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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

Target Enzyme in Alzheimer’s Disease: Acetylcholinesterase Inhibitors

Author(s): Mridula Saxena* and Ragini Dubey

Volume 19, Issue 4, 2019

Page: [264 - 275] Pages: 12

DOI: 10.2174/1568026619666190128125912

Price: $65

Abstract

Alzheimer’s Disease (AD), affecting a large population worldwide is characterized by the loss of memory and learning ability in the old population. The enzyme Acetylcholinesterase Enzyme (AChE) is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD but these drugs provide only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time. The development of different strategies targeting the AChE enzyme along with other targets like Butyl Cholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals antioxidant properties and free radical scavenging capacity has been focused in recent years. Literature search was conducted for the molecules and their rational design which have shown inhibition for AChE and the other abovementioned targets. Several hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates, and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule. It is followed by optimization of the activity through structural modifications guided by structure-activity relationship studies. It has led to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity against other abovementioned targets for further pre-clinical studies.

Keywords: Alzheimer's disease, Acetylcholinesterase, Molecular hybridization, Multi-target-directed ligands, Amyloid-β- peptides, Target enzyme.

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[1]
Mount, C.; Downton, C. Alzheimer disease: progress or profit? Nat. Med., 2006, 12(7), 780-784.
[http://dx.doi.org/10.1038/nm0706-780] [PMID: 16829947]
[2]
Cummings, J.L.; Doody, R.; Clark, C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology, 2007, 69(16), 1622-1634.
[http://dx.doi.org/10.1212/01.wnl. 0000295996.54210.69] [PMID: 17938373]
[3]
Klafki, H.W.; Staufenbiel, M.; Kornhuber, J.; Wiltfang, J. Therapeutic approaches to Alzheimer’s disease. Brain, 2006, 129(Pt 11), 2840-2855.
[http://dx.doi.org/10.1093/brain/awl280] [PMID: 17018549]
[4]
Prasher, V.P. Review of donepezil, rivastigmine, galantamine and memantine for the treatment of dementia in Alzheimer’s disease in adults with Down syndrome: implications for the intellectual disability population. Int. J. Geriatr. Psychiatry, 2004, 19(6), 509-515.
[http://dx.doi.org/10.1002/gps.1077] [PMID: 15211527]
[5]
Cummings, J.L.; Morstorf, T.; Zhong, K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res. Ther., 2014, 6(4), 37-43.
[http://dx.doi.org/10.1186/alzrt269] [PMID: 25024750]
[6]
Gerald, Z.; Ockert, W. Alzheimer’s disease market: hope deferred. Nat. Rev. Drug Discov., 2013, 12(1), 19-20.
[http://dx.doi.org/ 10.1038/nrd3922] [PMID: 23274463]
[7]
Anand, R.; Gill, K.D.; Mahdi, A.A. Therapeutics of Alzheimer’s disease: Past, present and future. Neuropharmacology, 2014, 76(Pt A), 27-50.
[http://dx.doi.org/10.1016/j.neuropharm.2013.07.004]] [PMID: 23891641]
[8]
(a)Pohanka, M. Acetylcholinesterase inhibitors: a patent review (2008 - present). Expert Opin. Ther. Pat, 2012, 22(8), 871-886.
[http://dx.doi.org/10.1517/13543776.2012.701620 ] [PMID: 22768972]
(b)Girek, M.; Paweł, S. Tacrine hybrids as multi target directed ligands in Alzheimer’s disease: infuence of chemical structures on biological activities, CC BY 4.0. cSaini, R.; Saxena, A.K. The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review. J. Alzheimers Neurodegener Dis, 2018, 4, 15.
[9]
Francis, P.T.; Palmer, A.M.; Snape, M.; Wilcock, G.K. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J. Neurol. Neurosurg. Psychiatry, 1999, 66(2), 137-147.
[http://dx.doi.org/10.1136/jnnp.66.2.137] [PMID: 10071091]
[10]
Sussman, J.L.; Harel, M.; Silman, I. Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs. Chem. Biol. Interact., 1993, 87(1-3), 187-197.
[http://dx.doi.org/10.1016/0009-2797(93)90042-W] [PMID: 8343975]
[11]
Nachon, F.; Carletti, E.; Ronco, C.; Trovaslet, M.; Nicolet, Y.; Jean, L.; Renard, P.Y. Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer’s drugs targeting acetyl- and butyryl-cholinesterase. Biochem. J., 2013, 453(3), 393-399.
[http://dx.doi.org/ 10.1042/BJ20130013] [PMID: 23679855]
[12]
Inestrosa, N.C.; Alvarez, A.; Pérez, C.A.; Moreno, R.D.; Vicente, M.; Linker, C.; Casanueva, O.I.; Soto, C.; Garrido, J. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron, 1996, 16(4), 881-891.
