{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:08:47Z","timestamp":1791925727404,"version":"4.3.4"},"reference-count":79,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["HrZZ-IP-2020-02-9343"],"award-info":[{"award-number":["HrZZ-IP-2020-02-9343"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["451-03-68\/2022-14\/200026"],"award-info":[{"award-number":["451-03-68\/2022-14\/200026"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["451-03-68\/2022-14\/200168"],"award-info":[{"award-number":["451-03-68\/2022-14\/200168"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education, Science and Technological Development of the Republic of Serbia","award":["HrZZ-IP-2020-02-9343"],"award-info":[{"award-number":["HrZZ-IP-2020-02-9343"]}]},{"name":"Ministry of Education, Science and Technological Development of the Republic of Serbia","award":["451-03-68\/2022-14\/200026"],"award-info":[{"award-number":["451-03-68\/2022-14\/200026"]}]},{"name":"Ministry of Education, Science and Technological Development of the Republic of Serbia","award":["451-03-68\/2022-14\/200168"],"award-info":[{"award-number":["451-03-68\/2022-14\/200168"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimer\u2019s disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new structurally distinct 4-aminoquinolines bearing an adamantane moiety. Inhibition studies revealed that all of the compounds were very potent inhibitors of AChE and butyrylcholinesterase (BChE), with inhibition constants (Ki) ranging between 0.075 and 25 \u00b5M. The tested compounds exhibited a modest selectivity between the two cholinesterases; the most selective for BChE was compound 14, which displayed a 10 times higher preference, while compound 19 was a 5.8 times more potent inhibitor of AChE. Most of the compounds were estimated to be able to cross the blood\u2013brain barrier (BBB) by passive transport. Evaluation of druglikeness singled out fourteen compounds with possible oral route of administration. The tested compounds displayed modest but generally higher antioxidant activity than the structurally similar AD drug tacrine. Compound 19 showed the highest reducing power, comparable to those of standard antioxidants. Considering their simple structure, high inhibition of AChE and BChE, and ability to cross the BBB, 4-aminoquinoline-based adamantanes show promise as structural scaffolds for further design of novel central nervous system drugs. Among them, two compounds stand out: compound 5 as the most potent inhibitor of both cholinesterases with a Ki constant in low nano molar range and the potential to cross the BBB, and compound 8, which met all our requirements, including high cholinesterase inhibition, good oral bioavailability, and antioxidative effect. The QSAR model revealed that AChE and BChE inhibition was mainly influenced by the ring and topological descriptors MCD, Nnum, RP, and RSIpw3, which defined the shape, conformational flexibility, and surface properties of the molecules.<\/jats:p>","DOI":"10.3390\/pharmaceutics14061305","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T04:39:55Z","timestamp":1655786395000},"page":"1305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Katarina","family":"Komatovi\u0107","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, University of Belgrade, Studentski trg 16, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mato\u0161evi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4127-525X","authenticated-orcid":false,"given":"Nata\u0161a","family":"Terzi\u0107-Jovanovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njego\u0161eva 12, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7710-8250","authenticated-orcid":false,"given":"Suzana","family":"\u017dunec","sequence":"additional","affiliation":[{"name":"Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1204-5487","authenticated-orcid":false,"given":"Sandra","family":"\u0160egan","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njego\u0161eva 12, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-1731","authenticated-orcid":false,"given":"Mario","family":"Zlatovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Belgrade, Studentski trg 16, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1709-6390","authenticated-orcid":false,"given":"Nikola","family":"Marakovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0164-4994","authenticated-orcid":false,"given":"Anita","family":"Bosak","sequence":"additional","affiliation":[{"name":"Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5948-0702","authenticated-orcid":false,"given":"Dejan M.","family":"Opsenica","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njego\u0161eva 12, 11000 Belgrade, Serbia"},{"name":"Centre of Excellence in Environmental Chemistry and Engineering, ICTM, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.pneurobio.2018.12.006","article-title":"Comprehensive review of mechanisms of pathogenesis involved in Alzheimer\u2019s disease and potential therapeutic strategies","volume":"174","author":"Sharma","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_2","unstructured":"Alzheimer\u2019s Association (2021). 2021 Alzheimer\u2019s Disease Facts and Figures. Alzheimer\u2019s Dement., 17, 321\u2013387."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"326","DOI":"10.2174\/1570159X14666151208112754","article-title":"Current treatment options for Alzheimer\u2019s disease and Parkinson\u2019s disease dementia","volume":"14","author":"Szeto","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_4","unstructured":"(2022, January 24). BBC News, Alzheimer\u2019s Drug Aducanumab Not Approved for Use in EU. Available online: https:\/\/www.bbc.com\/news\/health-59699907."