Multifunctional tacrine derivatives in Alzheimer's disease

Current Topics in Medicinal Chemistry

Volumn 13, Issue 15, 2013, Pages 1771-1786

  Minarini, Anna ^a   Milelli, Andrea ^a   Simoni, Elena ^a   Rosini, Michela ^a   Bolognesi, Maria Laura ^a   Marchetti, Chiara ^a   Tumiatti, Vincenzo ^a  

^a UNIVERSITY OF BOLOGNA   (Italy)

Author keywords

Dedicated to Professor Carlo Melchiorre on the occasion of his 70th birthday; Dual binding acetylcholinesterase inhibitors; Multi target directed ligands (MTDLs); Neurodegenerative diseases; Tacrine; Tacrine heterodimers; Tacrine homodimers; Tacrine hybrids

Indexed keywords

ALKOXYBENZENE DERIVATIVE; APORPHINE DERIVATIVE; BETA SECRETASE; CAFFEIC ACID DERIVATIVE; FERULIC ACID; HETERODIMER; HOMODIMER; MELATONIN; MEMANTINE; SILIBININ; TACRINE DERIVATIVE; THIOCTIC ACID; XANOMELINE;

ALZHEIMER DISEASE; BLOOD BRAIN BARRIER; HISTOPATHOLOGY; IC 50; LONG TERM POTENTIATION; NEUROPROTECTION; NONHUMAN; PROTEIN HYDROLYSIS; REVIEW; SIMULATION; SYNAPTIC TRANSMISSION; VASODILATATION;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; CALCIUM CHANNEL BLOCKERS; CALCIUM CHANNELS; CHOLINESTERASES; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; NOOTROPIC AGENTS; RECEPTOR, MUSCARINIC M1; RECEPTORS, N-METHYL-D-ASPARTATE; TACRINE;

EID: 84887888271     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/15680266113139990136     Document Type: Review

References (125)

1. Prince, M.; Bryce, R.; Ferri, C. The benefits of early diagnosis and intervention. King's College: London, 2011.
2. Kling, M. A.; Trojanowski, J. Q.; Wolk, D. A.; Lee, V. M.; Arnold, S. E. Vascular disease and dementias: paradigm shifts to drive research in new directions. Alzheimers Dement, 2013, 9, 76-92.
3. Mayeux, R.; Stern, Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect. Med, 2012, 2, a006239.
4. Masters, C. L.; Selkoe, D. J. Biochemistry of Amyloid beta-Protein and Amyloid Deposits in Alzheimer Disease. Cold Spring Harb Perspect. Med, 2012, 2, a006262.
5. Mucke, L.; Selkoe, D. J. Neurotoxicity of Amyloid beta-Protein: Synaptic and Network Dysfunction. Cold Spring Harb Perspect. Med, 2012, 2, a006338.
6. Kolarova, M.; Garcia-Sierra, F.; Bartos, A.; Ricny, J.; Ripova, D. Structure and pathology of tau protein in Alzheimer disease. Int. J. Alzheimers Dis, 2012, 2012, id 731526.
7. Iqbal, K.; Liu, F.; Gong, C. X.; Grundke-Iqbal, I. Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res, 2010, 7, 656-664.
8. Iqbal, K.; Grundke-Iqbal, I. Alzheimer's disease, a multifactorial disorder seeking multitherapies. Alzheimers Dement, 2010, 6, 420-424.
9. Hardy, J. A hundred years of Alzheimer's disease research. Neuron, 2006, 52, 3-13.
10. Patel, A. N.; Jhamandas, J. H. Neuronal receptors as targets for the action of amyloid-beta protein (Abeta) in the brain. Expert Rev. Mol. Med, 2010, 14, e2.
11. Querfurth, H. W.; LaFerla, F. M. Alzheimer's disease. N. Engl. J. Med, 2010, 362, 329-344.
12. Rafii, M. S.; Aisen, P. S. Recent developments in Alzheimer's disease therapeutics. BMC Med, 2009, 7, 7.
13. Salloway, S.; Mintzer, J.; Weiner, M. F.; Cummings, J. L. Diseasemodifying therapies in Alzheimer's disease. Alzheimers Dement, 2008, 4, 65-79.
