Anticholinesterase Agents For Alzheimer's Disease Treatment: An Updated
Overview

Luana   C.   Llanes; Isabelle      Kuehlewein; Igor   V. de   França; Luana Veiga      da Silva; José   W.   da Cruz Junior
doi:10.2174/0929867329666220803113411
Abstract

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease that compromises the cognitive system and causes dementia. In general, AD affects people over 65 years old, which implies a social impact if we consider future projections due to the increase in life expectancy. The drugs currently marketed only slow the progression of the disease. In this sense, the search for new drugs is a relevant topic in medicinal chemistry. The therapeutic strategy adopted herein is the cholinergic hypothesis, for which acetylcholinesterase enzyme (AChE) inhibitors constitute the main treatment for the disease.
Objective: This review compiles research in synthetic and natural compounds with AChE inhibitory function.
Methods: Data were collected based on investigations of AChE inhibitors in the last 5 years of the 2010 decade. Synthetic and natural compounds were investigated, for which Ligand Based Drug Design (LBDD) and Structure Based Drug Design (SBDD) strategies were performed to better understand the structure-activity relationship of promising therapeutic agents.
Results: Prediction of physicochemical and pharmacokinetic properties used to calculate the bioavailability radar, lipophilicity, drug-likeness, and pharmacokinetics parameters (SwissADME) indicated that most active compounds are associated with the following characteristics: molecular weight above 377 g/mol; molar refractivity over 114; fraction Csp3 below 0.39 and TPSA above 43 Å². The most active compounds had a lipophilicity parameter in the range between 2.5 and 4.52, a predominating lipophilic character. Atoms and bonds/interactions relevant for drug development were also investigated and the data pointed out the following tendencies: number of heavy atoms between 16 and 41; number of aromatic heavy atoms between 6 and 22; number of rotatable bonds between 1 and 14; number of H-bond acceptors between 1 and 11; number of H-bond donors below 7. Molecular docking studies indicated that all compounds had higher Goldscores than the drugs used as a positive control, indicating a stronger interaction with the enzyme.
Conclusion: The selected compounds represent a potential for new anticholinesterase drugs and may be good starting-point for the development of new candidates. Also, design rules can be extracted from our analysis.
Keywords: Alzheimer's disease (AD), AChE inhibitors, molecular docking, structure-activity relationship (SAR), structure-based drug design (SBDD), ligand-based drug design (LBDD), pharmacokinetics.
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[1]
Harris, J.R. Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease; Springer Science & Business Media, 2012. 
 [http://dx.doi.org/10.1007/978-94-007-5416-4]

[2]
Breijyeh, Z.; Karaman, R. Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules,  2020, 25(24), 5789.
 [http://dx.doi.org/10.3390/molecules25245789] [PMID: 33302541]

[3]
Alzheimer Association 2018 Alzheimer’s disease facts and figures. Alzheimers Dement.,  2018, 14, 701-701.

[4]
Hou, Y.; Dan, X.; Babbar, M.; Wei, Y.; Hasselbalch, S.G.; Croteau, D.L.; Bohr, V.A. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol.,  2019, 15(10), 565-581.
 [http://dx.doi.org/10.1038/s41582-019-0244-7] [PMID: 31501588]

[5]
Scheltens, P.; Blennow, K.; Breteler, M.B.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; der Flier, W.M. Alzheimer’s Disease. Lancet,  2016, 388, 505-517.
 [http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]

[6]
WHO. Dementia.   Available from:https://www.who.int/news-room/fact-sheets/detail/dementia (Accessed on: Sep 13, 2021).

[7]
Jensen, H.L.B.; Lillenes, M.S.; Rabano, A.; Günther, C-C.; Riaz, T.; Kalayou, S.T.; Ulstein, I.D.; Bøhmer, T.; Tønjum, T. Expression of nucleotide excision repair in Alzheimer’s disease is higher in brain tissue than in blood. Neurosci. Lett.,  2018, 672, 53-58.
 [http://dx.doi.org/10.1016/j.neulet.2018.02.043] [PMID: 29474873]

[8]
Agüera-Ortiz, L.; García-Ramos, R.; Grandas Pérez, F.J.; López-Álvarez, J.; Montes Rodríguez, J.M.; Olazarán Rodríguez, F.J.; Olivera Pueyo, J.; Pelegrin Valero, C.; Porta-Etessam, J. Depression in Alzheimer’s disease: A delphi consensus on etiology, risk factors, and clinical management. Front. Psychiatry,  2021, 12, 638651.
 [http://dx.doi.org/10.3389/fpsyt.2021.638651] [PMID: 33716830]

[9]
Shen, Z.; Yi, Y.; Bompelli, A.; Yu, F.; Wang, Y.; Zhang, R. Extracting lifestyle factors for alzheimer’s disease from clinical notes using deep learning with weak supervision. arXiv,  2021, 2021, 2101.09244.

[10]
Cho, S.; Lee, H.; Seo, J. Impact of genetic risk factors for Alzheimer’s disease on brain glucose metabolism. Mol. Neurobiol.,  2021, 58(6), 2608-2619.
 [http://dx.doi.org/10.1007/s12035-021-02297-x] [PMID: 33479841]

[11]
Więckowska-Gacek, A.; Mietelska-Porowska, A.; Wydrych, M.; Wojda, U. Western diet as a trigger of Alzheimer’s disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration. Ageing Res. Rev.,  2021, 70, 101397.
 [http://dx.doi.org/10.1016/j.arr.2021.101397] [PMID: 34214643]

[12]
Ventura, H.N.; Fonseca, L. The health of elderly people bearing Alzheimer’s disease: An integrative review. Rev. de Pes. Cuidado é Fund. Onl.,  2018, 10, 941-944.