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6446","DOI":"10.1021\/jm701225u","article-title":"Multi-target-directed drug design strategy: From a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer\u2019s disease","volume":"50","author":"Bolognesi","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1179573520907397","DOI":"10.1177\/1179573520907397","article-title":"Current and future treatments in Alzheimer disease: An update","volume":"12","author":"Yiannopoulou","year":"2020","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref_7","unstructured":"Giaccobini, E., and Dunitz, M. (2000). Mechanism of Action of Cholinesterase Inhibitors. Cholinesterase\u2019s and Cholinesterase Inhibitors, Informa Healthcare. [3rd ed.]."},{"key":"ref_8","unstructured":"Giacobini, E. (2003). Butyrylcholinesterase: Its Role in Brain Function, Informa Healthcare. [1st ed.]."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/ana.410420613","article-title":"Butyrylcholinesterase in the life cycle of amyloid plaques","volume":"42","author":"Guillozet","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17213","DOI":"10.1073\/pnas.0508575102","article-title":"Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer \u03b2-amyloid peptide in rodent","volume":"102","author":"Greig","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1126\/science.1678899","article-title":"Atomic structure of acetylcholinesterase from Torpedo californica: A prototypic acetylcholine-binding protein","volume":"253","author":"Sussman","year":"1991","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"41141","DOI":"10.1074\/jbc.M210241200","article-title":"Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products","volume":"278","author":"Nicolet","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_13","unstructured":"Giaccobini, E., and Dunitz, M. (2003). Comparison of structures of butyrylcholinesterase and acetylcholinesterase. Butyrylcholinesterase, Its Function and Inhibitors, Informa Healthcare. [3rd ed.]."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rosenberry, T., Brazzolotto, X., Macdonald, I., Wandhammer, M., Trovaslet-Leroy, M., Darvesh, S., and Nachon, F. (2017). Comparison of the binding of reversible inhibitors to human butyrylcholinesterase and acetylcholinesterase: A crystallographic, kinetic and calorimetric study. Molecules, 22.","DOI":"10.3390\/molecules22122098"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.abb.2007.12.007","article-title":"Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol","volume":"471","author":"Bosak","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_16","first-page":"63","article-title":"Exploring the active sites of cholinesterases by inhibition with bambuterol and haloxon","volume":"76","author":"Kovarik","year":"2003","journal-title":"Croat. Chem. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6716","DOI":"10.1021\/jm300289k","article-title":"Metaproterenol, isoproternol and their bisdimethylcarbaamte derivates as human cholinesterase inhibitors","volume":"55","author":"Bosak","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1080\/14756366.2017.1326109","article-title":"Resorcinol-, catechol- and saligenin-based bronchodilating beta2-agonists as inhibitors of human cholinesterase activity","volume":"32","author":"Bosak","year":"2017","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mato\u0161evi\u0107, A., Radman Kastelic, A., Mikeli\u0107, A., Zandona, A., Katalini\u0107, M., Primo\u017ei\u010d, I., Bosak, A., and Hrenar, T. (2021). Quinuclidine-based carbamates as potential CNS active compounds. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13030420"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jalz.2007.11.008","article-title":"The amyloid cascade hypothesis","volume":"4","author":"Korczyn","year":"2008","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1007\/s00401-014-1287-x","article-title":"Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer\u2019s disease","volume":"127","author":"Bayer","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"249","DOI":"10.2174\/1567205043332063","article-title":"Actylcholinesterase (AChE)-amyloid-beta-peptide complexes in Alzheimer\u2019s disease: The Wnt signalling pathway","volume":"1","author":"Inestrosa","year":"2004","journal-title":"Curr. Alzheimer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.cbi.2016.04.009","article-title":"AChE and the amyloid precursor protein (APP)\u2014Cross-talk in Alzheimer\u2019s disease","volume":"259","author":"Nalivaeva","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_24","first-page":"200","article-title":"Mitochondrial metabolism of reactive oxygen species","volume":"70","author":"Andreyev","year":"2005","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.neuint.2012.08.014","article-title":"Metal dyshomeostasis and oxidative stress in Alzheimer\u2019s disease","volume":"62","author":"Greenough","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1093\/ajcn\/71.2.621s","article-title":"Oxidative stress and Alzheimer disease","volume":"71","author":"Christen","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.ejmech.2013.03.051","article-title":"Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer\u2019s disease","volume":"64","author":"Xie","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.2174\/1567205015666180711110750","article-title":"Tacrine-coumarin and tacrine-7-chloroquinoline hybrids with thiourea linkers: Cholinesterase inhibition properties, kinetic study, molecular docking and permeability assay for blood-brain barrier","volume":"15","author":"Hamulakova","year":"2018","journal-title":"Curr. Alzheimer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5491","DOI":"10.1021\/jm060164b","article-title":"Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge","volume":"49","author":"Rydberg","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bosak, A., Ramic, A., Smidlehner, T., Hrenar, T., Primozic, I., and Kovarik, Z. (2018). Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205193"},{"key":"ref_31","first-page":"455","article-title":"Chemical modifications of cinchona alkaloids lead to enhanced inhibition of human butyrylcholinesterase","volume":"9","author":"Karlsson","year":"2014","journal-title":"Nat. Prod. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.bbrc.2010.12.084","article-title":"Cation\u2013\u03c0 and \u03c0\u2013\u03c0 stacking interactions allow selective inhibition of butyrylcholinesterase by modified quinine and cinchonidine alkaloids","volume":"404","author":"Nawaz","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1080\/01480540500262912","article-title":"Antimalarials inhibit human erythrocyte membrane acetylcholinesterase","volume":"28","author":"Katewa","year":"2005","journal-title":"Drug Chem. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1093\/rheumatology\/keh506","article-title":"Hydroxychloroquine therapy in patients with primary Sj\u00f6gren\u2019s syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase","volume":"44","author":"Dawson","year":"2005","journal-title":"Rheumatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e2140","DOI":"10.7717\/peerj.2140","article-title":"Identification of 4-aminoquinoline core for the design of new cholinesterase inhibitors","volume":"4","author":"Chen","year":"2016","journal-title":"PeerJ"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.cbi.2019.05.024","article-title":"Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase","volume":"308","author":"Bosak","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jinorgbio.2018.11.019","article-title":"In-vitro evaluation studies of 7-chloro-4-aminoquinoline Schiff bases and their copper complexes as cholinesterase inhibitors","volume":"191","author":"Zanon","year":"2019","journal-title":"J. Inorg. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"103328","DOI":"10.1016\/j.bioorg.2019.103328","article-title":"New 4-N-phenylaminoquinoline derivatives as antioxidant, metal chelating and cholinesterase inhibitors for Alzheimer\u2019s disease","volume":"93","author":"Cai","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18827","DOI":"10.3390\/molecules201018827","article-title":"Synthesis and crystallographic insight into the structural aspects of some novel adamantane-based ester derivatives","volume":"20","author":"Kwong","year":"2015","journal-title":"Molecules"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.molstruc.2015.12.048","article-title":"Synthesis, crystal structure, superoxide scavenging activity, anticancer and docking studies of novel adamantyl nitroxide derivatives","volume":"1108","author":"Zhu","year":"2016","journal-title":"J. Mol. Struct."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1007\/s11172-018-2338-6","article-title":"Aminoadamantane conjugates with carbazole derivatives as potential multitarget agents for the treatment of Alzheimer\u2019s disease. Effect of the spacer structure","volume":"67","author":"Makhaeva","year":"2018","journal-title":"Russ. Chem. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1021\/acschembio.9b00682","article-title":"N-benzyl derivatives of long-chained 4-amino-7-chloro-quionolines as inhibitors of pyocyanin production in Pseudomonas aeruginosa","volume":"14","author":"Aleksic","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1021\/acs.jmedchem.5b01374","article-title":"Reinvestigating old pharmacophores: Are 4-aminoquinolines and tetraoxanes potential two-stage antimalarials?","volume":"59","author":"Tot","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acsmedchemlett.8b00053","article-title":"Novel aminoquinoline deriva-tives significantly reduce parasite load in Leishmania infantum infected mice","volume":"9","author":"Orsini","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"New and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/S0003-2697(02)00506-7","article-title":"Molar absorption coefficients for the reduced Ellman reagent: Reassessment","volume":"312","author":"Eyer","year":"2003","journal-title":"Anal. Biochem."},{"key":"ref_47","first-page":"173","article-title":"Inhibition of human blood acetylcholinesterase and butyrylcholinesterase by ethopropazine","volume":"74","author":"Reiner","year":"2001","journal-title":"Croat. Chem. Acta"},{"key":"ref_48","unstructured":"Chemicalize (2022, May 22). Calculation Module. Available online: https:\/\/chemicalize.com\/."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1021\/ci800081s","article-title":"Fully automated molecular mechanics based induced fit protein-ligand docking method","volume":"48","author":"Koska","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_50","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_51","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1529\/biophysj.108.129601","article-title":"Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics","volume":"95","author":"Xu","year":"2008","journal-title":"Biophys. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.cbi.2019.05.047","article-title":"Assessment of scoring functions and in silico parameters for AChE-ligand interactions as a tool for predicting inhibition potency","volume":"308","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0076-6879(99)99005-5","article-title":"Ferric reducing\/antioxidant power assay: Direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration","volume":"299","author":"Benzie","year":"1999","journal-title":"Methods Enzymol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s40199-020-00378-1","article-title":"Chromone-lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities","volume":"29","author":"Nadri","year":"2021","journal-title":"Daru"},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/acschemneuro.6b00029","article-title":"Central nervous system multiparameter optimization desirability","volume":"7","author":"Wager","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0169-409X(02)00004-2","article-title":"Prediction of intestinal permeability","volume":"54","author":"Egan","year":"2002","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_58","unstructured":"(2021). Schr\u00f6dinger Suite Release, Maestro, Epik, QikProp, Schr\u00f6dinger, LLC."