{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T15:58:18Z","timestamp":1776873498240,"version":"3.51.2"},"reference-count":83,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T00:00:00Z","timestamp":1608595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009553","name":"Agentura Pro Zdravotnick\u00fd V\u00fdzkum \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["NU20-08-00296"],"award-info":[{"award-number":["NU20-08-00296"]}],"id":[{"id":"10.13039\/501100009553","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Faculty of Military Health Sciences, University of Defence","award":["FVZ201803"],"award-info":[{"award-number":["FVZ201803"]}]},{"name":"Faculty of Military Health Sciences, University of Defence","award":["Long-term development plan"],"award-info":[{"award-number":["Long-term development plan"]}]},{"name":"MH CZ - DRO","award":["00179906"],"award-info":[{"award-number":["00179906"]}]},{"name":"European Regional Development Fund: Project &quot;PharmaBrain&quot;","award":["CZ.02.1.01\/0.0\/0.0\/16_025\/0007444"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/16_025\/0007444"]}]},{"name":"&quot;e-Infrastruktura CZ&quot;","award":["INFRA LM2018140"],"award-info":[{"award-number":["INFRA LM2018140"]}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["SVV 260 547"],"award-info":[{"award-number":["SVV 260 547"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood\u2013brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1\/GluN2A and GluN1\/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.<\/jats:p>","DOI":"10.3390\/biom11010003","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T12:42:28Z","timestamp":1608640948000},"page":"3","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Pursuing the Complexity of Alzheimer\u2019s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists"],"prefix":"10.3390","volume":"11","author":[{"given":"Jan","family":"Konecny","sequence":"first","affiliation":[{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"},{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Misiachna","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"},{"name":"Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"},{"name":"Department of Physiology, Faculty of Science, Charles University in Prague, Albertov 6, 128 43 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9428-4109","authenticated-orcid":false,"given":"Martina","family":"Hrabinova","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"},{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lenka","family":"Pulkrabkova","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"},{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marketa","family":"Benkova","sequence":"additional","affiliation":[{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukas","family":"Prchal","sequence":"additional","affiliation":[{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-1738","authenticated-orcid":false,"given":"Tomas","family":"Kucera","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"},{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tereza","family":"Kobrlova","sequence":"additional","affiliation":[{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Finger","sequence":"additional","affiliation":[{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"},{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marharyta","family":"Kolcheva","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"},{"name":"Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stepan","family":"Kortus","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"},{"name":"Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0882-6304","authenticated-orcid":false,"given":"Daniel","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"},{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian","family":"Valko","sequence":"additional","affiliation":[{"name":"Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Horak","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"},{"name":"Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6376-8701","authenticated-orcid":false,"given":"Ondrej","family":"Soukup","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"},{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6977-7596","authenticated-orcid":false,"given":"Jan","family":"Korabecny","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic"},{"name":"Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1016\/S0140-6736(05)67889-0","article-title":"Global Prevalence of Dementia: A Delphi Consensus Study","volume":"366","author":"Ferri","year":"2005","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1017\/S135561771700100X","article-title":"Alzheimer\u2019s Disease: Past, Present, and