[http://dx.doi.org/10.1016/S0896-6273(00)80108-7] [PMID: 8608006]
[13]
Alvarez, A.; Opazo, C.; Alarcón, R.; Garrido, J.; Inestrosa, N.C. Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils. J. Mol. Biol., 1997, 272(3), 348-361.
[http://dx.doi.org/10.1006/jmbi.1997.1245] [PMID: 9325095]
[14]
De Ferrari, G.V.; Canales, M.A.; Shin, I.; Weiner, L.M.; Silman, I.; Inestrosa, N.C. A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry, 2001, 40(35), 10447-10457.
[http://dx.doi.org/10.1021/bi0101392] [PMID: 11523986]
[15]
Diamant, S.; Podoly, E.; Friedler, A.; Ligumsky, H.; Livnah, O.; Soreq, H. Butyrylcholinesterase attenuates amyloid fibril formation in vitro. Proc. Natl. Acad. Sci. USA, 2006, 103(23), 8628-8633.
[http://dx.doi.org/10.1073/pnas.0602922103] [PMID: 16731619]
[16]
Podoly, E.; Bruck, T.; Diamant, S.; Melamed-Book, N.; Weiss, A.; Huang, Y.; Livnah, O.; Langermann, S.; Wilgus, H.; Soreq, H. Human recombinant butyrylcholinesterase purified from the milk of transgenic goats interacts with beta-amyloid fibrils and suppresses their formation in vitro. Neurodegener. Dis., 2008, 5(3-4), 232-236.
[http://dx.doi.org/10.1159/000113711] [PMID: 18322399]
[17]
Watkins, P.B.; Zimmerman, H.J.; Knapp, M.J.; Gracon, S.I.; Lewis, K.W. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA, 1994, 271(13), 992-998.
[http://dx.doi.org/10.1001/jama.1994.03510370044030] [PMID: 8139084]
[18]
Youdim, M.B.H.; Buccafusco, J.J. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci., 2005, 26(1), 27-35.
[http://dx.doi.org/10.1016/j.tips.2004.11.007] [PMID: 15629202]
[19]
Bolognesi, M.L.; Matera, R.; Minarini, A.; Rosini, M.; Melchiorre, C. Alzheimer’s disease: new approaches to drug discovery. Curr. Opin. Chem. Biol., 2009, 13(3), 303-308.
[http://dx.doi.org/ 10.1016/j.cbpa.2009.04.619] [PMID: 19467915]
[20]
Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B. Multi-target-directed ligands in Alzheimer’s disease treatment. Curr. Med. Chem., 2011, 18(32), 4949-4975.
[http://dx.doi.org/10.2174/092986711797535245] [PMID: 22050745]
[21]
Rampa, A.; Belluti, F.; Gobbi, S.; Bisi, A. Hybrid-based multi-target ligands for the treatment of Alzheimer’s disease. Curr. Top. Med. Chem., 2011, 11(22), 2716-2730.
[http://dx.doi.org/ 10.2174/156802611798184409] [PMID: 22039875]
[22]
de los Ríos, C. Cholinesterase inhibitors: a patent review (2007 - 2011). Expert Opin. Ther. Pat., 2012, 22(8), 853-869.
[http://dx.doi.org/10.1517/13543776.2012.701619] [PMID: 22764681]
[23]
Anand, P.; Singh, B. A review on cholinesterase inhibitors for Alzheimer’s disease. Arch. Pharm. Res., 2013, 36(4), 375-399.
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[24]
Guzior, N.; Wieckowska, A.; Panek, D.; Malawska, B. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer’s disease. Curr. Med. Chem., 2015, 22(3), 373-404.
[http://dx.doi.org/10.2174/09298673216661411-06122628] [PMID: 25386820]
[25]
Biran, Y.; Masters, C.L.; Barnham, K.J.; Bush, A.I.; Adlard, P.A. Pharmacotherapeutic targets in Alzheimer’s disease. J. Cell. Mol. Med., 2009, 13(1), 61-86.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00595.x] [PMID: 19040415]
[26]
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, 53519-53532.
[http://dx.doi.org/10.1039/C6RA03455A]
[27]
Matias, M.; Silvestre, S.; Falcao, A.; Alves, G. Recent Highlights on Molecular Hybrids Potentially Useful in Central Nervous System Disorders. Mini Rev. Med. Chem., 2017, 17(6), 486-517.
[http://dx.doi.org/10.2174/1389557517666161111110121] [PMID: 27834131]
[28]
Singh, M.; Kaur, M.; Chadha, N.; Silakari, O. Hybrids: a new paradigm to treat Alzheimer’s disease. Mol. Divers., 2016, 20(1), 271-297.