14. Tayeb, H. O.; Yang, H. D.; Price, B. H.; Tarazi, F. I. Pharmacotherapies for Alzheimer's disease: beyond cholinesterase inhibitors. Pharmacol. Ther, 2012, 134, 8-25.
15. Winslow, B. T.; Onysko, M. K.; Stob, C. M.; Hazlewood, K. A. Treatment of Alzheimer disease. Am. Fam. Physician, 2011, 83, 1403-1412.
16. Terry, A. V., Jr.; Buccafusco, J. J. The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther, 2003, 306, 821-827.
17. Gualtieri, F.; Dei, S.; Manetti, D.; Romanelli, M. N.; Scapecchi, S.; Teodori, E. The medicinal chemistry of Alzheimer's and Alzheimer-like diseases with emphasis on the cholinergic hypothesis. Farmaco, 1995, 50, 489-503.
18. Melnikova, I. Therapies for Alzheimer's disease. Nat. Rev. Drug Discov, 2007, 6, 341-342.
19. Birks, J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst. Rev, 2006, (1): CD005593.
20. Perry, E. K.; Perry, R. H.; Blessed, G.; Tomlinson, B. E. Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol. Appl. Neurobiol, 1978, 4, 273-277.
21. Lane, R. M.; Potkin, S. G.; Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol, 2006, 9, 101-124.
22. Greig, N. H.; Utsuki, T.; Ingram, D. K.; Wang, Y.; Pepeu, G.; Scali, C.; Yu, Q. S.; Mamczarz, J.; Holloway, H. W.; Giordano, T.; Chen, D.; Furukawa, K.; Sambamurti, K.; Brossi, A.; Lahiri, D. K. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc. Natl. Acad. Sci. U S A, 2005, 102, 17213-17218.
23. Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem, 2005, 48, 6523-6543.
24. Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem, 2008, 51, 347-372.
25. Bolognesi, M. L.; Simoni, E.; Rosini, M.; Minarini, A.; Tumiatti, V.; Melchiorre, C. Multitarget-directed ligands: innovative chemical probes and therapeutic tools against Alzheimer's disease. Curr. Top. Med. Chem, 2011, 11, 2797-2806.
26. Costantino, L.; Barlocco, D. Designed multiple ligands: basic research vs clinical outcomes. Curr. Med. Chem, 2012, 19, 3353-3387.
27. Tumiatti, V.; Minarini, A.; Bolognesi, M. L.; Milelli, A.; Rosini, M.; Melchiorre, C. Tacrine derivatives and Alzheimer's disease. Curr. Med. Chem, 2010, 17, 1825-1838.
28. Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Melchiorre, C. From dual binding site acetylcholinesterase inhibitors to multi-target-directed ligands (MTDLs): a step forward in the treatment of Alzheimer's disease. Mini Rev. Med. Chem, 2008, 8, 960-967.
29. Summers, W. K. Tacrine, and Alzheimer's treatments. J. Alzheimers Dis, 2006, 9, 439-445.
30. Patocka, J.; Jun, D.; Kuca, K. Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease. Curr. Drug Metab, 2008, 9, 332-335.
31. Gracon, S. I.; Knapp, M. J.; Berghoff, W. G.; Pierce, M.; DeJong, R.; Lobbestael, S. J.; Symons, J.; Dombey, S. L.; Luscombe, F. A.; Kraemer, D. Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. Alzheimer Dis. Assoc. Disord, 1998, 12, 93-101.
32. Pacheco, G.; Palacios-Esquivel, R.; Moss, D. E. Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase. J. Pharmacol. Exp. Ther, 1995, 274, 767-770.
33. Arendt, T.; Bruckner, M. K.; Lange, M.; Bigl, V. Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development--a study of molecular forms. Neurochem. Int, 1992, 21, 381-396.
34. Chianella, C.; Gragnaniello, D.; Maisano Delser, P.; Visentini, M. F.; Sette, E.; Tola, M. R.; Barbujani, G.; Fuselli, S. BCHE and CYP2D6 genetic variation in Alzheimer's disease patients treated with cholinesterase inhibitors. Eur. J. Clin. Pharmacol, 2011, 67, 1147-1157.
35. Xiao, X. Q.; Wang, R.; Tang, X. C. Huperzine A and tacrine attenuate beta-amyloid peptide-induced oxidative injury. J. Neurosci. Res, 2000, 61, 564-569.