[13]
Henriques, A.D.; Benedet, A.L.; Camargos, E.F.; Rosa-Neto, P.; Nóbrega, O.T. Fluid and imaging biomarkers for Alzheimer’s disease: Where we stand and where to head to. Exp. Gerontol.,  2018, 107, 169-177.
 [http://dx.doi.org/10.1016/j.exger.2018.01.002] [PMID: 29307736]

[14]
Gyasi, Y.I.; Pang, Y.P.; Li, X.R.; Gu, J.X.; Cheng, X.J.; Liu, J.; Xu, T.; Liu, Y. Biological applications of near infrared fluorescence dye probes in monitoring Alzheimer’s disease. Eur. J. Med. Chem.,  2020, 187, 111982.
 [http://dx.doi.org/10.1016/j.ejmech.2019.111982] [PMID: 31877538]

[15]
Itzhaki, R.F.; Lin, W.R.; Shang, D.; Wilcock, G.K.; Faragher, B.; Jamieson, G.A. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet,  1997, 349(9047), 241-244.
 [http://dx.doi.org/10.1016/S0140-6736(96)10149-5] [PMID: 9014911]

[16]
Letenneur, L.; Pérès, K.; Fleury, H.; Garrigue, I.; Barberger-Gateau, P.; Helmer, C.; Orgogozo, J-M.; Gauthier, S.; Dartigues, J-F. Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: A population-based cohort study. PLoS One,  2008, 3(11), e3637.
 [http://dx.doi.org/10.1371/journal.pone.0003637] [PMID: 18982063]

[17]
Wozniak, M.A.; Frost, A.L.; Preston, C.M.; Itzhaki, R.F. Antivirals reduce the formation of key Alzheimer’s disease molecules in cell cultures acutely infected with herpes simplex virus type 1. PLoS One,  2011, 6(10), e25152.
 [http://dx.doi.org/10.1371/journal.pone.0025152] [PMID: 22003387]

[18]
Piacentini, R.; De Chiara, G.; Li Puma, D.D.; Ripoli, C.; Marcocci, M.E.; Garaci, E.; Palamara, A.T.; Grassi, C. HSV-1 and Alzheimer’s disease: More than a hypothesis. Front. Pharmacol.,  2014, 5, 97.
 [http://dx.doi.org/10.3389/fphar.2014.00097] [PMID: 24847267]

[19]
Harris, S.A.; Harris, E.A. Herpes simplex virus type 1 and other pathogens are key causative factors in sporadic Alzheimer’s disease. J. Alzheimers Dis.,  2015, 48(2), 319-353.
 [http://dx.doi.org/10.3233/JAD-142853] [PMID: 26401998]

[20]
Kłysik, K.; Pietraszek, A.; Karewicz, A.; Nowakowska, M. Acyclovir in the treatment of herpes viruses - A review. Curr. Med. Chem.,  2020, 27(24), 4118-4137.
 [http://dx.doi.org/10.2174/0929867325666180309105519] [PMID: 29521211]

[21]
Reitz, C.; Mayeux, R. Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem. Pharmacol.,  2014, 88(4), 640-651.
 [http://dx.doi.org/10.1016/j.bcp.2013.12.024] [PMID: 24398425]

[22]
Ferreira, S.T.; Klein, W.L. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol. Learn. Mem.,  2011, 96(4), 529-543.
 [http://dx.doi.org/10.1016/j.nlm.2011.08.003] [PMID: 21914486]

[23]
Coyle, J.T.; Price, D.L.; DeLong, M.R. Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science,  1983, 219(4589), 1184-1190.
 [http://dx.doi.org/10.1126/science.6338589] [PMID: 6338589]

[24]
Nguyen, V.T.T.; Sallbach, J.; Dos Santos Guilherme, M.; Endres, K. Influence of acetylcholine esterase inhibitors and memantine, clinically approved for Alzheimer’s dementia treatment, on intestinal properties of the mouse. Int. J. Mol. Sci.,  2021, 22(3), 1015.
 [http://dx.doi.org/10.3390/ijms22031015] [PMID: 33498392]

[25]
Campoy, F.J.; Vidal, C.J.; Muñoz-Delgado, E.; Montenegro, M.F.; Cabezas-Herrera, J.; Nieto-Cerón, S. Cholinergic system and cell proliferation. Chem. Biol. Interact.,  2016, 259(Pt B), 257-265.
 [http://dx.doi.org/10.1016/j.cbi.2016.04.014] [PMID: 27083142]

[26]
Verma, S.; Kumar, A.; Tripathi, T.; Kumar, A. Muscarinic and nicotinic acetylcholine receptor agonists: Current scenario in Alzheimer’s disease therapy. J. Pharm. Pharmacol.,  2018, 70(8), 985-993.
 [http://dx.doi.org/10.1111/jphp.12919] [PMID: 29663387]

[27]
Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: Targeting the cholinergic system. Curr. Neuropharmacol.,  2016, 14(1), 101-115.
 [http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]

[28]
Bartus, R.T. On neurodegenerative diseases, models, and treatment strategies: Lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp. Neurol.,  2000, 163(2), 495-529.
 [http://dx.doi.org/10.1006/exnr.2000.7397] [PMID: 10833325]

[29]
Silveyra, M.-X.; García-Ayllón, M.-S. Changes in acetylcholinesterase expression are associated with altered presenilin-1 levels. Neurobiol. Aging,  2012, 33, 627.

