N-alkylated Tacrine Derivatives as Potential Agents in Alzheimer’s Disease Therapy

Author(s): Eugenie Nepovimova, Jan Korabecny, Vendula Hepnarova, Daniel Jun, Rafael Dolezal, Lubica Muckova, Petr Jost, Ondrej Soukup, Jana Janockova, Ngoc Lam Pham, Thuy Duong Nguyen, Martin Valis, Kamil Kuca*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 4 , 2019

  Journal Home
Translate in Chinese
Submit Manuscript
Submit Proposal


Background: Based on the prevalence studies, the number of people suffering from dementia will almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050, assuming no changes in mortality, effective preventative measures, definitive diagnostic guidelines or curative treatment. From the abovementioned epidemiological data, it is obvious that dementia constitutes a major public health problem not only at present, but unfortunately also in the future.

Objectives and Methods: Several N-alkylated tacrine (THA) derivatives have already been synthesized by Pomponi et al., in 1997. However, these compounds were tested for their anti-AChE activity using enzyme isolated from Electrophorus electricus. For this reason, we have decided to extend the previously reported series of THA derivatives and consequently test them in the battery of experiments, the results of which have served to more relevant evaluation of these compounds from the perspective of Alzeimer´s disease compared to that published by Pomponi.

Results and Conclusion: In summary, all compounds of interest effectively inhibited ChEs in vitro. One of the most promising derivatives 8 bearing an N-octyl chain showed 2.5-fold higher AChE inhibitory activity in relation to tacrine. With respect to blood-brain barrier (BBB) penetration, it can be claimed that synthesized analogues are presumably able to cross the BBB. From the point of view of hepatotoxicity, selected Nalkylated tacrine derivatives exerted worse results compared to tacrine. However, in vitro results are only illustrative, therefore, only in vivo experiments could determine the real value of selected N-alkylated THA derivatives.

Keywords: Tacrine, Alzheimer's disease, acetylcholinesterase, butyrylcholinesterase, dementia, neuro.

Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 368(9533): 387-403. (2006).
Yankner BA. Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 16(5): 921-32. (1996).
Bossy-Wetzel E, Schwarzenbacher R, Lipton SA. Molecular pathways to neurodegeneration. Nat Med 10(Suppl.): S2-9. (2004).
Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 366(9503): 2112-7. (2005).
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement J Alzheimers Assoc 9(1): 63-75.e2. (2013).
Marešová P, Mohelská H, Dolejš J, Kuča K. Socio-economic Aspects of Alzheimer’s Disease. Curr Alzheimer Res 12(9): 903-11. (2015).
Kuca K, Soukup O, Maresova P, Korabecny J, Nepovimova E, Klimova B, et al. Current approaches against Alzheimer’s disease in clinical trials. J Braz Chem Soc 27(4): 641-9. (2016).
Talesa VN. Acetylcholinesterase in Alzheimer’s disease. Mech Ageing Dev 122(16): 1961-9. (2001).
Chatonnet A, Lockridge O. Comparison of butyrylcholinesterase and acetylcholinesterase. Biochem J 260(3): 625-34. (1989).
Ballard CG, Greig NH, Guillozet-Bongaarts AL, Enz A, Darvesh S. Cholinesterases: roles in the brain during health and disease. Curr Alzheimer Res 2(3): 307-18. (2005).
Darvesh S, Hopkins DA, Geula C. Neurobiology of butyrylcholinesterase. Nat Rev Neurosci 4(2): 131-8. (2003).
Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL. Acetylcholinesterase: from 3D structure to function. Chem Biol Interact 187(1-3): 10-22. (2010).
Inestrosa NC, Alvarez A, Pérez CA, Moreno RD, Vicente M, Linker C, et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 16(4): 881-91. (1996).
Shah RS, Lee H-G, Xiongwei Z, Perry G, Smith MA, Castellani RJ. Current approaches in the treatment of Alzheimer’s disease. Biomed Pharmacother Biomedecine Pharmacother 62(4): 199-207. (2008).
Giacobini E. Cholinesterase inhibitors: new roles and therapeutic alternatives. Pharmacol Res 50(4): 433-40. (2004).
Ibach B, Haen E. Acetylcholinesterase inhibition in Alzheimer’s Disease. Curr Pharm Des 10(3): 231-51. (2004).
Zemek F, Drtinova L, Nepovimova E, et al. Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin Drug Saf 13(6): 759-74. (2014).
Davis KL, Powchik P. Tacrine. Lancet Lond Engl 345(8950): 625-30. (1995).
Freeman SE, Dawson RM. Tacrine: a pharmacological review. Prog Neurobiol 36(4): 257-77. (1991).
Summers WK. Tacrine, and Alzheimer’s treatments. J Alzheimers Dis 9(3): 439-45. (2006).
Gracon SI, Knapp MJ, Berghoff WG, Pierce M, DeJong R, Lobbestael SJ, et al. Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. Alzheimer Dis Assoc Disord 12(2): 93-101. (1998).
Lahiri DK, Farlow MR, Sambamurti K. The secretion of amyloid beta-peptides is inhibited in the tacrine-treated human neuroblastoma cells. Brain Res Mol Brain Res 62(2): 131-40. (1998).
Lahiri DK, Lewis S, Farlow MR. Tacrine alters the secretion of the beta-amyloid precursor protein in cell lines. J Neurosci Res 37(6): 777-87. (1994).
Basun H, Nilsberth C, Eckman C, Lannfelt L, Younkin S. Plasma levels of Abeta42 and Abeta40 in Alzheimer patients during treatment with the acetylcholinesterase inhibitor tacrine. Dement Geriatr Cogn Disord 14(3): 156-60. (2002).
Svensson AL, Nordberg A. Tacrine and donepezil attenuate the neurotoxic effect of A beta(25-35) in rat PC12 cells. Neuroreport 9(7): 1519-22. (1998).
Takada Y, Yonezawa A, Kume T, Katsuki H, Kaneko S, Sugimoto H, et al. Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J Pharmacol Exp Ther 306(2): 772-7. (2003).
Spilovska K, Korabecny J, Nepovimova E, et al. Multitarget tacrine hybrids with neuroprotective properties to confront Alzheimer’s disease. Curr Top Med Chem 17(9): 1006-26. (2017).
Horak M, Holubova K, Nepovimova E. Krusek J1, Kaniakova M1, Korabecny J, et al. The pharmacology of tacrine at N-methyl-d-aspartate receptors. Prog Neuropsychopharmacol Biol Psychiatry 75: 54-62. (2017).
Soukup O, Jun D, Zdarova-Karasova J, Patocka J, Musilek K, Korabecny J, et al. A resurrection of 7-MEOTA: a comparison with tacrine. Curr Alzheimer Res 10(8): 893-906. (2013).
Pomponi M, Marta M, Colella A, Sacchi S, Patamia M, Gatta F, et al. Studies on a new series of THA analogues: effects of the aromatic residues that line the gorge of AChE. FEBS Lett 409(2): 155-60. (1997).
Worek F, Reiter G, Eyer P, Szinicz L. Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch Toxicol 76(9): 523-9. (2002).
Ellman GL, Courtney KD, Andres V, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7: 88-95. (1961).
Bajgar J. Determination of acetylcholinesterase activity in human blood - possible modification for fields conditions. Mili Medical Sci Letters 41: 78-80. (1972).
Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, et al. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 55(22): 10282-6. (2012).
Spilovska K, Korabecny J, Sepsova V, Jun D, Hrabinova M, Jost P, et al. Novel Tacrine-Scutellarin Hybrids as Multipotent Anti- Alzheimer’s Agents: Design, Synthesis and Biological Evaluation. Mol Basel Switz 22(6): pii: E1006 (2017).
Korabecny J, Andrs M, Nepovimova E, Dolezal R, Babkova K, Horova A, et al. 7-Methoxytacrine-p-anisidine hybrids as novel dual binding site acetylcholinesterase inhibitors for alzheimer’s disease treatment. Mol Basel Switz 20(12): 22084-101. (2015).
Nepovimova E, Korabecny J, Dolezal R, et al. Tacrine-trolox hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity. J Med Chem 58(22): 8985-9003. (2015).