36. Wang, R.; Zhou, J.; Tang, X. C. Tacrine attenuates hydrogen peroxide-induced apoptosis by regulating expression of apoptosis-related genes in rat PC12 cells. Brain Res. Mol. Brain Res, 2002, 107, 1-8.
37. Zhang, W.; Jin, H. W.; Xu, S. F.; Qu, L. T.; Wang, X. L. [Inhibition of tacrine on delayed rectifier and transient outward potassium currents in cultured rat hippocampal neurons]. Yao Xue Xue Bao, 2004, 39, 93-96.
38. Ezoulin, M. J.; Liu, Z.; Dutertre-Catella, H.; Wu, G.; Dong, C. Z.; Heymans, F.; Ombetta, J. E.; Rat, P.; Massicot, F. A new acetylcholinesterase inhibitor with anti-PAF activity modulates oxidative stress and pro-inflammatory mediators release in stimulated RAW 264. 7 macrophage cells. Comparison with tacrine. Int. Immunopharmacol, 2007, 7, 1685-1694.
39. Shevtsov, P. N.; Shevtsova, E. F.; Burbaeva, G. Effect of tacrine, amiridine, akatinol memantine, and triazolam on phosphorylation, structure, and assembly of microtubules from brain microtubular proteins in Alzheimer diseases. Bull. Exp. Biol. Med, 2008, 145, 218-222.
40. Pang, Y. P.; 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, 1996, 271, 23646-23649.
41. Silman, I.; Sussman, J. L. Acetylcholinesterase: 'classical' and 'nonclassical' functions and pharmacology. Curr. Opin. Pharmacol, 2005, 5, 293-302.
42. Johnson, G.; Moore, S. W. The peripheral anionic site of acetylcholinesterase: structure, functions and potential role in rational drug design. Curr. Pharm. Des, 2006, 12, 217-225.
43. Munoz-Torrero, D. Acetylcholinesterase inhibitors as diseasemodifying therapies for Alzheimer's disease. Curr. Med. Chem, 2008, 15, 2433-2455.
44. Cavalli, A.; Bolognesi, M. L.; Capsoni, S.; Andrisano, V.; Bartolini, M.; Margotti, E.; Cattaneo, A.; Recanatini, M.; Melchiorre, C. A small molecule targeting the multifactorial nature of Alzheimer's disease. Angew. Chem. Int. Ed. Engl, 2007, 46, 3689-3692.
45. Garcia-Palomero, E.; Munoz, P.; Usan, P.; Garcia, P.; Delgado, E.; De Austria, C.; Valenzuela, R.; Rubio, L.; Medina, M.; Martinez, A. Potent beta-amyloid modulators. Neurodegener. Dis, 2008, 5, 153-156.
46. Spuch, C.; Antequera, D.; Isabel Fernandez-Bachiller, M.; Isabel Rodriguez-Franco, M.; Carro, E. A new tacrine-melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer's disease. Neurotox. Res, 2010, 17, 421-431.
47. 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, 187-201.
48. Fang, J. H.; Wang, X. H.; Xu, Z. R.; Jiang, F. G. Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage. BMC Neurosci, 2010, 11, 31.
49. Nakamura, T.; Lipton, S. A. Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death Differ, 2011, 18, 1478-1486.
50. Fu, H.; Dou, J.; Li, W.; Cui, W.; Mak, S.; Hu, Q.; Luo, J.; Lam, C. S.; Pang, Y.; Youdim, M. B.; Han, Y. Promising multifunctional anti-Alzheimer's dimer bis(7)-Cognitin acting as an activator of protein kinase C regulates activities of alpha-secretase and BACE-1 concurrently. Eur. J. Pharmacol, 2009, 623, 14-21.
51. Luo, J.; Li, W.; Zhao, Y.; Fu, H.; Ma, D. L.; Tang, J.; Li, C.; Peoples, R. W.; Li, F.; Wang, Q.; Huang, P.; Xia, J.; Pang, Y.; Han, Y. Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin. J. Biol. Chem, 2010, 285, 19947-19958.
52. Yao, L.; Li, W.; She, H.; Dou, J.; Jia, L.; He, Y.; Yang, Q.; Zhu, J.; Capiro, N. L.; Walker, D. I.; Pennell, K. D.; Pang, Y.; Liu, Y.; Han, Y.; Mao, Z. Activation of transcription factor MEF2D by bis(3)-cognitin protects dopaminergic neurons and ameliorates Parkinsonian motor defects. J. Biol. Chem, 2012, 287, 34246-34255.