[30]
Arendt, T.; Brückner, M.K.; Morawski, M.; Jäger, C.; Gertz, H-J. Early neurone loss in Alzheimer’s disease: Cortical or subcortical? Acta Neuropathol. Commun.,  2015, 3(1), 10.
 [http://dx.doi.org/10.1186/s40478-015-0187-1] [PMID: 25853173]

[31]
Kumar, B.; Thakur, A.; Dwivedi, A.R.; Kumar, R.; Kumar, V. Multi-target-directed ligands as an effective strategy for the treatment of Alzheimer’s disease. Curr. Med. Chem.,  2022, 29(10), 1757-1803.
 [http://dx.doi.org/10.2174/0929867328666210512005508] [PMID: 33982650]

[32]
Chaves, S.; Várnagy, K.; Santos, M.A. Recent multi-target approaches on the development of anti- alzheimer’s agents integrating metal chelation activity. Curr. Med. Chem.,  2021, 28(35), 7247-7277.
 [http://dx.doi.org/10.2174/0929867328666210218183032] [PMID: 33602068]

[33]
Sharma, K. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Mol. Med. Rep.,  2019, 20(2), 1479-1487.
 [PMID: 31257471]

[34]
Forlenza, O.V. Tratamento farmacológico da doença de Alzheimer. Arch. Clin. Psychiatry,  2005, 32(3), 137-148.
 [http://dx.doi.org/10.1590/S0101-60832005000300006]

[35]
Zemek, F.; Drtinova, L.; Nepovimova, E.; Sepsova, V.; Korabecny, J.; Klimes, J.; Kuca, K. Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin. Drug Saf.,  2014, 13(6), 759-774.
 [PMID: 24845946]

[36]
Coyle, J.; Kershaw, P. Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: Effects on the course of Alzheimer’s disease. Biol. Psychiatry,  2001, 49(3), 289-299.
 [http://dx.doi.org/10.1016/S0006-3223(00)01101-X] [PMID: 11230880]

[37]
Ashani, Y.; Peggins, J.O., III; Doctor, B.P. Mechanism of inhibition of cholinesterases by huperzine A. Biochem. Biophys. Res. Commun.,  1992, 184(2), 719-726.
 [http://dx.doi.org/10.1016/0006-291X(92)90649-6] [PMID: 1575745]

[38]
Shaw, K.P.; Aracava, Y.; Akaike, A.; Daly, J.W.; Rickett, D.L.; Albuquerque, E.X. The reversible cholinesterase inhibitor physostigmine has channel-blocking and agonist effects on the acetylcholine receptor-ion channel complex. Mol. Pharmacol.,  1985, 28(6), 527-538.
 [PMID: 2417099]

[39]
Sheeja Malar, D.; Beema Shafreen, R.; Karutha Pandian, S.; Pandima Devi, K. Cholinesterase inhibitory, anti-amyloidogenic and neuroprotective effect of the medicinal plant Grewia tiliaefolia - An in vitro and in silico study. Pharm. Biol.,  2017, 55(1), 381-393.
 [http://dx.doi.org/10.1080/13880209.2016.1241811] [PMID: 27931177]

[40]
Lane, R.M.; Potkin, S.G.; Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol.,  2006, 9(1), 101-124.
 [http://dx.doi.org/10.1017/S1461145705005833] [PMID: 16083515]

[41]
Zouari-Bouassida, K.; Trigui, M.; Makni, S.; Jlaiel, L.; Tounsi, S. Seasonal variation in essential oils composition and the biological and pharmaceutical protective effects of Mentha longifolia leaves grown in Tunisia. BioMed Res. Int.,  2018, 2018, 7856517.
 [http://dx.doi.org/10.1155/2018/7856517] [PMID: 30627570]

[42]
Choi, D.Y.; Lee, Y.J.; Hong, J.T.; Lee, H.J. Antioxidant properties of natural polyphenols and their therapeutic potentials for Alzheimer’s disease. Brain Res. Bull.,  2012, 87(2-3), 144-153.
 [http://dx.doi.org/10.1016/j.brainresbull.2011.11.014] [PMID: 22155297]

[43]
Murray, A.P.; Faraoni, M.B.; Castro, M.J.; Alza, N.P.; Cavallaro, V. Natural AChE inhibitors from plants and their contribution to Alzheimer’s disease therapy. Curr. Neuropharmacol.,  2013, 11(4), 388-413.
 [http://dx.doi.org/10.2174/1570159X11311040004] [PMID: 24381530]

[44]
Eruygur, N.; Koçyiğit, U.M.; Taslimi, P.; Ataş, M.; Tekin, M.; Gülçin, İ. Screening the in vitro antioxidant, antimicrobial, anticholinesterase, antidiabetic activities of endemic Achillea cucullata (Asteraceae) ethanol extract. S. Afr. J. Bot.,  2019, 120, 141-145.
 [http://dx.doi.org/10.1016/j.sajb.2018.04.001]

[45]
Ullah, F.; Ayaz, M.; Sadiq, A.; Hussain, A.; Ahmad, S.; Imran, M.; Zeb, A. Phenolic, flavonoid contents, anticholinesterase and antioxidant evaluation of Iris germanica var; florentina. Nat. Prod. Res.,  2016, 30(12), 1440-1444.
 [http://dx.doi.org/10.1080/14786419.2015.1057585] [PMID: 26166432]

[46]
Hajlaoui, H.; Mighri, H.; Aouni, M.; Gharsallah, N.; Kadri, A. Chemical composition and in vitro evaluation of antioxidant, antimicrobial, cytotoxicity and anti-acetylcholinesterase properties of Tunisian Origanum majorana L. essential oil. Microb. Pathog.,  2016, 95, 86-94.
 [http://dx.doi.org/10.1016/j.micpath.2016.03.003] [PMID: 26997648]

[47]
Ahmad, S.; Ullah, F.; Sadiq, A.; Ayaz, M.; Imran, M.; Ali, I.; Zeb, A.; Ullah, F.; Shah, M.R. Chemical composition, antioxidant and anticholinesterase potentials of essential oil of Rumex hastatus D. Don collected from the North West of Pakistan. BMC Complement. Altern. Med.,  2016, 16(1), 29.
 [http://dx.doi.org/10.1186/s12906-016-0998-z] [PMID: 26810212]