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1002\/(SICI)1096-987X(19991130)20:15<1671::AID-JCC7>3.0.CO;2-Y","article-title":"Low-mode conformational search elucidated: Application to C39H80 and flexible docking of 9-deazaguanine inhibitors into PNP","volume":"20","author":"Guida","year":"1999","journal-title":"J. Comput. Chem."},{"key":"ref_60","first-page":"35","article-title":"Note sur la convergence de m\u00e9thodes de directions conjugu\u00e9es","volume":"3","author":"Polak","year":"1969","journal-title":"ESAIM Math. Model. Numer. Anal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1006\/bioo.1998.1121","article-title":"The kinetic inhibition of acetylcholinesterase from human erythrocyte by tacrine and some tacrine derivatives","volume":"27","author":"Porcelli","year":"1999","journal-title":"Bioorg. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.cbi.2006.06.002","article-title":"Inhibition of two different cholinesterases by tacrine","volume":"162","author":"Ahmed","year":"2006","journal-title":"Chem. Biol. Interact."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/00002093-200304000-00011","article-title":"Inhibition of human cholinesterases by drugs used to treat Alzheimer disease","volume":"17","author":"Darvesh","year":"2003","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2012.09.019","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"64","author":"Lipinski","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1023\/A:1015040217741","article-title":"Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs","volume":"16","author":"Kelder","year":"1999","journal-title":"Pharm. Res."},{"key":"ref_66","unstructured":"Hansch, C., and Leo, A. (1979). Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley & Sons."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"128318","DOI":"10.1016\/j.bmcl.2021.128318","article-title":"Estimation of the lipophilicity of purine-2,6-dione-based TRPA1 antagonists and PDE4\/7 inhibitors with analgesic activity","volume":"49","author":"Starek","year":"2021","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_68","unstructured":"Mannhold, R., Kubinyi, H., and Timmerman, H. (2000). Handbook of Molecular Descriptors, Methods and Principles in Medicinal Chemistry, Wiley-Vch. [11th ed.]."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1002\/cmdc.200800414","article-title":"Tacrine-melatonin hybrids as multifunctional agents for Alzheimer\u2019s disease, with cholinergic, antiox-idant, and neuroprotective properties","volume":"4","author":"Campillo","year":"2009","journal-title":"ChemMedChem"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4927","DOI":"10.1021\/jm100329q","article-title":"Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer\u2019s disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties","volume":"53","author":"Conde","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.bmcl.2014.12.084","article-title":"Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD","volume":"25","author":"Digiacomo","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Reichert, C.O., de Freitas, F.A., Sampaio-Silva, J., Rokita-Rosa, L., de Lima Barros, P., Levy, D., and Bydlowski, S.P. (2020). Ferroptosis mechanisms involved in neurodegenerative diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228765"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.1021\/jm800737y","article-title":"Novel 4-aminoquinolines active against chloroquine-resistant and sensitive P. falciparum strains that also inhibit botulinum serotype A","volume":"51","author":"Opsenica","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1021\/acschembio.6b01149","article-title":"Long-chained 4-aminoquinolines as quorum sensing inhibitors in Serratia marcescens and Pseudomonas aeruginosa","volume":"12","author":"Aleksic","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6315","DOI":"10.1038\/s41598-019-42816-4","article-title":"Examination of novel 4-aminoquinoline derivatives designed and synthesized by a hybrid pharmacophore approach to enhance their anticancer activities","volume":"9","author":"Solomon","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1021\/jm4012627","article-title":"Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem Cells","volume":"57","author":"Valente","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/0040-4020(94)00920-P","article-title":"Design and synthesis of hydrogen-bonded aggregates: Theory and computation applied to three systems based on the cyanuric acid-melamine lattice","volume":"51","author":"Simanek","year":"1995","journal-title":"Tetrahedron"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1080\/14756366.2019.1571055","article-title":"Design and synthesis of 4-piperazinyl quinoline derived urea\/thioureas for anti-breast cancer activity by a hybrid pharmacophore approach","volume":"34","author":"Viswas","year":"2019","journal-title":"J. Enz. Inh. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1475-2875-2-26","article-title":"The relationship of physico-chemical properties and structure to the differential antiplasmodial activity of the cinchona alkaloids","volume":"2","author":"Warhurst","year":"2003","journal-title":"Malar J."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/6\/1305\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:35:28Z","timestamp":1760139328000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/6\/1305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,20]]},"references-count":79,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["pharmaceutics14061305"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14061305","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,20]]}}}