[http://dx.doi.org/10.1007/s11030-015-9628-9] [PMID: 26328942]
[29]
Minarini, A.; Milelli, A.; Simoni, E.; Rosini, M.; Bolognesi, M.L.; Marchetti, C.; Tumiatti, V. Multifunctional tacrine derivatives in Alzheimer’s disease. Curr. Top. Med. Chem., 2013, 13(15), 1771-1786.
[http://dx.doi.org/10.2174/15680266113139990136] [PMID: 23931443]
[30]
Sameem, B.; Saeedi, M.; Mahdavi, M.; Shafiee, A. A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer’s disease. Eur. J. Med. Chem., 2017, 128, 332-345.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.060] [PMID: 27876467]
[31]
Lin, H.; Li, Q.; Gu, K.; Zhu, J.; Jiang, X.; Chen, Y.; Sun, H. Therapeutic Agents in Alzheimer’s Disease Through a Multi-targetdirected Ligands Strategy: Recent Progress Based on Tacrine Core. Curr. Top. Med. Chem., 2017, 17(27), 3000-3016.
[http://dx.doi.org/10.2174/1568026617666170717114944] [PMID: 28714419]
[32]
Ismaili, L.; Refouvelet, B.; Benchekroun, M.; Brogi, S.; Brindisi, M.; Gemma, S.; Campiani, G.; Filipic, S.; Agbaba, D.; Esteban, G.; Unzeta, M.; Nikolic, K.; Butini, S.; Marco-Contelles, J. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer’s disease. Prog. Neurobiol., 2017, 151, 4-34.
[http://dx.doi.org/10.1016/j.pneurobio.2015.12.003] [PMID: 26797191]
[33]
Heilbronn, E. Inhibition of cholinesterases by tetrahydroaminacrin. Acta Chem. Scand., 1961, 15, 1386-1390.
[http://dx.doi.org/ 10.3891/acta.chem.scand.15-1386]
[34]
Rakonczay, Z. Potencies and selectivities of inhibitors of acetylcholinesterase and its molecular forms in normal and Alzheimer’s disease brain. Acta Biol. Hung., 2003, 54(2), 183-189.
[http://dx.doi.org/10.1556/ABiol.54.2003.2.7] [PMID: 14535624]
[35]
Liston, D.R.; Nielsen, J.A.; Villalobos, A.; Chapin, D.; Jones, S.B.; Hubbard, S.T.; Shalaby, I.A.; Ramirez, A.; Nason, D.; White, W.F. Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer’s disease. Eur. J. Pharmacol., 2004, 486(1), 9-17.
[http://dx.doi.org/10.1016/j.ejphar.2003.11.080] [PMID: 14751402]
[36]
Crismon, M.L. Tacrine: first drug approved for Alzheimer’s disease. Ann. Pharmacother., 1994, 28(6), 744-751.
[http://dx.doi.org/ 10.1177/106002809402800612] [PMID: 7919566]
[37]
Wlodek, S.T.; Antosiewicz, J.; McCammon, J.A.; Straatsma, T.P.; Gilson, M.K.; Briggs, J.M.; Humblet, C.; Sussman, J.L. Binding of tacrine and 6-chlorotacrine by acetylcholinesterase. Biopolymers, 1996, 38(1), 109-117.
[http://dx.doi.org/10.1002/(SICI)1097-0282(199601)38:1<109:AID-BIP9>3.0.CO;2-#] [PMID: 8679940]
[38]
Fontana, R.J.; deVries, T.M.; Woolf, T.F.; Knapp, M.J.; Brown, A.S.; Kaminsky, L.S.; Tang, B.K.; Foster, N.L.; Brown, R.R.; Watkins, P.B. Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer’s disease. Br. J. Clin. Pharmacol., 1998, 46(3), 221-228.
[http://dx.doi.org/10.1046/j.1365-2125.1998.00776.x] [PMID: 9764962]
[39]
Tumiatti, V.; Minarini, A.; Bolognesi, M.L.; Milelli, A.; Rosini, M.; Melchiorre, C. Tacrine derivatives and Alzheimer’s disease. Curr. Med. Chem., 2010, 17(17), 1825-1838.
[http://dx.doi.org/ 10.2174/092986710791111206] [PMID: 20345341]
[40]
Soukup, O.; Jun, D.; Zdarova-Karasova, J.; Patocka, J.; Musilek, K.; Korabecny, J.; Krusek, J.; Kaniakova, M.; Sepsova, V.; Mandikova, J.; Trejtnar, F.; Pohanka, M.; Drtinova, L.; Pavlik, M.; Tobin, G.; Kuca, K. A resurrection of 7-MEOTA: a comparison with tacrine. Curr. Alzheimer Res., 2013, 10(8), 893-906.