[48]
Kaufmann, D.; Kaur Dogra, A.; Tahrani, A.; Herrmann, F.; Wink, M. Extracts from traditional Chinese medicinal plants inhibit acetylcholinesterase, a known Alzheimer’s disease target. Molecules,  2016, 21(9), 1161.
 [http://dx.doi.org/10.3390/molecules21091161] [PMID: 27589716]

[49]
Deveci, E.; Tel-Çayan, G.; Duru, M.E. Phenolic profile, antioxidant, anticholinesterase, and anti-tyrosinase activities of the various extracts of ferula elaeochytris and sideritis stricta. Int. J. Food Prop.,  2018, 21(1), 771-783.
 [http://dx.doi.org/10.1080/10942912.2018.1431660]

[50]
Temel, H.E.; Demirci, B.; Demirci, F.; Celep, F.; Kahraman, A.; Doğan, M.; Başer, K.H.C. Chemical characterization and anticholinesterase effects of essential oils derived from salvia species. J. Essent. Oil Res.,  2016, 28(4), 322-331.
 [http://dx.doi.org/10.1080/10412905.2016.1159257]

[51]
Sadiq, A.; Zeb, A.; Ullah, F.; Ahmad, S.; Ayaz, M.; Rashid, U.; Muhammad, N. Chemical characterization, analgesic, antioxidant, and anticholinesterase potentials of essential oils from Isodon rugosus wall. ex. Benth. Front. Pharmacol.,  2018, 9, 623.
 [http://dx.doi.org/10.3389/fphar.2018.00623] [PMID: 29950997]

[52]
Gali, L.; Bedjou, F. Antioxidant and anticholinesterase effects of the ethanol extract, ethanol extract fractions and total alkaloids from the cultivated Ruta chalepensis. S. Afr. J. Bot.,  2019, 120, 163-169.
 [http://dx.doi.org/10.1016/j.sajb.2018.04.011]

[53]
Hwang, J-S.; Cho, C.H.; Baik, M-Y.; Park, S-K.; Heo, H.J.; Cho, Y-S.; Kim, D-O. Effects of freeze-drying on antioxidant and anticholinesterase activities in various cultivars of kiwifruit (Actinidia spp.). Food Sci. Biotechnol.,  2017, 26(1), 221-228.
 [http://dx.doi.org/10.1007/s10068-017-0030-5] [PMID: 30263532]

[54]
Qu, Z.; Zhang, J.; Yang, H.; Gao, J.; Chen, H.; Liu, C.; Gao, W. Prunella vulgaris L., an edible and medicinal plant, attenuates scopolamine-induced memory impairment in rats. J. Agric. Food Chem.,  2017, 65(2), 291-300.
 [http://dx.doi.org/10.1021/acs.jafc.6b04597] [PMID: 28001065]

[55]
Venditti, A.; Frezza, C.; Sciubba, F.; Serafini, M.; Bianco, A.; Cianfaglione, K.; Lupidi, G.; Quassinti, L.; Bramucci, M.; Maggi, F. Volatile components, polar constituents and biological activity of tansy daisy (Tanacetum Macrophyllum (Waldst. et Kit.) Schultz Bip.). Ind. Crops Prod.,  2018, 118, 225-235.
 [http://dx.doi.org/10.1016/j.indcrop.2018.03.056]

[56]
Ali Reza, A.S.M.; Hossain, M.S.; Akhter, S.; Rahman, M.R.; Nasrin, M.S.; Uddin, M.J.; Sadik, G.; Khurshid Alam, A.H.M. In vitro antioxidant and cholinesterase inhibitory activities of Elatostema papillosum leaves and correlation with their phytochemical profiles: A study relevant to the treatment of Alzheimer’s disease. BMC Complement. Altern. Med.,  2018, 18(1), 123.
 [http://dx.doi.org/10.1186/s12906-018-2182-0] [PMID: 29622019]

[57]
Rahman, M.A.; Uddin, S.; Wilcock, C. Medicinal plants used by chakma tribe in hill tracts districts of Bangladesh. Indian J. Tradit. Knowl.,  2007, 6, 508-517.

[58]
Naghibi, F.; Mosadegh, M.; Mohammadi Motamed, S.; Ghorbani, A.B. Labiatae family in folk medicine in Iran: From ethnobotany to pharmacology. Iran. J. Pharm. Sci.,  2005, 4, 63-79.

[59]
Mimica-Dukić, N.; Božin, B.; Soković, M.; Mihajlović, B.; Matavulj, M. Antimicrobial and antioxidant activities of three Mentha species essential oils. Planta Med.,  2003, 69(5), 413-419.
 [http://dx.doi.org/10.1055/s-2003-39704] [PMID: 12802721]

[60]
Džamić, A.M.; Soković, M.D.; Ristić, M.S.; Novaković, M.; Grujić-Jovanović, S.; Tešević, V.; Marin, P.D. Antifungal and antioxidant activity of Mentha longifolia (L.) Hudson (Lamiaceae) essential oil. Bot. Serb.,  2010, 34, 57-61.

[61]
Zhao, H.; Zhou, S.; Zhang, M.; Feng, J.; Wang, S.; Wang, D.; Geng, Y.; Wang, X. An in vitro AChE inhibition assay combined with UF-HPLC-ESI-Q-TOF/MS approach for screening and characterizing of AChE inhibitors from roots of Coptis chinensis Franch. J. Pharm. Biomed,  2016, 120, 235-240.
 [http://dx.doi.org/10.1016/j.jpba.2015.12.025] [PMID: 26760241]

[62]
Kalaycıoğlu, Z.; Gazioğlu, I.; Erim, F.B. Comparison of antioxidant, anticholinesterase, and antidiabetic activities of three curcuminoids isolated from Curcuma longa L. Nat. Prod. Res.,  2017, 31(24), 2914-2917.
 [http://dx.doi.org/10.1080/14786419.2017.1299727] [PMID: 28287280]