53. Han, R. W.; Zhang, R. S.; Chang, M.; Peng, Y. L.; Wang, P.; Hu, S. Q.; Choi, C. L.; Yin, M.; Wang, R.; Han, Y. F. Reversal of scopolamine-induced spatial and recognition memory deficits in mice by novel multifunctional dimers bis-cognitins. Brain Res, 2012, 1470, 59-68.
54. Castro, A.; Martinez, A. Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors. Curr. Pharm. Des, 2006, 12, 4377-4387.
55. Inestrosa, N. C.; Dinamarca, M. C.; Alvarez, A. Amyloidcholinesterase interactions. Implications for Alzheimer's disease. FEBS J, 2008, 275, 625-632.
56. Butini, S.; Campiani, G.; Borriello, M.; Gemma, S.; Panico, A.; Persico, M.; Catalanotti, B.; Ros, S.; Brindisi, M.; Agnusdei, M.; Fiorini, I.; Nacci, V.; Novellino, E.; Belinskaya, T.; Saxena, A.; Fattorusso, C. Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors. J. Med. Chem, 2008, 51, 3154-3170.
57. Bolognesi, M. L.; Cavalli, A.; Valgimigli, L.; Bartolini, M.; Rosini, M.; Andrisano, V.; Recanatini, M.; Melchiorre, C. Multi-targetdirected drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease. J. Med. Chem, 2007, 50, 6446-6449.
58. Bolognesi, M. L.; Bartolini, M.; Mancini, F.; Chiriano, G.; Ceccarini, L.; Rosini, M.; Milelli, A.; Tumiatti, V.; Andrisano, V.; Melchiorre, C. Bis(7)-tacrine derivatives as multitarget-directed ligands: Focus on anticholinesterase and antiamyloid activities. ChemMedChem, 2010, 5, 1215-1220.
59. Wood, P. L.; Khan, M. A.; Moskal, J. R. Cellular thiol pools are responsible for sequestration of cytotoxic reactive aldehydes: central role of free cysteine and cysteamine. Brain Res, 2007, 1158, 158-163.
60. Fox, J. H.; Barber, D. S.; Singh, B.; Zucker, B.; Swindell, M. K.; Norflus, F.; Buzescu, R.; Chopra, R.; Ferrante, R. J.; Kazantsev, A.; Hersch, S. M. Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation. J. Neurochem, 2004, 91, 413-422.
61. Tremblay, M. E.; Saint-Pierre, M.; Bourhis, E.; Levesque, D.; Rouillard, C.; Cicchetti, F. Neuroprotective effects of cystamine in aged parkinsonian mice. Neurobiol. Aging, 2006, 27, 862-870.
62. Stack, E. C.; Ferro, J. L.; Kim, J.; Del Signore, S. J.; Goodrich, S.; Matson, S.; Hunt, B. B.; Cormier, K.; Smith, K.; Matson, W. R.; Ryu, H.; Ferrante, R. J. Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson's disease. Biochim. Biophys. Acta, 2008, 1782, 151-162.
63. Dedeoglu, A.; Kubilus, J. K.; Jeitner, T. M.; Matson, S. A.; Bogdanov, M.; Kowall, N. W.; Matson, W. R.; Cooper, A. J.; Ratan, R. R.; Beal, M. F.; Hersch, S. M.; Ferrante, R. J. Therapeutic effects of cystamine in a murine model of Huntington's disease. J. Neurosci, 2002, 22, 8942-8950.
64. Minarini, A.; Milelli, A.; Tumiatti, V.; Rosini, M.; Simoni, E.; Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Motori, E.; Angeloni, C.; Hrelia, S. Cystamine-tacrine dimer: A new multi-targetdirected ligand as potential therapeutic agent for Alzheimer's disease treatment. Neuropharmacology, 2012, 62, 997-1003.
65. Gella, A.; Durany, N. Oxidative stress in Alzheimer disease. Cell Adh. Migr, 2009, 3, 88-93.
66. Lee, H. P.; Zhu, X.; Casadesus, G.; Castellani, R. J.; Nunomura, A.; Smith, M. A.; Lee, H. G.; Perry, G. Antioxidant approaches for the treatment of Alzheimer's disease. Expert Rev. Neurother, 2010, 10, 1201-1208.