Future","volume":"23","author":"Bondi","year":"2017","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"748212","DOI":"10.1155\/2015\/748212","article-title":"Working Memory and Executive Function Decline across Normal Aging, Mild Cognitive Impairment, and Alzheimer\u2019s Disease","volume":"2015","author":"Kirova","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.jalz.2011.05.2410","article-title":"Neuropsychiatric Symptoms in Alzheimer\u2019s Disease","volume":"7","author":"Lyketsos","year":"2011","journal-title":"Alzheimers Dement"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Weller, J., and Budson, A. (2018). Current Understanding of Alzheimer\u2019s Disease Diagnosis and Treatment. F1000Res, 7.","DOI":"10.12688\/f1000research.14506.1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.31887\/DCNS.2000.2.2\/asschachter","article-title":"Alzheimer\u2019s Disease","volume":"2","author":"Schachter","year":"2000","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"(2020). 2020 Alzheimer\u2019s Disease Facts and Figures. Alzheimer\u2019s Dement., 16, 391\u2013460.","DOI":"10.1002\/alz.12068"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"173554","DOI":"10.1016\/j.ejphar.2020.173554","article-title":"Alzheimer\u2019s Disease: Recent Treatment Strategies","volume":"887","author":"Vaz","year":"2020","journal-title":"Eur. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"117996","DOI":"10.1016\/j.lfs.2020.117996","article-title":"Alzheimer\u2019s Disease; a Review of the Pathophysiological Basis and Therapeutic Interventions","volume":"256","author":"Abeysinghe","year":"2020","journal-title":"Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Goedert, M., and Crowther, R.A. (1989). Amyloid Plaques, Neurofibrillary Tangles and Their Relevance for the Study of Alzheimer\u2019s Disease. Neurobiol. Aging, 10.","DOI":"10.1016\/0197-4580(89)90076-6"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1073\/pnas.85.5.1691","article-title":"Distribution of Precursor Amyloid-Beta-Protein Messenger RNA in Human Cerebral Cortex: Relationship to Neurofibrillary Tangles and Neuritic Plaques","volume":"85","author":"Lewis","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1365-2613.2007.00568.x","article-title":"Cleavage and Conformational Changes of Tau Protein Follow Phosphorylation during Alzheimer\u2019s Disease","volume":"89","author":"Mena","year":"2008","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/j.1365-2990.2007.00853.x","article-title":"Conformational Changes and Cleavage of Tau in Pick Bodies Parallel the Early Processing of Tau Found in Alzheimer Pathology","volume":"34","author":"Mena","year":"2008","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/nan.12084","article-title":"Phosphorylation of Tau Protein at Sites Ser(396-404) Is One of the Earliest Events in Alzheimer\u2019s Disease and Down Syndrome","volume":"40","author":"Perry","year":"2014","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/S0140-6736(76)91936-X","article-title":"Selective Loss of Central Cholinergic Neurons in Alzheimer\u2019s Disease","volume":"2","author":"Davies","year":"1976","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0165-0173(96)00009-4","article-title":"Cognitive Functions of Cortical Acetylcholine: Toward a Unifying Hypothesis","volume":"23","author":"Sarter","year":"1997","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1152\/jn.1992.67.5.1230","article-title":"Cholinergic Modulation of Cortical Associative Memory Function","volume":"67","author":"Hasselmo","year":"1992","journal-title":"J. Neurophysiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.3233\/JAD-160763","article-title":"Role of Glutamate and NMDA Receptors in Alzheimer\u2019s Disease","volume":"57","author":"Wang","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative Stress and the Amyloid Beta Peptide in Alzheimer\u2019s Disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/S0891-5849(02)00794-3","article-title":"Lipid Peroxidation and Protein Oxidation in Alzheimer\u2019s Disease Brain: Potential Causes and Consequences Involving Amyloid Beta-Peptide-Associated Free Radical Oxidative Stress","volume":"32","author":"Butterfield","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1126\/science.8073293","article-title":"Rapid Induction of Alzheimer A Beta Amyloid Formation by Zinc","volume":"265","author":"Bush","year":"1994","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1515\/bmc-2016-0029","article-title":"Alzheimer\u2019s Disease as an Inflammatory Disease","volume":"8","author":"Perea","year":"2017","journal-title":"Biomol. Concepts"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"779","DOI":"10.3233\/JAD-180766","article-title":"Treatment Combinations for Alzheimer\u2019s Disease: Current and Future Pharmacotherapy