances and challenges in modeling cannabidiol pharmacokinetics and hepatotoxicity","volume":"52","author":"Beers","year":"2024","journal-title":"Drug Metab. Dispos."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e00682","DOI":"10.1002\/prp2.682","article-title":"Diversity of molecular targets and signaling pathways for CBD","volume":"8","author":"Devi","year":"2020","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Martinez Naya, N., Kelly, J., Corna, G., Golino, M., Polizio, A.H., Abbate, A., Toldo, S., and Mezzaroma, E. (2024). An overview of cannabidiol as a multifunctional drug: Pharmacokinetics and cellular effects. Molecules, 29.","DOI":"10.3390\/molecules29020473"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s11064-026-04737-3","article-title":"Senescence as a Central Node in Alzheimer\u2019s Disease: Molecular Triggers, Cellular Effectors, and RNA-Based Interventions","volume":"51","author":"Some","year":"2026","journal-title":"Neurochem. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100575","DOI":"10.1016\/j.cotox.2026.100575","article-title":"Effect of cannabidiol on traumatic brain injury related neuronal damage pathways: Brain injury and cannabidiol","volume":"46","author":"Engin","year":"2026","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chan, J.Z., and Duncan, R.E. (2021). Regulatory effects of cannabidiol on mitochondrial functions: A review. Cells, 10.","DOI":"10.3390\/cells10051251"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110995","DOI":"10.1016\/j.cbi.2024.110995","article-title":"Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells","volume":"394","author":"Kim","year":"2024","journal-title":"Chem.-Biol. Interact."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Schouten, M., Dalle, S., Mantini, D., and Koppo, K. (2024). Cannabidiol and brain function: Current knowledge and future perspectives. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1328885"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"174829","DOI":"10.1016\/j.ejphar.2022.174829","article-title":"Cannabidiol protects against Alzheimer\u2019s disease in C. elegans via ROS scavenging activity of its phenolic hydroxyl groups","volume":"919","author":"Zhang","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/toxres\/tfaa021","article-title":"Cannabidiol attenuates methamphetamine-induced conditioned place preference via the Sigma1R\/AKT\/GSK-3\u03b2\/CREB signaling pathway in rats","volume":"9","author":"Yang","year":"2020","journal-title":"Toxicol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s12640-025-00729-3","article-title":"Cannabidiol-induced autophagy ameliorates tau protein clearance","volume":"43","author":"Vrechi","year":"2025","journal-title":"Neurotox. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1177\/13872877251386440","article-title":"Exploring multitarget molecular mechanisms of cannabidiol in Alzheimer\u2019s disease treatment using molecular simulations and modeling","volume":"108","author":"Bi","year":"2025","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ben-Shabat, S., Yarmolinsky, L., Sharon, N., Zeadnaa-Aldda, T., Dayan, S., Khalfin, B., and Fleisher-Berkovich, S. (2026). Cannabinoids, the Blood\u2013Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives. Biomolecules, 16.","DOI":"10.3390\/biom16020225"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"111653","DOI":"10.1016\/j.cellsig.2025.111653","article-title":"The role of cannabinoid-mediated signaling pathways and mechanisms in brain disorders","volume":"128","author":"Liu","year":"2025","journal-title":"Cell. Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1021\/acschemneuro.5c01009","article-title":"Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice","volume":"17","author":"Chaulagain","year":"2026","journal-title":"ACS Chem. Neurosci."},{"key":"ref_36","unstructured":"Sackinger, E.P. (2024). Cannabidiol Effects on NMDA and AMPA Receptor Activity and Cognitive Function at a High Dose in 5xFAD Mice. [Master\u2019s Thesis, Oregon State University]."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s40263-020-00741-5","article-title":"Critical aspects affecting cannabidiol oral bioavailability and metabolic elimination, and related clinical implications","volume":"34","author":"Perucca","year":"2020","journal-title":"CNS Drugs"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hossain, K.R., Alghalayini, A., and Valenzuela, S.M. (2023). Current challenges and opportunities for improved cannabidiol solubility. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914514"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"113799","DOI":"10.1016\/j.fct.2023.113799","article-title":"Review of the oral toxicity of cannabidiol (CBD)","volume":"176","author":"Gingrich","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s42238-024-00239-7","article-title":"Cannabinoid spoilage, metabolism and cannabidiol (CBD) conversion to Tetrahydrocannabinol (THC) mechanisms with energetic parameters","volume":"7","author":"Henriques","year":"2025","journal-title":"J. Cannabis Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.22159\/ijpps.2025v17i2.52596","article-title":"Novel heterocyclic hybrids as promising scaffold for the management of Alzheimer\u2019s disease","volume":"17","author":"Alka","year":"2025","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Angelova, V.T., Stoyanov, B.P., and Simeonova, R. (2024). New insights into the development of donepezil-based hybrid and natural molecules as multi-target drug agents for Alzheimer\u2019s disease treatment. Molecules, 29.","DOI":"10.3390\/molecules29225314"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.1007\/s12035-022-02779-6","article-title":"Molecular insights into therapeutic potentials of hybrid compounds targeting Alzheimer\u2019s disease","volume":"59","author":"Jana","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"348","DOI":"10.2174\/1385272823666191021124443","article-title":"Molecular hybridization as a tool in the design of multi-target directed drug candidates for neurodegenerative diseases","volume":"18","author":"Gontijo","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e202501097","DOI":"10.1002\/cmdc.202501097","article-title":"Exploring the Hydrazone Group in Multifunctional Approaches for Alzheimer\u2019s Disease Therapy","volume":"21","author":"Grondona","year":"2026","journal-title":"ChemMedChem"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Found. Crystallogr."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Angelova, V.T., Georgiev, B., Pencheva, T., Pajeva, I., Rangelov, M., Todorova, N., Zheleva-Dimitrova, D., Kalcheva-Yovkova, E., Valkova, I.V., and Vassilev, N. (2023). Design, synthesis, in silico studies and in vitro evaluation of new indole-and\/or donepezil-like hybrids as multitarget-directed agents for Alzheimer\u2019s disease. Pharmaceuticals, 16.","DOI":"10.3390\/ph16091194"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"de Souza, M.L., de Paiva, J.P.B., Franco, G.d.R.R., Gontijo, V.S., Alves, M.A., de Souza, H.M.R., Lontra, A.C.P., de Oliveira, E.A., Giorno, T.B.S., and Guedes, I.A. (2025). Design, Synthesis, and Evaluation of Antinociceptive Properties of Novel CBD-Based Terpene-Cinnamoyl-Acyl-Hydrazone Analogues. Pharmaceuticals, 18.","DOI":"10.20944\/preprints202504.2053.v1"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.1039\/D6MD00185H","article-title":"New terpenyl\u2013cinnamoyl\u2013hydrazone analogues of cannabidiol with potent antinociceptive effect","volume":"17","author":"Lontra","year":"2026","journal-title":"RSC Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"118925","DOI":"10.1016\/j.biopha.2025.118925","article-title":"Pharmacological characterization of the anti-nociceptive and anti-inflammatory effects of new CBD-based terpenyl-N-acyl-aryl-hydrazone analogues","volume":"194","author":"Lontra","year":"2026","journal-title":"Biomed. Pharmacother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1080\/17568919.2025.2515821","article-title":"New cannabidiol structure-related terpene N-acyl-hydrazones with potent antinociceptive and anti-inflammatory activity","volume":"17","author":"Fernandes","year":"2025","journal-title":"Future Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103187","DOI":"10.1016\/j.arr.2026.103187","article-title":"Revisiting butyrylcholinesterase in Alzheimer\u2019s disease: A hub linking cholinergic, metabolic and affective pathways","volume":"119","author":"Svobodova","year":"2026","journal-title":"Ageing Res. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/13543776.2025.2602702","article-title":"An updated patent review of acetylcholinesterase inhibitors for the treatment of alzheimer\u2019s disease (2021\u2013present)","volume":"36","author":"Begines","year":"2026","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s42238-026-00403-1","article-title":"Design, synthesis, and biological profiling of fluorinated cannabidiol and cannabigerol derivatives as promising therapeutic agents","volume":"8","author":"Bege","year":"2026","journal-title":"J. Cannabis Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2623314","DOI":"10.1080\/14756366.2026.2623314","article-title":"Thymol carbamates bearing cyclic amines as potent and selective BuChE inhibitors alleviate memory impairments for Alzheimer\u2019s disease therapy","volume":"41","author":"Wu","year":"2026","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Abdallah, R.M., Hasan, H.E., and Hammad, A. (2024). Predictive modeling of skin permeability for molecules: Investigating FDA-approved drug permeability with various AI algorithms. PLoS Digit. Health, 3.","DOI":"10.1371\/journal.pdig.0000483"},{"key":"ref_58","first-page":"81","article-title":"Potential multitarget inhibitor discovery for breast cancer (TNBC\/IBC) from HDAC6 inhibitors: In silico approaches from experimental data","volume":"10","author":"Ertik","year":"2026","journal-title":"Turk. Comput. Theor. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"pbaf004","DOI":"10.1093\/pcmedi\/pbaf004","article-title":"Precision medication based on the evaluation of drug metabolizing enzyme and transporter functions","volume":"8","author":"Ma","year":"2025","journal-title":"Precis. Clin. Med."},{"key":"ref_60","first-page":"90145","article-title":"Andres, RM Featherstone","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1016\/S0024-3205(02)02034-9","article-title":"Acetylcholinesterase inhibitory activity of some Amaryllidaceae alkaloids and Narcissus extracts","volume":"71","author":"Bastida","year":"2002","journal-title":"Life Sci."},{"key":"ref_62","first-page":"111809","article-title":"Genetic and functional dynamics of Butyrylcholinesterase in Alzheimer\u2019s disease: From mechanisms to clinical relevance","volume":"423","author":"Bavec","year":"2025","journal-title":"Chem.-Biol. Interact."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Gambardella, M.D., Wang, Y., and Pang, J. (2025). The Selectivity of Butyrylcholinesterase Inhibitors Revisited. Molecules, 30.","DOI":"10.3390\/molecules30214201"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"116569","DOI":"10.1016\/j.ejmech.2024.116569","article-title":"New insights into butyrylcholinesterase: Pharmaceutical applications, selective inhibitors and multitarget-directed ligands","volume":"275","author":"Sun","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease","volume":"20","author":"Butterfield","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Plascencia-Villa, G., and Perry, G. (2023). Roles of oxidative stress in synaptic dysfunction and neuronal cell death in Alzheimer\u2019s disease. Antioxidants, 12.","DOI":"10.3390\/antiox12081628"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Xiao, X., Yan, X., Liang, C., and Yang, Y. (2026). Metabolic dysfunction and mitochondrial failure in Alzheimer\u2019s disease: Integrating pathophysiology, clinical evidence and emerging interventions. Front. Neurol., 17.","DOI":"10.3389\/fneur.2026.1772036"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"21978","DOI":"10.1021\/acs.est.5c05017","article-title":"Dual roles of phenolic groups in pyrogenic carbon as mediators and quenchers for hydroxyl radical production","volume":"59","author":"Nie","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"7416","DOI":"10.1021\/jo00078a020","article-title":"Chain-breaking phenolic antioxidants: Steric and electronic effects in polyalkylchromanols, tocopherol analogs, hydroquinones, and superior antioxidants of the polyalkylbenzochromanol and naphthofuran class","volume":"58","author":"Barclay","year":"1993","journal-title":"J. Org. Chem."},{"key":"ref_70","unstructured":"Bruker, A. (2009). Saint. SADABS, Bruker AXS Inc."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.phytol.2017.03.005","article-title":"In Vitro Enzyme Inhibitory Properties, Antioxidant Activities, and Phytochemical Profile of Potentilla Thuringiaca","volume":"20","author":"Grochowski","year":"2017","journal-title":"Phytochem. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1271\/bbb.58.1780","article-title":"A simple screening method for antioxidants and isolation of several antioxidants produced by marine bacteria from fish and shellfish","volume":"58","author":"Takao","year":"1994","journal-title":"Biosci. Biotechnol. Biochem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2657\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:27:48Z","timestamp":1785558468000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2657"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":72,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31152657"],"URL":"https:\/\/doi.org\/10.3390\/molecules31152657","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}