[63]
Karakaya, S.; Koca, M.; Yılmaz, S.V.; Yıldırım, K.; Pınar, N.M.; Demirci, B.; Brestic, M.; Sytar, O. Molecular docking studies of coumarins isolated from extracts and essential oils of Zosima absinthifolia link as potential inhibitors for Alzheimer’s disease. Molecules,  2019, 24(4), 722.
 [http://dx.doi.org/10.3390/molecules24040722] [PMID: 30781573]

[64]
Yang, X.; Zhang, W.; Ying, X.; Stien, D. New flavonoids from Portulaca oleracea L. and their activities. Fitoterapia,  2018, 127, 257-262.
 [http://dx.doi.org/10.1016/j.fitote.2018.02.032] [PMID: 29501925]

[65]
Türkan, F.; Taslimi, P.; Saltan, F.Z. Tannic acid as a natural antioxidant compound: Discovery of a potent metabolic enzyme inhibitor for a new therapeutic approach in diabetes and Alzheimer’s disease. J. Biochem. Mol. Toxicol.,  2019, 33(8), e22340.
 [http://dx.doi.org/10.1002/jbt.22340] [PMID: 30974029]

[66]
Ademosun, A.O.; Oboh, G.; Bello, F.; Ayeni, P.O. Antioxidative properties and effect of quercetin and its glycosylated form (rutin) on acetylcholinesterase and butyrylcholinesterase activities. J. Evid. Based Complementary Altern. Med.,  2016, 21(4), NP11-NP17.
 [http://dx.doi.org/10.1177/2156587215610032] [PMID: 26438716]

[67]
Farag, M.A.; Ezzat, S.M.; Salama, M.M.; Tadros, M.G. Anti-acetylcholinesterase potential and metabolome classification of 4 Ocimum species as determined via UPLC/qTOF/MS and chemometric tools. J. Pharm. Biomed.,  2016, 125, 292-302.
 [http://dx.doi.org/10.1016/j.jpba.2016.03.037] [PMID: 27061877]

[68]
Salleh, W.M.N.H.W.; Ahmad, F.; Yen, K.H.; Zulkifli, R.M. Anticholinesterase and anti-inflammatory constituents from beilschmiedia pulverulenta kosterm. Nat. Prod. Sci.,  2016, 22(4), 225.
 [http://dx.doi.org/10.20307/nps.2016.22.4.225]

[69]
Niu, B.; Zhang, M.; Du, P.; Jiang, L.; Qin, R.; Su, Q.; Chen, F.; Du, D.; Shu, Y.; Chou, K-C. Small molecular floribundiquinone B derived from medicinal plants inhibits acetylcholinesterase activity. Oncotarget,  2017, 8(34), 57149-57162.
 [http://dx.doi.org/10.18632/oncotarget.19169] [PMID: 28915661]

[70]
Wei, X.; Jiang, J-S.; Feng, Z-M.; Zhang, P-C. Anthraquinone-benzisochromanquinone dimers from the roots of Berchemia floribunda. Chem. Pharm. Bull. (Tokyo),  2008, 56(9), 1248-1252.
 [http://dx.doi.org/10.1248/cpb.56.1248] [PMID: 18758095]

[71]
Bourne, Y.; Taylor, P.; Radić, Z.; Marchot, P. Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site. EMBO J.,  2003, 22(1), 1-12.
 [http://dx.doi.org/10.1093/emboj/cdg005] [PMID: 12505979]

[72]
Dzoyem, J.P.; Nkuete, A.H.L.; Ngameni, B.; Eloff, J.N. Anti-inflammatory and anticholinesterase activity of six flavonoids isolated from Polygonum and Dorstenia species. Arch. Pharm. Res.,  2017, 40(10), 1129-1134.
 [http://dx.doi.org/10.1007/s12272-015-0612-9] [PMID: 26048035]

[73]
Ji, H.F.; Zhang, H.Y. Theoretical evaluation of flavonoids as multipotent agents to combat Alzheimer’s disease. J. Mol. Struct.,  2006, 767(1-3), 3-9.
 [http://dx.doi.org/10.1016/j.theochem.2006.04.041]

[74]
Blaikie, L.; Kay, G.; Kong Thoo Lin, P. Current and emerging therapeutic targets of alzheimer’s disease for the design of multi-target directed ligands. MedChemComm,  2019, 10(12), 2052-2072.
 [http://dx.doi.org/10.1039/C9MD00337A] [PMID: 32206241]

[75]
Ferreira, J.P.S.; Albuquerque, H.M.T.; Cardoso, S.M.; Silva, A.M.S.; Silva, V.L.M. Dual-target compounds for Alzheimer’s disease: Natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR). Eur. J. Med. Chem.,  2021, 221, 113492.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113492] [PMID: 33984802]

[76]
Shidore, M.; Machhi, J.; Shingala, K.; Murumkar, P.; Sharma, M.K.; Agrawal, N.; Tripathi, A.; Parikh, Z.; Pillai, P.; Yadav, M.R. Benzylpiperidine-linked diarylthiazoles as potential anti-alzheimer’s agents: Synthesis and biological evaluation. J. Med. Chem.,  2016, 59(12), 5823-5846.
 [http://dx.doi.org/10.1021/acs.jmedchem.6b00426] [PMID: 27253679]

[77]
Więckowska, A.; Kołaczkowski, M.; Bucki, A.; Godyń, J.; Marcinkowska, M.; Więckowski, K.; Zaręba, P.; Siwek, A.; Kazek, G.; Głuch-Lutwin, M.; Mierzejewski, P.; Bienkowski, P.; Sienkiewicz-Jarosz, H.; Knez, D.; Wichur, T.; Gobec, S.; Malawska, B. Novel multi-target-directed ligands for Alzheimer’s disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation. Eur. J. Med. Chem.,  2016, 124, 63-81.
 [http://dx.doi.org/10.1016/j.ejmech.2016.08.016] [PMID: 27560283]