67. 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, 109-117.
68. Rosini, M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.; McClymont, D. W.; Tarozzi, A.; Bolognesi, M. L.; Minarini, A.; Tumiatti, V.; Andrisano, V.; Mellor, I. R.; Melchiorre, C. Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush. J. Med. Chem, 2008, 51, 4381-4384.
69. Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M. L.; Hrelia, P.; Minarini, A.; Tarozzi, A.; Melchiorre, C. Rational approach to discover multipotent anti-Alzheimer drugs. J. Med. Chem, 2005, 48, 360-363.
70. Bolognesi, M. L.; Minarini, A.; Tumiatti, V.; Melchiorre, C. Lipoic acid, a lead structure for multi-target-directed drugs for neurodegeneration. Mini Rev. Med. Chem, 2006, 6, 1269-1274.
71. Rosini, M.; Simoni, E.; Bartolini, M.; Tarozzi, A.; Matera, R.; Milelli, A.; Hrelia, P.; Andrisano, V.; Bolognesi, M. L.; Melchiorre, C. Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer's disease. Eur. J. Med. Chem, 2011, 46, 5435-5442.
72. Fang, L.; Kraus, B.; Lehmann, J.; Heilmann, J.; Zhang, Y.; Decker, M. Design and synthesis of tacrine-ferulic acid hybrids as multipotent anti-Alzheimer drug candidates. Bioorg. Med. Chem. Lett, 2008, 18, 2905-2909.
73. Heilmann, J.; Calis, I.; Kirmizibekmez, H.; Schuhly, W.; Harput, S.; Sticher, O. Radical scavenger activity of phenylethanoid glycosides in FMLP stimulated human polymorphonuclear leukocytes: structure-activity relationships. Planta Med, 2000, 66, 746-748.
74. Yan, J. J.; Cho, J. Y.; Kim, H. S.; Kim, K. L.; Jung, J. S.; Huh, S. O.; Suh, H. W.; Kim, Y. H.; Song, D. K. Protection against beta-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br. J. Pharmacol, 2001, 133, 89-96.
75. Davalos, A.; Gomez-Cordoves, C.; Bartolome, B. Extending applicability of the oxygen radical absorbance capacity (ORACfluorescein) assay. J. Agric. Food Chem, 2004, 52, 48-54.
76. Fleck, C.; Appenroth, D.; Fang, L.; Schott, Y.; Lehmann, J.; Decker, M. Investigation into the in vivo effects of five novel tacrine/ferulic acid and beta-carboline derivatives on scopolamineinduced cognitive impairment in rats using radial maze paradigm. Arzneimittel-Forschung, 2010, 60, 299-306.
77. Pi, R.; Mao, X.; Chao, X.; Cheng, Z.; Liu, M.; Duan, X.; Ye, M.; Chen, X.; Mei, Z.; Liu, P.; Li, W.; Han, Y. Tacrine-6-ferulic acid, a novel multifunctional dimer, inhibits amyloid-beta-mediated Alzheimer's disease-associated pathogenesis in vitro and in vivo. PLoS One, 2012, 7, e31921.
78. Huang, W. Y.; Chao, X. J.; Ouyang, Y.; Liu, A. M.; He, X. X.; Chen, M. H.; Wang, L. H.; Liu, J.; Yu, S. W.; Rapposelli, S.; Pi, R. B. Tacrine-6-ferulic acid, a novel multifunctional dimer against Alzheimer's disease, prevents oxidative stress-induced neuronal death through activating Nrf2/ARE/HO-1 pathway in HT22 cells. CNS Neurosci. Ther, 2012, 18, 950-951.
79. Zhang, H.; Mak, S.; Cui, W.; Li, W.; Han, R.; Hu, S.; Ye, M.; Pi, R.; Han, Y. Tacrine(2)-ferulic acid, a novel multifunctional dimer, attenuates 6-hydroxydopamine-induced apoptosis in PC12 cells by activating Akt pathway. Neurochem. Int, 2011, 59, 981-988.
80. Fernandez, A. P.; Pozo-Rodrigalvarez, A.; Serrano, J.; Martinez-Murillo, R. Nitric Oxide: Target for Therapeutic Strategies in Alzheimer's Disease. Curr. Pharm. Des, 2010, 16, 2837-2850.