[http://dx.doi.org/ 10.2174/1567205011310080011] [PMID: 24093535]
[41]
Kozurkova, M.; Hamulakova, S.; Gazova, Z.; Paulikova, H.; Kristian, P. Neuroactive multifunctional tacrine congeners with cholinesterase, anti-amyloid aggregation and neuroprotective properties. Pharmaceuticals, 2011, 4, 382-418.
[http://dx.doi.org/10.3390/ph4020382]
[42]
Li, W.; Mak, M.; Jiang, H.; Wang, Q.; Pang, Y.; Chen, K.; Han, Y. Novel anti-Alzheimer’s dimer Bis(7)-cognitin: cellular and molecular mechanisms of neuroprotection through multiple targets. Neurotherapeutics, 2009, 6(1), 187-201.
[http://dx.doi.org/10.1016/j.nurt.2008.10.040] [PMID: 19110209]
[43]
Hu, M-K.; Wu, L.J.; Hsiao, G.; Yen, M.H. Homodimeric tacrine congeners as acetylcholinesterase inhibitors. J. Med. Chem., 2002, 45(11), 2277-2282.
[http://dx.doi.org/10.1021/jm010308g] [PMID: 12014965]
[44]
Pang, Y-P.; Brimijoin, S. Tha analogs useful as cholinesterase inhib¬itors. 1997. Patent WO1997021681, Mayo Foundation For Medical Edu-cation And Research, USA.
[45]
Wang, H.; Carlier, P.R.; Ho, W.L.; Wu, D.C.; Lee, N.T.; Li, C.P.; Pang, Y.P.; Han, Y.F. Effects of bis(7)-tacrine, a novel anti-Alzheimer’s agent, on rat brain AChE. Neuroreport, 1999, 10(4), 789-793.
[http://dx.doi.org/10.1097/00001756-199903170-00023] [PMID: 10208549]
[46]
Carlier, P.R.; Han, Y.F.; Chow, E.S.; Li, C.P.; Wang, H.; Lieu, T.X.; Wong, H.S.; Pang, Y.P. Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis. Bioorg. Med. Chem., 1999, 7(2), 351-357.
[http://dx.doi.org/ 10.1016/S0968-0896(98)00213-2] [PMID: 10218828]
[47]
Savini, L.; Campiani, G.; Gaeta, A.; Pellerano, C.; Fattorusso, C.; Chiasserini, L.; Fedorko, J.M.; Saxena, A. Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase. Bioorg. Med. Chem. Lett., 2001, 11(13), 1779-1782.
[http://dx.doi.org/10.1016/S0960-894X(01) 00294-3] [PMID: 11425559]
[48]
Pisoni, D.S.; da Costa, J.S.; Gamba, D.; Petzhold, C.L.; Borges, A.C.A.; Ceschi, M.A.; Lunardi, P.; Gonçalves, C.A.S. Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones. Eur. J. Med. Chem., 2010, 45, 526.
[49]
Frideling, A.; Faure, R.; Galy, J-P.; Kenz, A.; Alkorta, I.; Elguero, J. Tetrahydroacridin-9-ones, 9-chlorotetrahydroacridines, 9-amino-tetrahydroacridines and 9-(pyrazol-1-yl)-tetrahydroacridines derived from chiral cyclanones. Eur. J. Med. Chem., 2004, 39(1), 37-48.
[http://dx.doi.org/10.1016/j.ejmech.2003.10.003] [PMID: 14987832]
[50]
Bañón-Caballero, A.; Guillena, G.; Nájera, C. Solvent-free enantioselective Friedländer condensation with wet 1,1′-binaphthalene-2,2′-diamine-derived prolinamides as organocatalysts. J. Org. Chem., 2013, 78(11), 5349-5356.
[http://dx.doi.org/10.1021/jo400522m] [PMID: 23663142]
[51]
Desai, M.C.; Thadeio, P.F.; Lipinski, C.A.; Liston, D.R.; Spencer, R.W.; Williams, I.H. Physical parameters for brian uptake: optimizing log P, log D and pKa of THA. Bioorg. Med. Chem. Lett., 1991, 1, 411.
[http://dx.doi.org/10.1016/S0960-894X(00)80267-X]
[52]
Djerassi, C.; Krakower, G.W. Optical Rotatory Dispersion Studies. XXI. Effect of Ring Size2. J. Am. Chem. Soc., 1959, 81, 237.
[http://dx.doi.org/10.1021/ja01510a055]
[53]
Lopes, J.P.B. Costa, S.d. J.; Ceschi, M.A.; Goncalves, C.A.S.; Konrath, E.L.; Karl, A.L.; Guedes, I.A.; Dardenne, L.E.; Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach. J. Braz. Chem. Soc., 2017, 28, 2218-2228.
[54]
Hamulakova, S.; Janovec, L.; Hrabinova, M.; Kristian, P.; Kuca, K.; Banasova, M.; Imrich, J. Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2012, 55, 23-31.