[78]
Peauger, L.; Azzouz, R.; Gembus, V.; Ţînţaş, M-L.; Sopková-de Oliveira Santos, J.; Bohn, P.; Papamicaël, C.; Levacher, V. Donepezil-based central acetylcholinesterase inhibitors by means of a “bio-oxidizable” prodrug strategy: Design, synthesis, and in vitro biological evaluation. J. Med. Chem.,  2017, 60(13), 5909-5926.
 [http://dx.doi.org/10.1021/acs.jmedchem.7b00702] [PMID: 28613859]

[79]
García-Font, N.; Hayour, H.; Belfaitah, A.; Pedraz, J.; Moraleda, I.; Iriepa, I.; Bouraiou, A.; Chioua, M.; Marco-Contelles, J.; Oset-Gasque, M.J. Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer’s disease. Eur. J. Med. Chem.,  2016, 118, 178-192.
 [http://dx.doi.org/10.1016/j.ejmech.2016.04.023] [PMID: 27128182]

[80]
Hepnarova, V.; Korabecny, J.; Matouskova, L.; Jost, P.; Muckova, L.; Hrabinova, M.; Vykoukalova, N.; Kerhartova, M.; Kucera, T.; Dolezal, R.; Nepovimova, E.; Spilovska, K.; Mezeiova, E.; Pham, N.L.; Jun, D.; Staud, F.; Kaping, D.; Kuca, K.; Soukup, O. The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer’s disease. Eur. J. Med. Chem.,  2018, 150, 292-306.
 [http://dx.doi.org/10.1016/j.ejmech.2018.02.083] [PMID: 29533874]

[81]
Eghtedari, M.; Sarrafi, Y.; Nadri, H.; Mahdavi, M.; Moradi, A.; Homayouni Moghadam, F.; Emami, S.; Firoozpour, L.; Asadipour, A.; Sabzevari, O.; Foroumadi, A. New tacrine-derived AChE/BuChE inhibitors: Synthesis and biological evaluation of 5-amino-2-phenyl- 4H-pyrano[2,3-b]quinoline-3-carboxylates. Eur. J. Med. Chem.,  2017, 128, 237-246.
 [http://dx.doi.org/10.1016/j.ejmech.2017.01.042] [PMID: 28189905]

[82]
Ulus, R.; Zengin Kurt, B.; Gazioğlu, I.; Kaya, M. Microwave assisted synthesis of novel hybrid tacrine-sulfonamide derivatives and investigation of their antioxidant and anticholinesterase activities. Bioorg. Chem.,  2017, 70, 245-255.
 [http://dx.doi.org/10.1016/j.bioorg.2017.01.005] [PMID: 28153340]

[83]
Hiremathad, A.; Chand, K.; Esteves, A.R.; Cardoso, S.M.; Ramsay, R.R.; Chaves, S.; Keri, R.S.; Santos, M.A. Tacrine-allyl/propargylcysteine-benzothiazole trihybrids as potential anti-alzheimer’s drug candidates. RSC Advances,  2016, 6(58), 53519-53532.
 [http://dx.doi.org/10.1039/C6RA03455A]

[84]
Palanimuthu, D.; Poon, R.; Sahni, S.; Anjum, R.; Hibbs, D.; Lin, H-Y.; Bernhardt, P.V.; Kalinowski, D.S.; Richardson, D.R. A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer’s disease. Eur. J. Med. Chem.,  2017, 139, 612-632.
 [http://dx.doi.org/10.1016/j.ejmech.2017.08.021] [PMID: 28841514]

[85]
Sameem, B.; Saeedi, M.; Mahdavi, M.; Nadri, H.; Moghadam, F.H.; Edraki, N.; Khan, M.I.; Amini, M. Synthesis, docking study and neuroprotective effects of some novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety. Bioorg. Med. Chem.,  2017, 25(15), 3980-3988.
 [http://dx.doi.org/10.1016/j.bmc.2017.05.043] [PMID: 28587871]

[86]
Ghanei-Nasab, S.; Khoobi, M.; Hadizadeh, F.; Marjani, A.; Moradi, A.; Nadri, H.; Emami, S.; Foroumadi, A.; Shafiee, A. Synthesis and anticholinesterase activity of coumarin-3-carboxamides bearing tryptamine moiety. Eur. J. Med. Chem.,  2016, 121, 40-46.
 [http://dx.doi.org/10.1016/j.ejmech.2016.05.014] [PMID: 27214510]

[87]
Barbosa, F.A.R.; Canto, R.F.S.; Saba, S.; Rafique, J.; Braga, A.L. Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer’s disease. Bioorg. Med. Chem.,  2016, 24(22), 5762-5770.
 [http://dx.doi.org/10.1016/j.bmc.2016.09.031] [PMID: 27681239]

[88]
Reis, J.; Cagide, F.; Valencia, M.E.; Teixeira, J.; Bagetta, D.; Pérez, C.; Uriarte, E.; Oliveira, P.J.; Ortuso, F.; Alcaro, S.; Rodríguez-Franco, M.I.; Borges, F. Multi-target-directed ligands for Alzheimer’s disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors. Eur. J. Med. Chem.,  2018, 158, 781-800.
 [http://dx.doi.org/10.1016/j.ejmech.2018.07.056] [PMID: 30245401]

[89]
Hebda, M.; Bajda, M.; Więckowska, A.; Szałaj, N.; Pasieka, A.; Panek, D.; Godyń, J.; Wichur, T.; Knez, D.; Gobec, S.; Malawska, B. Synthesis, molecular modelling and biological evaluation of novel heterodimeric, multiple ligands targeting cholinesterases and amyloid beta. Molecules,  2016, 21(4), 410.
 [http://dx.doi.org/10.3390/molecules21040410] [PMID: 27023510]