81. Chen, Y.; Sun, J. F.; Fang, L.; Liu, M.; Peng, S. X.; Liao, H.; Lehmann, J.; Zhang, Y. H. Tacrine-Ferulic Acid-Nitric Oxide (NO) Donor Trihybrids as Potent, Multifunctional Acetyl-and Butyrylcholinesterase Inhibitors. J. Med. Chem, 2012, 55, 4309-4321.
82. Lupp, A.; Appenroth, D.; Fang, L.; Decker, M.; Lehmann, J.; Fleck, C. Tacrine-NO donor and tacrine-ferulic acid hybrid molecules as new anti-Alzheimer agents: hepatotoxicity and influence on the cytochrome P450 system in comparison to tacrine. Arzneimittel-Forschung, 2010, 60, 229-237.
83. Chao, X.; He, X.; Yang, Y.; Zhou, X.; Jin, M.; Liu, S.; Cheng, Z.; Liu, P.; Wang, Y.; Yu, J.; Tan, Y.; Huang, Y.; Qin, J.; Rapposelli, S.; Pi, R. Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease. Bioorg. Med. Chem. Lett, 2012, 22, 6498-6502.
84. Fernandez-Bachiller, M. I.; Perez, C.; Campillo, N. E.; Paez, J. A.; Gonzalez-Munoz, G. C.; Usan, P.; Garcia-Palomero, E.; Lopez, M. G.; Villarroya, M.; Garcia, A. G.; Martinez, A.; Rodriguez-Franco, M. I. Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties. ChemMedChem, 2009, 4, 828-841.
85. Fang, L.; Appenroth, D.; Decker, M.; Kiehntopf, M.; Roegler, C.; Deufel, T.; Fleck, C.; Peng, S.; Zhang, Y.; Lehmann, J. Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates. J. Med. Chem, 2008, 51, 713-716.
86. Guinaudeau, H.; Leboeuf, M.; Cave, A. Aporphinoid Alkaloids, V. J. Nat. Prod, 1994, 57, 1033-1135.
87. Tang, H.; Wei, Y. B.; Zhang, C.; Ning, F. X.; Qiao, W.; Huang, S. L.; Ma, L.; Huang, Z. S.; Gu, L. Q. Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase. Eur. J. Med. Chem, 2009, 44, 2523-2532.
88. Tang, H.; Zhao, L. Z.; Zhao, H. T.; Huang, S. L.; Zhong, S. M.; Qin, J. K.; Chen, Z. F.; Huang, Z. S.; Liang, H. Hybrids of oxoisoaporphine-tacrine congeners: Novel acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation inhibitors. Eur. J. Med. Chem, 2011, 46, 4970-4979.
89. Hung, T. M.; Na, M.; Min, B. S.; Ngoc, T. M.; Lee, I.; Zhang, X.; Bae, K. Acetylcholinesterase inhibitory effect of lignans isolated from Schizandra chinensis. Arch. Pharm. Res, 2007, 30, 685-690.
90. Jeong, E. J.; Lee, H. K.; Lee, K. Y.; Jeon, B. J.; Kim, D. H.; Park, J. H.; Song, J. H.; Huh, J.; Lee, J. H.; Sung, S. H. The effects of lignan-riched extract of Shisandra chinensis on amyloid-beta-induced cognitive impairment and neurotoxicity in the cortex and hippocampus of mouse. J. Ethnopharmacol, 2013, 146, 347-354.
91. Nadri, H.; Pirali-Hamedani, M.; Shekarchi, M.; Abdollahi, M.; Sheibani, V.; Amanlou, M.; Shafiee, A.; Foroumadi, A. Design, synthesis and anticholinesterase activity of a novel series of 1-benzyl-4-(6-alkoxy-3-oxobenzofuran-2(3H)-ylidene) methyl) pyridinium derivatives. Bioorg. Med. Chem, 2010, 18, 6360-6366.
92. 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, 763-770.
93. 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, 2609-2616.
94. Rizzo, S.; Bisi, A.; Bartolini, M.; Mancini, F.; Belluti, F.; Gobbi, S.; Andrisano, V.; Rampa, A. Multi-target strategy to address Alzheimer's disease: design, synthesis and biological evaluation of new tacrine-based dimers. Eur. J. Med. Chem, 2011, 46, 4336-4343.