[http://dx.doi.org/10.1016/j.ejmech.2012.06.051] [PMID: 22818849]
[55]
Qian, S.; He, L.; Mak, M.; Han, Y.; Ho, C.Y.; Zuo, Z. Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors. Int. J. Pharm., 2014, 477(1-2), 442-453.
[http://dx.doi.org/10.1016/j.ijpharm. 2014.10.058] [PMID: 25445524]
[56]
Elsinghorst, P.W.; Tanarro, C.M.G.; Gütschow, M. Novel heterobivalent tacrine derivatives as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase. J. Med. Chem., 2006, 49(25), 7540-7544.
[http://dx.doi.org/10.1021/jm060742o] [PMID: 17149883]
[57]
Luo, W.; Li, Y.P.; He, Y.; Huang, S.L.; Tan, J.H.; Ou, T.M.; Li, D.; Gu, L.Q.; Huang, Z.S. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as dual inhibitors for cholinesterases and amyloid beta aggregation. Bioorg. Med. Chem., 2011, 19(2), 763-770.
[http://dx.doi.org/10.1016/j.bmc.2010.12.022] [PMID: 21211982]
[58]
Luo, W.; Li, Y-P.; He, Y.; Huang, S-L.; Li, D.; Gu, L.Q.; Huang, Z.S. Synthesis and evaluation of heterobivalent tacrine derivatives as potential multi-functional anti-Alzheimer agents. Eur. J. Med. Chem., 2011, 46(6), 2609-2616.
[http://dx.doi.org/10.1016/j.ejmech.2011.03.058] [PMID: 21497959]
[59]
Szymanski, P.; Karpiński, A.; Mikiciuk-Olasik, E. Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2011, 46(8), 3250-3257.
[http://dx.doi.org/10.1016/j.ejmech.2011.04.038] [PMID: 21570751]
[60]
Szymański, P.; Markowicz, M.; Mikiciuk-Olasik, E. Synthesis and biological activity of derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Bioorg. Chem., 2011, 39(4), 138-142.
[http://dx.doi.org/10.1016/j.bioorg.2011.05.001] [PMID: 21621811]
[61]
Zhang, C.; Du, Q.Y.; Chen, L.D.; Wu, W.H.; Liao, S.Y.; Yu, L.H.; Liang, X.T. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer’s disease. Eur. J. Med. Chem., 2016, 116, 200-209.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.077] [PMID: 27061983]
[62]
Szymanski, P.; Karpiński, A.; Mikiciuk-Olasik, E. Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2011, 46(8), 3250-3257.
[http://dx.doi.org/10.1016/j.ejmech. 2011.04.038] [PMID: 21570751]
[63]
Szymański, P.; Lázničková, A.; Lázniček, M.; Bajda, M.; Malawska, B.; Markowicz, M.; Mikiciuk-Olasik, E. 2,3-dihydro-1H-cyclopenta[b]quinoline derivatives as acetylcholinesterase inhibitors-synthesis, radiolabeling and biodistribution. Int. J. Mol. Sci., 2012, 13(8), 10067-10090.
[http://dx.doi.org/10.3390/ijms130810067] [PMID: 22949848]
[64]
Huang, L.; Su, T.; Shan, W.; Luo, Z.; Sun, Y.; He, F.; Li, X. Inhibition of cholinesterase activity and amyloid aggregation by berberine- phenyl-benzoheterocyclic and tacrine-phenyl-benzoheterocyclic hybrids. Bioorg. Med. Chem., 2012, 20(9), 3038-3048.
[http://dx.doi.org/10.1016/j.bmc.2012.02.059] [PMID: 22472046]
[65]
Keri, R.S.; Quintanova, C.; Marques, S.M.; Esteves, A.R.; Cardoso, S.M.; Santos, M.A. Design, synthesis and neuroprotective evaluation of novel tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg. Med. Chem., 2013, 21(15), 4559-4569.
[http://dx.doi.org/10.1016/j.bmc.2013.05.028] [PMID: 23768661]
[66]
Wang, Y.; Guan, X.L.; Wu, P.F.; Wang, C.M.; Cao, H.; Li, L.; Guo, X.J.; Wang, F.; Xie, N.; Jiang, F.C.; Chen, J.G. Multifunctional mercapto-tacrine derivatives for treatment of age-related neurodegenerative diseases. J. Med. Chem., 2012, 55(7), 3588-3592.
[http://dx.doi.org/10.1021/jm300124p] [PMID: 22420827]
[67]
Soto-Ortega, D.D.; Murphy, B.P.; Gonzalez-Velasquez, F.J.; Wilson, K.A.; Xie, F.; Wang, Q.; Moss, M.A. Inhibition of amyloid-β aggregation by coumarin analogs can be manipulated by functionalization of the aromatic center. Bioorg. Med. Chem., 2011, 19(8), 2596-2602.
