{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T08:44:27Z","timestamp":1762073067125,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Slovenian Research Agency ARRS","award":["P1-0208"],"award-info":[{"award-number":["P1-0208"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular level. Given the limited therapeutic success of approved drugs, it is imperative to explore rationally supported therapeutic approaches to combat this disease. The search for novel scaffolds that bind to different receptors and inhibit AD disease-related enzymes could lead to new therapeutic solutions. Here, we describe N-hydroxy-N-propargylamide hybrids 1\u20136, which were designed by combining the structures of Contilisant\u2014a multifunctional anti-AD ligand\u2014and ferulic acid, a natural antioxidant with various other biological activities. Among the synthesized compounds, we identified compound 4 as a micromolar inhibitor of hAChE with a potent radical-scavenging capacity comparable to resveratrol and Trolox. In addition, compound 4 chelated copper(II) ions associated with amyloid \u03b2 pathology, mitochondrial dysfunction, and oxidative stress. The promising in vitro activity combined with favorable drug-like properties and predicted blood-brain barrier permeability make compound 4 a multifunctional ligand that merits further studies at the biochemical and cellular levels.<\/jats:p>","DOI":"10.3390\/molecules27217437","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T03:36:44Z","timestamp":1667360204000},"page":"7437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["N-Hydroxy-N-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1327-1681","authenticated-orcid":false,"given":"\u00d3scar M.","family":"Bautista-Aguilera","sequence":"first","affiliation":[{"name":"Universidad de Alcal\u00e1, Departamento de Qu\u00edmica Org\u00e1nica y Qu\u00edmica Inorg\u00e1nica, Ctra, Madrid-Barcelona Km 33.6, 28871 Alcal\u00e1 de Henares, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 M.","family":"Alonso","sequence":"additional","affiliation":[{"name":"Universidad de Alcal\u00e1, Departamento de Qu\u00edmica Org\u00e1nica y Qu\u00edmica Inorg\u00e1nica, Ctra, Madrid-Barcelona Km 33.6, 28871 Alcal\u00e1 de Henares, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8411-304X","authenticated-orcid":false,"given":"Marco","family":"Catto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3475-9624","authenticated-orcid":false,"given":"Isabel","family":"Iriepa","sequence":"additional","affiliation":[{"name":"Universidad de Alcal\u00e1, Departamento de Qu\u00edmica Org\u00e1nica y Qu\u00edmica Inorg\u00e1nica, Ctra, Madrid-Barcelona Km 33.6, 28871 Alcal\u00e1 de Henares, Madrid, Spain"},{"name":"Institute of Chemical Research Andr\u00e9s M. del R\u00edo, Alcal\u00e1 University, 28805 Alcal\u00e1 de Henares, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9917-1384","authenticated-orcid":false,"given":"Damijan","family":"Knez","sequence":"additional","affiliation":[{"name":"University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-3083","authenticated-orcid":false,"given":"Stanislav","family":"Gobec","sequence":"additional","affiliation":[{"name":"University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Marco-Contelles","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (IQOG, CSIC), C\/Juan de la Cierva 3, 28006 Madrid, Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.bioorg.2018.04.008","article-title":"Norditerpenoid alkaloids of Delphinium denudatum as cholinesterase inhibitors","volume":"78","author":"Ahmad","year":"2018","journal-title":"Bioorg. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1021\/acschemneuro.5b00313","article-title":"TREM2 Function in Alzheimer\u2019s disease and neurodegeneration","volume":"7","author":"Ulrich","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/s13054-019-2580-9","article-title":"Effect of dementia on the incidence, short-term outcomes, and resource utilization of invasive mechanical ventilation in the elderly: A nationwide population-based study","volume":"23","author":"Bouza","year":"2019","journal-title":"Crit. Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1007\/s007020200083","article-title":"The cholinergic pathology in Alzheimer\u2019s disease-discrepancies between clinical experience and pathophysiological findings","volume":"109","year":"2002","journal-title":"J. Neural Transm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.2174\/092986710791111206","article-title":"Tacrine derivatives and Alzheimer\u2019s disease","volume":"17","author":"Tumiatti","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1021\/jm400970m","article-title":"Oxidative stress in Alzheimer\u2019s disease: Are we connecting the dots?","volume":"57","author":"Rosini","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3233\/JAD-2008-15208","article-title":"Drug development based on the metals hypothesis of Alzheimer\u2019s disease","volume":"15","author":"Bush","year":"2008","journal-title":"J. Alzheimers Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta16210","article-title":"The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer\u2019s disease (review of Technology Appraisal No. 111): A systematic review and economic model","volume":"16","author":"Bond","year":"2012","journal-title":"Health Technol. Assess."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1517\/13543784.16.12.1987","article-title":"An update on the pharmacology of galantamine","volume":"16","author":"Villarroya","year":"2007","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1159\/000353801","article-title":"Memantine in patients with moderate to severe Alzheimer\u2019s disease: Meta-analyses using realistic definitions of response","volume":"37","author":"Wilkinson","year":"2014","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101957","DOI":"10.1016\/j.jchemneu.2021.101957","article-title":"The role of monoamine oxidase Enzymes in the pathophysiology of neurological disorders","volume":"114","author":"Jones","year":"2021","journal-title":"J. Chem. Neuroanat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"112787","DOI":"10.1016\/j.ejmech.2020.112787","article-title":"A Comprehensive review of monoamine oxidase inhibitors as anti-Alzheimer\u2019s disease agents: A review","volume":"206","author":"Manzoor","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1001\/jama.2019.22360","article-title":"Diagnosis and treatment of Parkinson disease: A review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1007\/s13311-021-01097-4","article-title":"KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson\u2019s disease","volume":"18","author":"Nam","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ejmech.2012.03.022","article-title":"Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer\u2019s disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine","volume":"52","author":"Samadi","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6937","DOI":"10.1021\/acs.jmedchem.8b00848","article-title":"Contilisant, a tetratarget small molecule for Alzheimer\u2019s disease therapy combining cholinesterase, monoamine oxidase inhibition, and H3R antagonism with S1R agonism profile","volume":"61","author":"Budni","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"886367","DOI":"10.3389\/fchem.2022.886367","article-title":"From biomass-derived p-hydroxycinnamic acids to novel sustainable and non-toxic phenolics-based UV-filters: A multidisciplinary journey","volume":"10","author":"Rioux","year":"2022","journal-title":"Front. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1002\/cssc.202002141","article-title":"Accessing p-hydroxycinnamic acids: Chemical synthesis, biomass recovery, or engineered microbial production?","volume":"14","author":"Flourat","year":"2021","journal-title":"ChemSusChem"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113278","DOI":"10.1016\/j.ejmech.2021.113278","article-title":"A review on ferulic acid and analogs based scaffolds for the management of Alzheimer\u2019s disease","volume":"215","author":"Singh","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"776","DOI":"10.2174\/1389557515666150522102545","article-title":"Ferulic acid and Alzheimer\u2019s disease: Promises and pitfalls","volume":"15","author":"Nabavi","year":"2015","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1248\/bpb.b18-00661","article-title":"A new series of salicylic acid derivatives as non-saccharide \u03b1-glucosidase inhibitors and antioxidants","volume":"42","author":"Chen","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1039\/c3ob00043e","article-title":"N-terminal dual protein functionalization by strain-promoted alkyne-nitrone cycloaddition","volume":"11","author":"Temming","year":"2013","journal-title":"Org. Biomol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.ejps.2017.08.004","article-title":"Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone: A water-soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity","volume":"109","author":"Pisani","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1021\/ja993663t","article-title":"Prediction of properties from simulations: Free energies of solvation in hexadecane, octanol, and water","volume":"122","author":"Duffy","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/S0960-894X(00)00172-4","article-title":"Prediction of drug solubility from Monte Carlo simulations","volume":"10","author":"Jorgensen","year":"2000","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_29","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_30","doi-asserted-by":"crossref","first-page":"101271","DOI":"10.1016\/j.arr.2021.101271","article-title":"The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer\u2019s disease pathology: From antioxidant to epigenetic therapy","volume":"67","author":"Izquierdo","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12295","DOI":"10.1002\/trc2.12295","article-title":"Alzheimer\u2019s disease drug development pipeline: 2022","volume":"8","author":"Cummings","year":"2022","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/s13197-011-0251-1","article-title":"Genesis and development of DPPH method of antioxidant assay","volume":"48","author":"Kedare","year":"2011","journal-title":"J. Food Sci. Technol."},{"key":"ref_33","unstructured":"Kumar Maurya, P.K., and Chandra, P. (2017). Hydroxamic acids as potent antioxidants and their methods of evaluation. Oxidative Stress: Diagnostic Methods and Applications in Medical Science, Springer. Chapter 5."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10700","DOI":"10.1021\/jm301411g","article-title":"Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of alzheimer\u2019s disease","volume":"55","author":"Yanovsky","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.3389\/fphar.2018.01247","article-title":"Advances in multi-functional ligands and the need for metal-related pharmacology for the management of alzheimer disease","volume":"9","author":"Sharma","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5160","DOI":"10.1073\/pnas.1916944117","article-title":"Mechanistic approaches for chemically modifying the coordination sphere of copper-amyloid-\u03b2 complexes","volume":"117","author":"Han","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1021\/cc030039a","article-title":"Hydroxamate-based iron chelators: Combinatorial syntheses of desferrioxamine b analogs and evaluation of binding affinities","volume":"6","author":"Poreddy","year":"2004","journal-title":"J. Comb. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.ejmech.2018.10.016","article-title":"Investigating alkyl nitrates as nitric oxide releasing precursors of multitarget acetylcholinesterase-monoamine oxidase B inhibitors","volume":"161","author":"Pisani","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: The biomolecular simulation program","volume":"30","author":"Brooks","year":"2009","journal-title":"J. Comp. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.ejmech.2018.06.044","article-title":"Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer\u2019s disease","volume":"155","author":"Chioua","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Diez-Iriepa, D., Iriepa, I., Knez, D., Gobec, S., de los R\u00edos, C., Bravo, I., L\u00f3pez-Mu\u00f1oz, F., Marco-Contelles, J., and Hadjipavlou-Litina, D. (2022). Polyfunctionalized \u03b1-phenyl-tert-buty(benzyl)lnitrones: Multifunctional antioxidants for stroke treatment. Antioxidants, 11.","DOI":"10.3390\/antiox11091735"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4442","DOI":"10.1016\/j.bmc.2015.06.010","article-title":"Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents","volume":"23","author":"Knez","year":"2015","journal-title":"Bioorg. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7437\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:08:59Z","timestamp":1760144939000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,1]]},"references-count":42,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["molecules27217437"],"URL":"https:\/\/doi.org\/10.3390\/molecules27217437","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2022,11,1]]}}}