Nepovimova E, Korabecny J, Dolezal R, Nguyen TD, Jun D, Soukup O, et al. A 7-methoxytacrine–4-pyridinealdoxime hybrid as a novel prophylactic agent with reactivation properties in organophosphate intoxication. Toxicol Res 5(4): 1012-6. (2016).
Korabecny J, Dolezal R, Cabelova P, Horova A, Hruba E, Ricny J, et al. 7-MEOTA-donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies. Eur J Med Chem 82: 426-38. (2014).
Hamulakova S, Janovec L, Hrabinova M, Spilovska K, Korabecny J, Kristian P, et al. Synthesis and biological evaluation of novel tacrine derivatives and tacrine-coumarin hybrids as cholinesterase inhibitors. J Med Chem 57(16): 7073-84. (2014).
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1-2): 55-63. (1983).
Di L, Kerns EH, Fan K, McConnell OJ, Carter GT. High throughput artificial membrane permeability assay for blood-brain barrier. Eur J Med Chem 38(3): 223-32. (2003).
Bautista-Aguilera ÓM, Hagenow S, Palomino-Antolin A, et al. Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine h3 r antagonism for neurodegenerative diseases. Angew Chem Int Ed Engl 56(41): 12765-9. (2017).
Korabecny J, Musilek K, Holas O, Binder J, Zemek F, Marek J, et al. Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease. Bioorg Med Chem Lett 20(20): 6093-5. (2010).
Nordberg A, Ballard C, Bullock R, Darreh-Shori T, Somogyi M. A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer’s disease Prim Care Companion CNS Disord 15(2): pii: PCC.12r01412 (2013).
Darvesh S. Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer’s Disease. Curr Alzheimer Res 13(10): 1173-7. (2016).
Recanatini M, Cavalli A, Belluti F, et al. SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. J Med Chem 43(10): 2007-18. (2000).
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2): 455-61. (2010).
Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 90(19): 9031-5. (1993).
Spilovska K, Korabecny J, Horova A, Musilek K, Nepovimova E, Drtinova L, et al. Design, synthesis and in vitro testing of 7-methoxytacrine-amantadine analogues: a novel cholinesterase inhibitors for the treatment of Alzheimer’s disease. Med Chem Res 24(6): 2645-55. (2015).
Pang YP, Quiram P, Jelacic T, Hong F, Brimijoin S. Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer’s disease. J Biol Chem 271(39): 23646-9. (1996).
Korabecny J, Musilek K, Zemek F, Horova A, Holas O, Nepovimova E, et al. Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine-new tacrine derivate with cholinergic properties. Bioorg Med Chem Lett 21(21): 6563-6. (2011).
McEneny-King A, Osman W, Edginton AN, Rao PPN. Cytochrome P450 binding studies of novel tacrine derivatives: predicting the risk of hepatotoxicity. Bioorg Med Chem Lett 27(11): 2443-9. (2017).
Ji L, Schüürmann G. Model and mechanism: n-hydroxylation of primary aromatic amines by cytochrome P450. Angew Chem Int Ed 52(2): 744-8. (2013).
Monteith DK, Emmerling MR, Garvin J, Theiss JC. Cytotoxicity study of tacrine, structurally and pharmacologically related compounds using rat hepatocytes. Drug Chem Toxicol 19(1-2): 71-84. (1996).
Park BK, Madden S, Spaldin V, Woolf TF, Pool WF. Tacrine transaminitis: potential mechanisms. Alzheimer Dis Assoc Disord 8(2): S39-49. (1994).
Mersch-Sundermann V, Knasmüller S, Wu XJ, Darroudi F, Kassie F. Use of a human-derived liver cell line for the detection of cytoprotective, antigenotoxic and cogenotoxic agents. Toxicology 198(1-3): 329-34. (2004).
Kassa J, Korabecny J, Sepsova V, Tumova M. The evaluation of prophylactic efficacy of newly developed reversible inhibitors of acetylcholinesterase in soman-poisoned mice - a comparison with commonly used pyridostigmine. Basic Clin Pharmacol Toxicol 115(6): 571-6. (2014).
Misik J, Korabecny J, Nepovimova E, Cabelova P, Kassa J. The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test. Biomed Pap Med Fac Univ Palacky Olomouc Czechoslov 159(4): 547-53. (2015).
Misik J, Korabecny J, Nepovimova E, Kracmarova A, Kassa J. Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-quinuclidinyl benzilate-induced cognitive deficit in rats--Is there a potential for Alzheimer’s disease treatment? Neurosci Lett 612: 261-8. (2016).
De-Mello N, Carobrez AP. Elevated T-maze as an animal model of memory: effects of scopolamine. Behav Pharmacol 13(2): 139-48. (2002).
D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36(1): 60-90. (2001).
Gacar N, Mutlu O, Utkan T, Komsuoglu Celikyurt I, Gocmez SS, et al. Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats. Pharmacol Biochem Behav 99(3): 316-23. (2011).
Misik J, Kassa J. A comparison of cholinesterase inhibitors in the treatment of quinuclidinyl benzilate-induced behavioural deficit in rats performing the multiple T-maze. J Appl Biomed 12(4): 211-7. (2014).
Misik J, Vanek J, Musilek K, Kassa J. Cholinergic antagonist 3-quinuclidinyl benzilate - Impact on learning and memory in Wistar rats. Behav Brain Res 266: 193-200. (2014).
Misik J, Nepovimova E, Pejchal J, Kassa J, Korabecny J, Soukup O. Cholinesterase Inhibitor 6-Chlorotacrine - In Vivo Toxicological Profile and Behavioural Effects. Curr Alzheimer Res 15(6): 552-60. (2018).

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [333 - 343]
Pages: 11
DOI: 10.2174/1567205016666190314163942
Price: $58

Article Metrics

PDF: 23
PRC: 1