[http://dx.doi.org/10.1016/j.bmc.2011.03.010] [PMID: 21458277]
[68]
Alagille, D.; DaCosta, H.; Baldwin, R.M.; Tamagnan, G.D. 2-Arylimidazo[2,1-b]benzothiazoles: a new family of amyloid binding agents with potential for PET and SPECT imaging of Alzheimer’s brain. Bioorg. Med. Chem. Lett., 2011, 21(10), 2966-2968.
[http://dx.doi.org/10.1016/j.bmcl.2011.03.052] [PMID: 21458990]
[69]
Wang, Y.; Guan, X.L.; Wu, P.F.; Wang, C.M.; Cao, H.; Li, L.; Guo, X.J.; Wang, F.; Xie, N.; Jiang, F.C.; Chen, J.G. Multifunctional mercapto-tacrine derivatives for treatment of age-related neurodegenerative diseases. J. Med. Chem., 2012, 55(7), 3588-3592.
[http://dx.doi.org/10.1021/jm300124p] [PMID: 22420827]
[70]
Chen, Y.; Sun, J.; Fang, L.; Liu, M.; Peng, S.; Liao, H.; Lehmann, J.; Zhang, Y. Tacrine-ferulic acid-nitric oxide (NO) donor trihybrids as potent, multifunctional acetyl- and butyrylcholinesterase inhibitors. J. Med. Chem., 2012, 55(9), 4309-4321.
[http://dx.doi.org/10.1021/jm300106z] [PMID: 22512543]
[71]
Fernández-Bachiller, M.I.; Pérez, C.; Monjas, L.; Rademann, J.; Rodríguez-Franco, M.I. New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer’s disease, with cholinergic, antioxidant, and β-amyloid-reducing properties. J. Med. Chem., 2012, 55(3), 1303-1317.
[http://dx.doi.org/10.1021/jm201460y] [PMID: 22243648]
[72]
Xie, S.S.; Wang, X.B.; Li, J.Y.; Yang, L.; Kong, L.Y. Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease. Eur. J. Med. Chem., 2013, 64, 540-553.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.051] [PMID: 23685572]
[73]
Xie, S.S.; Wang, X.; Jiang, N.; Yu, W.; Wang, K.D.G.; Lan, J.S.; Li, Z.R.; Kong, L.Y. Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer’s disease. Eur. J. Med. Chem., 2015, 95, 153-165.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.040] [PMID: 25812965]
[74]
Hornick, A.; Lieb, A.; Vo, N.P.; Rollinger, J.M.; Stuppner, H.; Prast, H. The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory. Neuroscience, 2011, 197, 280-292.
[http://dx.doi.org/10.1016/j.neuroscience.2011.09.006] [PMID: 21945033]
[75]
Hamulakova, S.; Poprac, P.; Jomova, K.; Brezova, V.; Lauro, P.; Drostinova, L.; Jun, D.; Sepsova, V.; Hrabinova, M.; Soukup, O.; Kristian, P.; Gazova, Z.; Bednarikova, Z.; Kuca, K.; Valko, M. Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer’s disease using multifunctional tacrine-coumarin hybrid molecules. J. Inorg. Biochem., 2016, 161, 52-62.
[http://dx.doi.org/10.1016/j.jinorgbio.2016.05.001] [PMID: 27230386]
[76]
Sun, Q.; Peng, D.Y.; Yang, S.G.; Zhu, X.L.; Yang, W.C.; Yang, G.F. Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase. Bioorg. Med. Chem., 2014, 22(17), 4784-4791.
[http://dx.doi.org/10.1016/j.bmc.2014.06.057] [PMID: 25088549]
[77]
a)Rodríguez-Franco, M.I.; Fernández-Bachiller, M.I.; Pérez, C.; Hernández-Ledesma, B.; Bartolomé, B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem., 2006, 49(2), 459-462.
[http://dx.doi.org/10.1021/jm050746d] [PMID: 16420031]
b)Di Pietro, O.; Pérez-Areales, F.J.; Juárez-Jiménez, J.; Espargaró, A.; Clos, M.V.; Pérez, B.; Lavilla, R.; Sabaté, R.; Luque, F.J.; Muñoz-Torrero, D. Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies. Eur. J. Med. Chem., 2014, 84, 107-117. PMID: 16420031
[http://dx.doi.org/10.1016/j.ejmech.2014.07.021] [PMID: 25016233]
c)Zawadzka, A.; Czarnocki, Z.; Lozinkka, I.; Moleda, Z.; Panasiewicz, M. Novel Hybrid Cholinesterase Inhibitors. Patent US2014/0080860 A1, March 20. 2014.