[90]
Lolak, N.; Akocak, S.; Türkeş, C.; Taslimi, P.; Işık, M.; Beydemir, Ş.; Gülçin, İ.; Durgun, M. Synthesis, characterization, inhibition effects, and molecular docking studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors of novel benzenesulfonamides incorporating 1,3,5-triazine structural motifs. Bioorg. Chem.,  2020, 100, 103897.
 [http://dx.doi.org/10.1016/j.bioorg.2020.103897] [PMID: 32413628]

[91]
AlFadly, E.D.; Elzahhar, P.A.; Tramarin, A.; Elkazaz, S.; Shaltout, H.; Abu-Serie, M.M.; Janockova, J.; Soukup, O.; Ghareeb, D.A.; El-Yazbi, A.F.; Rafeh, R.W.; Bakkar, N.Z.; Kobeissy, F.; Iriepa, I.; Moraleda, I.; Saudi, M.N.S.; Bartolini, M.; Belal, A.S.F. Tackling neuroinflammation and cholinergic deficit in Alzheimer’s disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase. Eur. J. Med. Chem.,  2019, 167, 161-186.
 [http://dx.doi.org/10.1016/j.ejmech.2019.02.012] [PMID: 30771604]

[92]
Mehrabi, F.; Pourshojaei, Y.; Moradi, A.; Sharifzadeh, M.; Khosravani, L.; Sabourian, R.; Rahmani-Nezhad, S.; Mohammadi-Khanaposhtani, M.; Mahdavi, M.; Asadipour, A.; Rahimi, H. R.; Moghimi, S.; Foroumadi, A. Design, synthesis, molecular modeling and anticholinesterase activity of benzylidene-benzofuran-3-ones containing cyclic amine side chain. Fut. Med. Chem.,  2017, 9(7), 659-671.

[93]
Li, J.C.; Zhang, J.; Rodrigues, M.C.; Ding, D.J.; Longo, J.P.F.; Azevedo, R.B.; Muehlmann, L.A.; Jiang, C.S. Synthesis and evaluation of novel 1,2,3-triazole-based acetylcholinesterase inhibitors with neuroprotective activity. Bioorg. Med. Chem. Lett.,  2016, 26(16), 3881-3885.
 [http://dx.doi.org/10.1016/j.bmcl.2016.07.017] [PMID: 27426301]

[94]
Srivastava, P.; Tripathi, P.N.; Sharma, P.; Rai, S.N.; Singh, S.P.; Srivastava, R.K.; Shankar, S.; Shrivastava, S.K. Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory. Eur. J. Med. Chem.,  2019, 163, 116-135.
 [http://dx.doi.org/10.1016/j.ejmech.2018.11.049] [PMID: 30503937]

[95]
Kurt, B.Z.; Gazioglu, I.; Dag, A.; Salmas, R.E.; Kayık, G.; Durdagi, S.; Sonmez, F. Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives. Bioorg. Med. Chem.,  2017, 25(4), 1352-1363.
 [http://dx.doi.org/10.1016/j.bmc.2016.12.037] [PMID: 28089589]

[96]
Shrivastava, S.K.; Sinha, S.K.; Srivastava, P.; Tripathi, P.N.; Sharma, P.; Tripathi, M.K.; Tripathi, A.; Choubey, P.K.; Waiker, D.K.; Aggarwal, L.M.; Dixit, M.; Kheruka, S.C.; Gambhir, S.; Shankar, S.; Srivastava, R.K.; Shankar, S.; Srivastava, R.K. Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease. Bioorg. Chem.,  2019, 82, 211-223.
 [http://dx.doi.org/10.1016/j.bioorg.2018.10.009] [PMID: 30326403]

[97]
Karaman, N.; Sıcak, Y.; Taşkın-Tok, T.; Öztürk, M.; Karaküçük-İyidoğan, A.; Dikmen, M.; Koçyiğit-Kaymakçıoğlu, B.; Oruç-Emre, E.E. New piperidine-hydrazone derivatives: Synthesis, biological evaluations and molecular docking studies as AChE and BChE inhibitors. Eur. J. Med. Chem.,  2016, 124, 270-283.
 [http://dx.doi.org/10.1016/j.ejmech.2016.08.037] [PMID: 27592396]

[98]
Si, W.; Zhang, T.; Zhang, L.; Mei, X.; Dong, M.; Zhang, K.; Ning, J. Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors. Bioorg. Med. Chem. Lett.,  2016, 26(9), 2380-2382.
 [http://dx.doi.org/10.1016/j.bmcl.2015.07.052] [PMID: 27017111]

[99]
Lee, S.; Barron, M.G.A. A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs. J. Comput. Aided Mol. Des.,  2016, 30(4), 347-363.
 [http://dx.doi.org/10.1007/s10822-016-9910-7] [PMID: 27055524]

[100]
Dgachi, Y.; Ismaili, L.; Knez, D.; Benchekroun, M.; Martin, H.; Szałaj, N.; Wehle, S.; Bautista-Aguilera, O.M.; Luzet, V.; Bonnet, A.; Malawska, B.; Gobec, S.; Chioua, M.; Decker, M.; Chabchoub, F.; Marco-Contelles, J. Synthesis and biological assessment of racemic benzochromenopyrimidinimines as antioxidant, cholinesterase, and Aβ1-42 aggregation inhibitors for Alzheimer’s disease therapy. ChemMedChem,  2016, 11(12), 1318-1327.
 [http://dx.doi.org/10.1002/cmdc.201500539] [PMID: 26804623]

[101]
Mermer, A.; Demirbaş, N.; Şirin, Y.; Uslu, H.; Özdemir, Z.; Demirbaş, A. Conventional and microwave prompted synthesis, antioxidant, anticholinesterase activity screening and molecular docking studies of new quinolone-triazole hybrids. Bioorg. Chem.,  2018, 78, 236-248.
 [http://dx.doi.org/10.1016/j.bioorg.2018.03.017] [PMID: 29614435]