95. Pietta, P. G. Flavonoids as antioxidants. J. Nat. Prod, 2000, 63, 1035-1042.
96. Shimmyo, Y.; Kihara, T.; Akaike, A.; Niidome, T.; Sugimoto, H. Flavonols and flavones as BACE-1 inhibitors: structure-activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features. Biochim. Biophys. Acta, 2008, 1780, 819-825.
97. Fernandez-Bachiller, M. I.; Perez, C.; Monjas, L.; Rademann, J.; Rodriguez-Franco, M. I. New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and beta-amyloid-reducing properties. J. Med. Chem, 2012, 55, 1303-1317.
98. Fu, H.; Li, W.; Luo, J.; Lee, N. T.; Li, M.; Tsim, K. W.; Pang, Y.; Youdim, M. B.; Han, Y. Promising anti-Alzheimer's dimer bis(7)-tacrine reduces beta-amyloid generation by directly inhibiting BACE-1 activity. Biochem. Biophys. Res. Commun, 2008, 366, 631-636.
99. Camps, P.; Formosa, X.; Munoz-Torrero, D.; Petrignet, J.; Badia, A.; Clos, M. V. Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: subnanomolar dual binding site acetylcholinesterase inhibitors. J. Med. Chem, 2005, 48, 1701-1704.
100. Camps, P.; Cusack, B.; Mallender, W. D.; El Achab, R. E.; Morral, J.; Munoz-Torrero, D.; Rosenberry, T. L. Huprine X is a novel highaffinity inhibitor of acetylcholinesterase that is of interest for treatment of Alzheimer's disease. Mol. Pharmacol, 2000, 57, 409-417.
101. Galdeano, C.; Viayna, E.; Sola, I.; Formosa, X.; Camps, P.; Badia, A.; Clos, M. V.; Relat, J.; Ratia, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Salmona, M.; Minguillon, C.; Gonzalez-Munoz, G. C.; Rodriguez-Franco, M. I.; Bidon-Chanal, A.; Luque, F. J.; Munoz-Torrero, D. Huprine-tacrine heterodimers as antiamyloidogenic compounds of potential interest against Alzheimer's and prion diseases. J. Med. Chem, 2012, 55, 661-669.
102. Pera, M.; Roman, S.; Ratia, M.; Camps, P.; Munoz-Torrero, D.; Colombo, L.; Manzoni, C.; Salmona, M.; Badia, A.; Clos, M. V. Acetylcholinesterase triggers the aggregation of PrP 106-126. Biochem. Biophys. Res. Commun, 2006, 346, 89-94.
103. 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, 992-998.
104. Loguercio, C.; Festi, D. Silybin and the liver: from basic research to clinical practice. World J. Gastroenterol, 2011, 17, 2288-2301.
105. Chen, X.; Zenger, K.; Lupp, A.; Kling, B.; Heilmann, J.; Fleck, C.; Kraus, B.; Decker, M. Tacrine-silibinin codrug shows neuro-and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo. J. Med. Chem, 2012, 55, 5231-5242.
106. Barnham, K. J.; Bush, A. I. Metals in Alzheimer's and Parkinson's diseases. Curr. Opin. Chem. Biol, 2008, 12, 222-228.
107. Dong, J.; Atwood, C. S.; Anderson, V. E.; Siedlak, S. L.; Smith, M. A.; Perry, G.; Carey, P. R. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry, 2003, 42, 2768-2773.
108. Smith, D. G.; Cappai, R.; Barnham, K. J. The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim. Biophys. Acta, 2007, 1768, 1976-1990.
109. Ritchie, C. W.; Bush, A. I.; Mackinnon, A.; Macfarlane, S.; Mastwyk, M.; MacGregor, L.; Kiers, L.; Cherny, R.; Li, Q. X.; Tammer, A.; Carrington, D.; Mavros, C.; Volitakis, I.; Xilinas, M.; Ames, D.; Davis, S.; Volitakis, I.; Xilinas, M.; Ames, D.; Davis, S.; Beyreuther, K.; Tanzi, R. E.; Masters, C. L. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting A beta amyloid deposition and toxicity in Alzheimer disease-A pilot phase 2 clinical trial. Arch. Neurol, 2003, 60, 1685-1691.