[78]
Nepovimova, E.; Uliassi, E.; Korabecny, J.; Peña-Altamira, L.E.; Samez, S.; Pesaresi, A.; Garcia, G.E.; Bartolini, M.; Andrisano, V.; Bergamini, C.; Fato, R.; Lamba, D.; Roberti, M.; Kuca, K.; Monti, B.; Bolognesi, M.L. Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-β aggregation and to exert anticholinesterase and antioxidant effects. J. Med. Chem., 2014, 57(20), 8576-8589.
[http://dx.doi.org/10.1021/jm5010804] [PMID: 25259726]
[79]
Schneider, L.S.; Anand, R.; Farlow, M.R. Systematic review of the efficacy of rivastigmine for patients with Alzheimer’s disease. Int J GeriatrPsychopharmacol, 1998, 1, S26-S34.
[80]
Corey-Bloom, J.; Anand, R.; Veach, J. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J GeriatrPsychopharmacol, 1998, 1, 55-65.
[81]
Rösler, M.; Anand, R.; Cicin-Sain, A.; Gauthier, S.; Agid, Y.; Dal-Bianco, P.; Stähelin, H.B.; Hartman, R.; Gharabawi, M. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ, 1999, 318(7184), 633-638.
[http://dx.doi.org/10.1136/bmj.318.7184.633] [PMID: 10066203]
[82]
Finkel, S.I. Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer’s disease. Clin. Ther., 2004, 26(7), 980-990.
[http://dx.doi.org/10.1016/S0149-2918(04)90172-5] [PMID: 15336465]
[83]
Onor, M.L.; Trevisiol, M.; Aguglia, E. Rivastigmine in the treatment of Alzheimer’s disease: an update. Clin. Interv. Aging, 2007, 2(1), 17-32.
[http://dx.doi.org/10.2147/ciia.2007.2.1.17] [PMID: 18044073]
[84]
Shakya, N.; Fatima, Z.; Nath, C.; Saxena, A.K. Council Of Scientific and Industrial Research India assignee.Substituted carbamic acid quinolin-6-yl esters useful as acetylcholinesterase inhibitors. 2006. Patent WO2006070394, July 6. 2006.
[85]
Roy, K.K.; Dixit, A.; Saxena, A.K. An investigation of structurally diverse carbamates for acetylcholinesterase (AChE) inhibition using 3D-QSAR analysis. J. Mol. Graph. Model., 2008, 27(2), 197-208.
[http://dx.doi.org/10.1016/j.jmgm.2008.04.006] [PMID: 18515163]
[86]
Chaudhaery, S.S.; Roy, K.K.; Saxena, A.K. Consensus superiority of the pharmacophore-based alignment, over maximum common substructure (MCS): 3D-QSAR studies on carbamates as acetylcholinesterase inhibitors. J. Chem. Inf. Model., 2009, 49(6), 1590-1601.
[http://dx.doi.org/10.1021/ci900049e] [PMID: 19441865]
[87]
Chaudhaery, S.S.; Roy, K.K.; Shakya, N.; Saxena, G.; Sammi, S.R.; Nazir, A.; Nath, C.; Saxena, A.K. Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: pharmacophore-based virtual screening, synthesis, and pharmacology. J. Med. Chem., 2010, 53(17), 6490-6505.
[http://dx.doi.org/10.1021/jm100573q] [PMID: 20684567]
[88]
Roy, K.K.; Tota, S.; Tripathi, T.; Chander, S.; Nath, C.; Saxena, A.K. Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer’s disease. Bioorg. Med. Chem., 2012, 20(21), 6313-6320.
[http://dx.doi.org/10.1016/j.bmc.2012.09.005] [PMID: 23026084]
[89]
Shakya, N.; Fatima, Z.; Nath, C.; Saxena, A.K. Substituted carbamic acid quinolin-6-yl esters as acetylcholinesterase inhibitors.2009 Eur. Patent No. 1831172
[90]
Roy, K.K.; Tota, S.K.; Shukla, R.; Nath, C.; Saxena, A.K. Substituted 1, 2, 3, 4-tetrahydroquinolin-7-yl carbamates their preparation and use there of as Acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer’s and other neurodegenerative disease. 2015. US8946261
[91]
Sen, Y.; Lin, F.; Qingli, D.; Rong, C. Jiangsu Xianxiong Pharmaceutical Research Co., Ltd., China assignee. Piperazine compound and its application. 2014. CN102603675
[92]
Imramovsky, A.; Stepankova, S.; Vanco, J.; Pauk, K.; Monreal-Ferriz, J.; Vinsova, J.; Jampilek, J. Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking. Molecules, 2012, 17(9), 10142-10158.
[http://dx.doi.org/ 10.3390/molecules170910142] [PMID: 22922284]
[93]
Bohn, P.; Gourand, F.; Papamicael, C.; Ibazizene, M.; Dhilly, M.; Gembus, V. Alix, Florent.; Mihaela-Liliana, Ţ.; Marsais, F.; Barré, L.; Levacheet, V.; Dihydroquinoline carbamate derivatives as “bio-oxidizable” prodrugs for brain delivery of acetylcholinesterase inhibitors: [13C] radiosynthesis and biological evaluation. Chem Neurosci., 2015, 6, 737-744.