[102]
Pudlo, M.; Luzet, V.; Ismaïli, L.; Tomassoli, I.; Iutzeler, A.; Refouvelet, B. Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease. Bioorg. Med. Chem.,  2014, 22(8), 2496-2507.
 [http://dx.doi.org/10.1016/j.bmc.2014.02.046] [PMID: 24657052]

[103]
Detsi, A.; Bouloumbasi, D.; Prousis, K.C.; Koufaki, M.; Athanasellis, G.; Melagraki, G.; Afantitis, A.; Igglessi-Markopoulou, O.; Kontogiorgis, C.; Hadjipavlou-Litina, D.J. Design and synthesis of novel quinolinone-3-aminoamides and their α-lipoic acid adducts as antioxidant and anti-inflammatory agents. J. Med. Chem.,  2007, 50(10), 2450-2458.
 [http://dx.doi.org/10.1021/jm061173n] [PMID: 17444626]

[104]
Cheung, J.; Rudolph, M.J.; Burshteyn, F.; Cassidy, M.S.; Gary, E.N.; Love, J.; Franklin, M.C.; Height, J.J. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J. Med. Chem.,  2012, 55(22), 10282-10286.
 [http://dx.doi.org/10.1021/jm300871x] [PMID: 23035744]

[105]
Nicolet, Y.; Lockridge, O.; Masson, P.; Fontecilla-Camps, J.C.; Nachon, F. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J. Biol. Chem.,  2003, 278(42), 41141-41147.
 [http://dx.doi.org/10.1074/jbc.M210241200] [PMID: 12869558]

[106]
Biessels, G.J.; Deary, I.J.; Ryan, C.M. Cognition and diabetes: A lifespan perspective. Lancet Neurol.,  2008, 7(2), 184-190.
 [http://dx.doi.org/10.1016/S1474-4422(08)70021-8] [PMID: 18207116]

[107]
Messier, C.; Gagnon, M. Cognitive decline associated with dementia and type 2 diabetes: The interplay of risk factors. Diabetologia,  2009, 52(12), 2471-2474.
 [http://dx.doi.org/10.1007/s00125-009-1533-2] [PMID: 19779694]

[108]
Haan, M.N. Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer’s disease. Nat. Clin. Pract. Neurol.,  2006, 2(3), 159-166.
 [http://dx.doi.org/10.1038/ncpneuro0124] [PMID: 16932542]

[109]
Qiu, W.Q.; Folstein, M.F. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer’s disease: Review and hypothesis. Neurobiol. Aging,  2006, 27(2), 190-198.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2005.01.004] [PMID: 16399206]

[110]
Rizvi, S.M.D.; Shaikh, S.; Naaz, D.; Shakil, S.; Ahmad, A.; Haneef, M.; Abuzenadah, A.M. Kinetics and molecular docking study of an anti-diabetic drug glimepiride as acetylcholinesterase inhibitor: Implication for Alzheimer’s disease-diabetes dual therapy. Neurochem. Res.,  2016, 41(6), 1475-1482.
 [http://dx.doi.org/10.1007/s11064-016-1859-3] [PMID: 26886763]

[111]
Colović, M.B.; Krstić, D.Z.; Lazarević-Pašti, T.D.; Bondžić, A.M.; Vasić, V.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr. Neuropharmacol.,  2013, 11(3), 315-335.
 [http://dx.doi.org/10.2174/1570159X11311030006] [PMID: 24179466]

[112]
Dias, M.V.B.; Ely, F.; Palma, M.S.; de Azevedo, W.F., Jr; Basso, L.A.; Santos, D.S. Chorismate synthase: An attractive target for drug development against orphan diseases. Curr. Drug Targets,  2007, 8(3), 437-444.
 [http://dx.doi.org/10.2174/138945007780058924] [PMID: 17348836]

[113]
Filgueira de Azevedo, W., Jr; dos Santos, G.C.; dos Santos, D.M.; Olivieri, J.R.; Canduri, F.; Silva, R.G.; Basso, L.A.; Renard, G.; da Fonseca, I.O.; Mendes, M.A.; Palma, M.S.; Santos, D.S. Docking and small angle X-ray scattering studies of purine nucleoside phosphorylase. Biochem. Biophys. Res. Commun.,  2003, 309(4), 923-928.
 [http://dx.doi.org/10.1016/j.bbrc.2003.08.093] [PMID: 13679062]

[114]
Krüger, A.; Gonçalves, V.M.; Wrenger, C.; Kronenberger, T. ADME profiling in drug discovery and a new path paved on silica. Drug Discov. Dev.,  2019, 2019, 86174.

[115]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep.,  2017, 7(1), 42717.
 [http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]

[116]
Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem.,  2000, 43(20), 3714-3717.
 [http://dx.doi.org/10.1021/jm000942e] [PMID: 11020286]

[117]
Lipinski, C.A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods,  2000, 44(1), 235-249.
 [http://dx.doi.org/10.1016/S1056-8719(00)00107-6] [PMID: 11274893]

[118]
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem.,  2002, 45(12), 2615-2623.
 [http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]

[119]
Egan, W.J.; Merz, K.M., Jr; Baldwin, J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem.,  2000, 43(21), 3867-3877.
 [http://dx.doi.org/10.1021/jm000292e] [PMID: 11052792]

[120]
Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol.,  1997, 267(3), 727-748.
 [http://dx.doi.org/10.1006/jmbi.1996.0897] [PMID: 9126849]
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DOI https://dx.doi.org/10.2174/0929867329666220803113411	Print ISSN 0929-8673
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Current Medicinal Chemistry

Anticholinesterase Agents For Alzheimer's Disease Treatment: An Updated Overview

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