110. Mclachlan, D. R. C.; Dalton, A. J.; Kruck, T. P. A.; Bell, M. Y.; Smith, W. L.; Kalow, W.; Andrews, D. F. Intramuscular Desferrioxamine in Patients with Alzheimers-Disease. Lancet, 1991, 337, 1304-1308.
111. Squitti, R.; Rossini, P. M.; Cassetta, E.; Moffa, F.; Pasqualetti, P.; Cortesi, M.; Colloca, A.; Rossi, L.; Finazzi-Agro, A. Dpenicillamine reduces serum oxidative stress in Alzheimer's disease patients. Eur. J. Clin. Invest, 2002, 32, 51-59.
112. Fernandez-Bachiller, M. I.; Perez, C.; Gonzalez-Munoz, G. C.; Conde, S.; Lopez, M. G.; Villarroya, M.; Garcia, A. G.; Rodriguez-Franco, M. I. Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J. Med. Chem, 2010, 53, 4927-4937.
113. Antequera, D.; Bolos, M.; Spuch, C.; Pascual, C.; Ferrer, I.; Fernandez-Bachiller, M. I.; Rodriguez-Franco, M. I.; Carro, E. Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Abeta accumulation and cell death: involvement in hippocampal neuronal loss in Alzheimer's disease. Neurobiol. Dis, 2012, 46, 682-691.
114. 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-phenylbenzoheterocyclic hybrids. Bioorg. Med. Chem, 2012, 20, 3038-3048.
115. Lee, Y. S.; Silva, A. J. The molecular and cellular biology of enhanced cognition. Nat. Rev. Neurosci, 2009, 10, 126-140.
116. Cai, F.; Wang, F.; Lin, F. K.; Liu, C.; Ma, L. Q.; Liu, J.; Wu, W. N.; Wang, W.; Wang, J. H.; Chen, J. G. Redox modulation of long-term potentiation in the hippocampus via regulation of the glycogen synthase kinase-3beta pathway. Free Radic. Biol. Med, 2008, 45, 964-970.
117. Yue, J.; Dong, G.; He, C.; Chen, J.; Liu, Y.; Peng, R. Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats. Toxicology, 2009, 264, 185-191.
118. 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, 3588-3592.
119. Fisher, A. M1 muscarinic agonists target major hallmarks of Alzheimer's disease--the pivotal role of brain M1 receptors. Neurodegener. Dis, 2008, 5, 237-240.
120. Sadot, E.; Gurwitz, D.; Barg, J.; Behar, L.; Ginzburg, I.; Fisher, A. Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J. Neurochem, 1996, 66, 877-880.
121. Fang, L.; Jumpertz, S.; Zhang, Y.; Appenroth, D.; Fleck, C.; Mohr, K.; Trankle, C.; Decker, M. Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors. J. Med. Chem, 2010, 53, 2094-2103.
122. Marco-Contelles, J.; Leon, R.; de los Rios, C.; Samadi, A.; Bartolini, M.; Andrisano, V.; Huertas, O.; Barril, X.; Luque, F. J.; Rodriguez-Franco, M. I.; Lopez, B.; Lopez, M. G.; Garcia, A. G.; Carreiras Mdo, C.; Villarroya, M. Tacripyrines, the first tacrinedihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease. J. Med. Chem, 2009, 52, 2724-2732.
123. Bartolini, M.; Pistolozzi, M.; Andrisano, V.; Egea, J.; Lopez, M. G.; Iriepa, I.; Moraleda, I.; Galvez, E.; Marco-Contelles, J.; Samadi, A. Chemical and Pharmacological Studies on Enantiomerically Pure p-Methoxytacripyrines, Promising Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease. ChemMedChem, 2011, 6, 1990-1997.
124. Camps, P.; Formosa, X.; Galdeano, C.; Munoz-Torrero, D.; Ramirez, L.; Gomez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M. V.; Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M. P.; Rodriguez-Franco, M. I.; Huertas, O.; Dafni, T.; Luque, F. J. Pyrano[3, 2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase-and beta-amyloid-directed anti-Alzheimer compounds. J. Med. Chem, 2009, 52, 5365-5379.
125. Ouberai, M.; Brannstrom, K.; Vestling, M.; Olofsson, A.; Dumy, P.; Chierici, S.; Garcia, J. Clicked tacrine conjugates as acetylcholinesterase and beta-amyloid directed compounds. Org. Biomol. Chem, 2011, 9, 1140-1147.