[http://dx.doi.org/10.1021/cn5003539] [PMID: 25695305]
[94]
Belluti, F.; Bartolini, M.; Bottegoni, G.; Bisi, A.; Cavalli, A.; Andrisano, V.; Rampa, A. Benzophenone-based derivatives: a novel series of potent and selective dual inhibitors of acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation. Eur. J. Med. Chem., 2011, 46(5), 1682-1693.
[http://dx.doi.org/ 10.1016/j.ejmech.2011.02.019] [PMID: 21397996]
[95]
Samadi, A.; de la Fuente Revenga, M.; Pérez, C.; Iriepa, I.; Moraleda, I.; Rodríguez-Franco, M.I.; Marco-Contelles, J. Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: new dual AChE inhibitors as potential drugs for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2013, 67, 64-74.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.021] [PMID: 23838422]
[96]
Samadi, A.; Estrada, M.; Pérez, C.; Rodríguez-Franco, M.I.; Iriepa, I.; Moraleda, I.; Chioua, M.; Marco-Contelles, J. Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer’s disease: synthesis, biological assessment, and molecular modeling. Eur. J. Med. Chem., 2012, 57, 296-301.
[http://dx.doi.org/10.1016/j.ejmech.2012.09.030] [PMID: 23078965]
[97]
Bolea, I.; Juárez-Jiménez, J.; de Los Ríos, C.; Chioua, M.; Pouplana, R.; Luque, F.J.; Unzeta, M.; Marco-Contelles, J.; Samadi, A. Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease. J. Med. Chem., 2011, 54(24), 8251-8270.
[http://dx.doi.org/10.1021/jm200853t] [PMID: 22023459]
[98]
Bautista-Aguilera, O.M.; Esteban, G.; Bolea, I.; Nikolic, K.; Agbaba, D.; Moraleda, I.; Iriepa, I.; Samadi, A.; Soriano, E.; Unzeta, M.; Marco-Contelles, J. Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2014, 75, 82-95.
[http://dx.doi.org/10.1016/j.ejmech.2013.12.028] [PMID: 24530494]
[99]
Meng, F.C.; Mao, F.; Shan, W.J.; Qin, F.; Huang, L.; Li, X.S. Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating agents. Bioorg. Med. Chem. Lett., 2012, 22(13), 4462-4466.
[http://dx.doi.org/1 0.1016/j.bmcl.2012.04.029] [PMID: 22633691]
[100]
Alipour, M.; Khoobi, M.; Moradi, A.; Nadri, H.; Homayouni Moghadam, F.; Emami, S.; Hasanpour, Z.; Foroumadi, A.; Shafiee, A. Synthesis and anti-cholinesterase activity of new 7-hydroxycoumarin derivatives. Eur. J. Med. Chem., 2014, 82, 536-544.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.056] [PMID: 24941128]
[101]
Heinrich, M.; Lee Teoh, H. Galanthamine from snowdrop--the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J. Ethnopharmacol., 2004, 92(2-3), 147-162.
[http://dx.doi.org/10.1016/j.jep.2004.02.012] [PMID: 15137996]
[102]
Marco-Contelles, J.; do Carmo Carreiras, M.; Rodríguez, C.; Villarroya, M.; García, A.G. Synthesis and pharmacology of galantamine. Chem. Rev., 2006, 106(1), 116-133.
[http://dx.doi.org/ 10.1021/cr040415t] [PMID: 16402773]
[103]
Bores, G.M.; Huger, F.P.; Petko, W.; Mutlib, A.E.; Camacho, F.; Rush, D.K.; Selk, D.E.; Wolf, V.; Kosley, R.W., Jr; Davis, L.; Vargas, H.M. Pharmacological evaluation of novel Alzheimer’s disease therapeutics: acetylcholinesterase inhibitors related to galanthamine. J. Pharmacol. Exp. Ther., 1996, 277(2), 728-738.
[PMID: 8627552]
[104]
Sramek, J.J.; Frackiewicz, E.J.; Cutler, N.R. Review of the acetylcholinesterase inhibitor galanthamine. Expert Opin. Investig. Drugs, 2000, 9(10), 2393-2402.
[http://dx.doi.org/10.1517/13543784.9.10.2393] [PMID: 11060814]
[105]
Atanasova, M.; Stavrakov, G.; Philipova, I.; Zheleva, D.; Yordanov, N.; Doytchinova, I. Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity. Bioorg. Med. Chem., 2015, 23(17), 5382-5389.
[http://dx.doi.org/10.1016/j.bmc.2015.07.058] [PMID: 26260334]

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