Options","volume":"67","author":"Cummings","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"l6217","DOI":"10.1136\/bmj.l6217","article-title":"Cognitive Symptoms of Alzheimer\u2019s Disease: Clinical Management and Prevention","volume":"367","author":"Joe","year":"2019","journal-title":"BMJ"},{"key":"ref_25","first-page":"759","article-title":"Outcomes of Alzheimer\u2019s Disease Therapy with Acetylcholinesterase Inhibitors and Memantine","volume":"13","author":"Zemek","year":"2014","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1358\/dot.2016.52.4.2479357","article-title":"Memantine and Donepezil: A Fixed Drug Combination for the Treatment of Moderate to Severe Alzheimer\u2019s Dementia","volume":"52","author":"Owen","year":"2016","journal-title":"Drugs Today"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1080\/14656566.2018.1519022","article-title":"An Evaluation of Memantine ER + Donepezil for the Treatment of Alzheimer\u2019s Disease","volume":"19","author":"Calhoun","year":"2018","journal-title":"Expert Opin. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1021\/jm7009364","article-title":"Multi-Target-Directed Ligands to Combat Neurodegenerative Diseases","volume":"51","author":"Cavalli","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.tips.2020.04.008","article-title":"A Perspective on Multi-Target Drugs for Alzheimer\u2019s Disease","volume":"41","author":"Benek","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/alzrt269","article-title":"Alzheimer\u2019s Disease Drug-Development Pipeline: Few Candidates, Frequent Failures","volume":"6","author":"Cummings","year":"2014","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S1359-6446(04)03163-0","article-title":"From Magic Bullets to Designed Multiple Ligands","volume":"9","author":"Morphy","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1021\/acs.jmedchem.8b00760","article-title":"Polypharmacology by Design: A Medicinal Chemist\u2019s Perspective on Multitargeting Compounds","volume":"62","author":"Proschak","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S1474-4422(12)70291-0","article-title":"Tracking Pathophysiological Processes in Alzheimer\u2019s Disease: An Updated Hypothetical Model of Dynamic Biomarkers","volume":"12","author":"Jack","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1080\/14737175.2019.1621751","article-title":"Do BACE Inhibitor Failures in Alzheimer Patients Challenge the Amyloid Hypothesis of the Disease?","volume":"19","author":"Panza","year":"2019","journal-title":"Expert Rev. Neurother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.3233\/JAD-161118","article-title":"Therapeutics of Neurotransmitters in Alzheimer\u2019s Disease","volume":"57","author":"Kandimalla","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E419","DOI":"10.9778\/cmajo.20150057","article-title":"Treatment for Mild Cognitive Impairment: A Systematic Review and Meta-Analysis","volume":"3","author":"Warren","year":"2015","journal-title":"CMAJ Open"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1001\/jama.1994.03510370044030","article-title":"Hepatotoxic Effects of Tacrine Administration in Patients With Alzheimer\u2019s Disease","volume":"271","author":"Watkins","year":"1994","journal-title":"JAMA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.pnpbp.2017.01.003","article-title":"The Pharmacology of Tacrine at N-Methyl-d-Aspartate Receptors","volume":"75","author":"Horak","year":"2017","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.neuropharm.2018.08.010","article-title":"7-Methoxyderivative of Tacrine Is a \u201cfoot-in-the-Door\u201d Open-Channel Blocker of GluN1\/GluN2 and GluN1\/GluN3 NMDA Receptors with Neuroprotective Activity in Vivo","volume":"140","author":"Kaniakova","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0014-2999(94)90750-1","article-title":"Tetrahydroaminoacridine Blocks and Prolongs NMDA Receptor-Mediated Responses in a Voltage-Dependent Manner","volume":"253","author":"Vorobjev","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_41","first-page":"151","article-title":"9-Aminoacridines Act at a Site Different from That for Mg2+ in Blockade of the N-Methyl-D-Aspartate Receptor Channel","volume":"46","author":"Nelson","year":"1994","journal-title":"Mol. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"893","DOI":"10.2174\/1567205011310080011","article-title":"A Resurrection of 7-MEOTA: A Comparison with Tacrine","volume":"10","author":"Soukup","year":"2013","journal-title":"Curr. Alzheimer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"103164","DOI":"10.1016\/j.bioorg.2019.103164","article-title":"New Classes of Carbazoles as Potential Multi-Functional Anti-Alzheimer\u2019s Agents","volume":"91","author":"Choubdar","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ejmech.2013.07.029","article-title":"Discovery of Novel N-Substituted Carbazoles as Neuroprotective Agents with Potent Anti-Oxidative Activity","volume":"68","author":"Zhu","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_45","first-page":"744","article-title":"Tacrine: First Drug Approved for Alzheimer\u2019s Disease","volume":"28","author":"Crismon","year":"1994","journal-title":"Ann. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.talanta.2008.06.007","article-title":"Improvement of Acetylcholinesterase-Based Assay for Organophosphates in Way of Identification by Reactivators","volume":"77","author":"Pohanka","year":"2008","journal-title":"Talanta"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16882","DOI":"10.3390\/ijms140816882","article-title":"Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study","volume":"14","author":"Sepsova","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"12303","DOI":"10.1038\/s41598-019-48845-3","article-title":"Structural Features in the Glycine-Binding Sites of the GluN1 and GluN3A Subunits Regulate the Surface Delivery of NMDA Receptors","volume":"9","author":"Skrenkova","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/jnc.12002","article-title":"Single Amino Acid Residue in the M4 Domain of GluN1 Subunit Regulates the Surface Delivery of NMDA Receptors","volume":"123","author":"Kaniakova","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3389\/fnmol.2018.00110","article-title":"Surface Expression, Function, and Pharmacology of Disease-Associated Mutations in the Membrane Domain of the Human GluN2B Subunit","volume":"11","author":"Vyklicky","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.bbadis.2016.11.020","article-title":"Multi-Target-Directed Therapeutic Potential of 7-Methoxytacrine-Adamantylamine Heterodimers in the Alzheimer\u2019s Disease Treatment","volume":"1863","author":"Gazova","year":"2017","journal-title":"Biochim. Et Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hemel\u00edkov\u00e1, K., Kolcheva, M., Skrenkova, K., Kaniakov\u00e1, M., and Hor\u00e1k, M. (2019). Lectins Modulate the Functional Properties of GluN1\/GluN3-Containing NMDA Receptors. Neuropharmacology.","DOI":"10.1016\/j.neuropharm.2019.107671"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"821","DOI":"10.2174\/1567205016666190228122218","article-title":"Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer\u2019s Disease","volume":"16","author":"Kaniakova","year":"2019","journal-title":"Curr. Alzheimer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"112584","DOI":"10.1016\/j.ejmech.2020.112584","article-title":"The Wide-Spectrum Antimicrobial Effect of Novel N-Alkyl Monoquaternary Ammonium Salts and Their Mixtures; the QSAR Study against Bacteria","volume":"206","author":"Soukup","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1042\/BJ20130013","article-title":"Crystal Structures of Human Cholinesterases in Complex with Huprine W and Tacrine: Elements of Specificity for Anti-Alzheimer\u2019s Drugs Targeting Acetyl- and Butyryl-Cholinesterase","volume":"453","author":"Nachon","year":"2013","journal-title":"Biochem. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10282","DOI":"10.1021\/jm300871x","article-title":"Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands","volume":"55","author":"Cheung","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Spilovska, K., Korabecny, J., Sepsova, V., Jun, D., Hrabinova, M., Jost, P., Muckova, L., Soukup, O., Janockova, J., and Kucera, T. (2017). Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer\u2019s Agents: Design, Synthesis and Biological Evaluation. Molecules, 22.","DOI":"10.3390\/molecules22061006"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Mezeiova, E., Korabecny, J., Sepsova, V., Hrabinova, M., Jost, P., Muckova, L., Kucera, T., Dolezal, R., Misik, J., and Spilovska, K. (2017). Development of 2-Methoxyhuprine as Novel Lead for Alzheimer\u2019s Disease Therapy. Molecules, 22.","DOI":"10.3390\/molecules22081265"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock 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_61","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1109\/TSMCB.2006.883272","article-title":"An Effective PSO-Based Memetic Algorithm for Flow Shop Scheduling","volume":"37","author":"Liu","year":"2007","journal-title":"IEEE Trans. Syst. ManCybern. Part B (Cybern.)"},{"key":"ref_62","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_63","doi-asserted-by":"crossref","first-page":"9824","DOI":"10.1021\/acs.jmedchem.9b01220","article-title":"The Blood-Brain Barrier (BBB) Score","volume":"62","author":"Gupta","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1021\/ci500467k","article-title":"ILOGP: A Simple, Robust, and Efficient Description of n-Octanol\/Water Partition Coefficient for Drug Design Using the GB\/SA Approach","volume":"54","author":"Daina","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4134","DOI":"10.1016\/j.arabjc.2019.06.001","article-title":"Degradation Kinetics of Fluvoxamine in Buffer Solutions: In Silico ADMET Profiling and Identification of Degradation Products by LC-MS\/ESI","volume":"13","author":"Naz","year":"2020","journal-title":"Arab. J. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"449","DOI":"10.2165\/00003088-199528060-00003","article-title":"Clinical Pharmacokinetics of Tacrine","volume":"28","author":"Madden","year":"1995","journal-title":"Clin. Pharm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.clinthera.2008.04.005","article-title":"Pharmacokinetics of Single-Dose and Multiple-Dose Memantine in Healthy Chinese Volunteers Using an Analytic Method of Liquid Chromatography-Tandem Mass Spectrometry","volume":"30","author":"Liu","year":"2008","journal-title":"Clin. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","article-title":"Lead- and Drug-like Compounds: The Rule-of-Five Revolution","volume":"1","author":"Lipinski","year":"2004","journal-title":"Drug Discov. Today Technol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1021\/jm0492002","article-title":"A Bioavailability Score","volume":"48","author":"Martin","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/cmdc.201600182","article-title":"A BOILED-Egg to Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules","volume":"11","author":"Daina","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5646","DOI":"10.1016\/j.ejmech.2010.09.018","article-title":"Characteristics of Known Drug Space. Natural Products, Their Derivatives and Synthetic Drugs","volume":"45","author":"Bade","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1021\/jm000292e","article-title":"Prediction of Drug Absorption Using Multivariate Statistics","volume":"43","author":"Egan","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1021\/cc9800071","article-title":"A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases","volume":"1","author":"Ghose","year":"1999","journal-title":"J. Comb. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1021\/jm015507e","article-title":"Simple Selection Criteria for Drug-like Chemical Matter","volume":"44","author":"Muegge","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.talanta.2009.12.052","article-title":"Colorimetric Dipstick for Assay of Organophosphate Pesticides and Nerve Agents Represented by Paraoxon, Sarin and VX","volume":"81","author":"Pohanka","year":"2010","journal-title":"Talanta"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Nordberg, A., Ballard, C., Bullock, R., Darreh-Shori, T., and Somogyi, M. (2013). A Review of Butyrylcholinesterase as a Therapeutic Target in the Treatment of Alzheimer\u2019s Disease. Prim. Care Companion CNS Disord., 15.","DOI":"10.4088\/PCC.12r01412"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"17213","DOI":"10.1073\/pnas.0508575102","article-title":"Selective Butyrylcholinesterase Inhibition Elevates Brain Acetylcholine, Augments Learning and Lowers Alzheimer Beta-Amyloid Peptide in Rodent","volume":"102","author":"Greig","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"8985","DOI":"10.1021\/acs.jmedchem.5b01325","article-title":"Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity","volume":"58","author":"Nepovimova","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"112593","DOI":"10.1016\/j.ejmech.2020.112593","article-title":"Discovery of Novel Berberine Derivatives with Balanced Cholinesterase and Prolyl Oligopeptidase Inhibition Profile","volume":"203","author":"Sobolova","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ejmech.2019.02.021","article-title":"Novel Tacrine-Tryptophan Hybrids: Multi-Target Directed Ligands as Potential Treatment for Alzheimer\u2019s Disease","volume":"168","author":"Chalupova","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2045-8118-10-16","article-title":"The HCMEC\/D3 Cell Line as a Model of the Human Blood Brain Barrier","volume":"10","author":"Weksler","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/s41422-019-0216-x","article-title":"Sodium Oligomannate Therapeutically Remodels Gut Microbiota and Suppresses Gut Bacterial Amino Acids-Shaped Neuroinflammation to Inhibit Alzheimer\u2019s Disease Progression","volume":"29","author":"Wang","year":"2019","journal-title":"Cell Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/1\/3\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:27Z","timestamp":1760179707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/1\/3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,22]]},"references-count":83,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["biom11010003"],"URL":"https:\/\/doi.org\/10.3390\/biom11010003","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,22]]}}}