Dual inhibitors of β-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates

Current Topics in Medicinal Chemistry

Volumn 13, Issue 15, 2013, Pages 1820-1842

  Viayna, Elisabet ^a   Sabate, Raimon ^b   Muñoz Torrero, Diego ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

^b UNIVERSITY OF BARCELONA   (Spain)

Author keywords

Aggregation; Alzheimer's disease; Amyloid; Bacterial inclusion bodies; Dual inhibitors; In vivo assays

Indexed keywords

4 AMINOQUINOLINE; ACETYLCHOLINESTERASE; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; BENZOFURAN DERIVATIVE; BERBERINE; CHELERYTHRINE; CURCUMIN; CYSTAMINE; DONEPEZIL; FLAVONE DERIVATIVE; GALANTAMINE; GREEN FLUORESCENT PROTEIN; HOMOTAURINE; PYRIMIDINE DERIVATIVE; RESVERATROL; RIVASTIGMINE; TACRINE; TRIAZINE DERIVATIVE;

ALZHEIMER DISEASE; ANTIOXIDANT ACTIVITY; ATOMIC FORCE MICROSCOPY; CELL INCLUSION; FLOW CYTOMETRY; HUMAN; IC 50; INFRARED SPECTROSCOPY; MOLECULAR DOCKING; MOLECULAR DYNAMICS; NERVE CELL PLASTICITY; NEUROPATHOLOGY; NONHUMAN; PROTEIN DEGRADATION; PROTEIN PROTEIN INTERACTION; REVIEW; SIMULATION; STRUCTURE ACTIVITY RELATION; SYNAPTIC TRANSMISSION; TRANSMISSION ELECTRON MICROSCOPY; X RAY DIFFRACTION;

ACETYLCHOLINESTERASE; ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ACID ENDOPEPTIDASES; DRUG DESIGN; ENZYME INHIBITORS; ESCHERICHIA COLI; FLOCCULATION; GENES, REPORTER; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; NOOTROPIC AGENTS; RECOMBINANT PROTEINS;

EID: 84887887445     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/15680266113139990139     Document Type: Review

References (147)

1. Aguzzi, A.; O'Connor, T. Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nat. Rev. Drug Discovery, 2010, 9, 237-248.
2. Bartolini, M.; Andrisano, V. Strategies for the inhibition of protein aggregation in human diseases. ChemBioChem, 2010, 11, 1018-1035.
3. Kapurniotu, A. Shedding light on Alzheimer's [-amyloid aggregation with chemical tools. ChemBioChem, 2012, 13, 27-29.
4. Estrada, L. D.; Soto, C. Disrupting [-amyloid aggregation for Alzheimer's disease treatment. Curr. Top. Med. Chem, 2007, 7, 115-126.
5. Neddenriep, B.; Calciano, A.; Conti, D.; Sauve, E.; Paterson, M.; Bruno, E.; Moffet, D. A. Short peptides as inhibitors of amyloid aggregation. Open Biotechnol. J, 2011, 5, 39-46.
6. Hammer, N. D.; Wang, X.; McGuffie, B. A.; Chapman, M. R. Amyloids: friend or foe? J. Alzheimer Dis, 2008, 13, 407-419.
7. Chiti, F.; Dobson, C. M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem, 2006, 75, 333-366.
8. Selkoe, D. J. Resolving controversies on the path to Alzheimer's therapeutics. Nat. Med. 2011, 17, 1060-1065.
9. Hamley, I. W. The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization. Chem. Rev, 2012, 112, 5147-5192.
10. Blennow, K.; Hampel, H.; Weiner, M.; Zetterberg, H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 2010, 6, 131-144.
11. Selkoe, D. J. The molecular pathology of Alzheimer's disease. Neuron, 1991, 6, 487-498.
12. Hardy, J. A.; Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science, 1992, 256, 184-185.
13. Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 2002, 297, 353-356.
14. Hardy, J. Testing times for the "amyloid cascade hypothesis. " Neurobiol. Aging, 2002, 23, 1073-1074.
15. Pimplikar, S. W. Reassessing the amyloid cascade hypothesis of Alzheimer's disease. Int. J. Biochem. Cell Biol, 2009, 41, 1261-1268.
16. Kung, H. F. The [-amyloid hypothesis in Alzheimer's disease: seeing is believing. ACS Med. Chem. Lett, 2012, 3, 265-267.
17. Yankner, B. A.; Lu, T. Amyloid [-protein toxicity and the pathogenesis of Alzheimer's disease. J. Biol. Chem, 2009, 284, 4755-4759.
18. Bertram, L.; Tanzi, R. E. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat. Rev. Neurosci, 2008, 9, 768-778.
19. Wilquet, V.; De Strooper, B. Amyloid-beta precursor protein processing in neurodegeneration. Curr. Opin. Neurobiol, 2004, 14, 582-588.
20. Hawkes, C. A.; Ng, V.; McLaurin, J. Small molecule inhibitors of AAAaggregation and neurotoxicity. Drug Dev. Res, 2009, 70, 111-124.
21. Rentz, D. M.; Locascio, J. J.; Becker, J. A.; Moran, E. K.; Eng, E.; Bruckner, R. L.; Sperling R. A.; Johnson, K. A. Cognition, reserve, and amyloid deposition in normal aging. Ann. Neurol, 2010, 67, 353-364.
22. Nordberg, A. Amyloid plaque imaging in vivo: current achievement and future prospects. Eur. J. Nucl. Med. Mol. Imaging, 2008, 35(Suppl. 1), S46-S50.
23. Villemagne, V. L.; Fodero-Tavoletti, M. T.; Pike, K. E.; Cappai, R.; Masters, C. L.; Rowe, C. C. The ART of loss: AMMimaging in the evaluation of Alzheimer's disease and other dementias. Mol. Neurobiol, 2008, 38, 1-15.
24. Valensin, D.; Gabbiani, C.; Messori, L. Metal compounds as inhibitors of o-amyloid aggregation. Perspectives for an innovative metallotherapeutics on Alzheimer's disease. Coord. Chem. Rev, 2012, 256, 2357-2366.
25. Deshpande, A.; Mina, E.; Glabe, C.; Busciglio, J. Different conformations of amyloid ooinduce neurotoxicity by distinct mechanisms in human cortical neurons. J. Neurosci, 2006, 26, 6011-6018.
26. Walsh, D. M.; Selkoe, D. J. A[oligomers-a decade of discovery. J. Neurochem. 2007, 101, 1172-1184.
27. Yoshiike, Y.; Akagi, T.; Takashima, A. Surface structure of amyloid-beta fibrils contributes to cytotoxicity. Biochemistry 2007, 46, 9805-9812.
28. 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.
29. Kamenetz, F.; Tomita, T.; Hsieh, H.; Seabrook, G.; Borchelt, D.; Iwatsubo, T.; Sisodia, S.; Malinow, R. APP processing and synaptic function. Neuron, 2003, 37, 925-937.
30. Plant, L. D.; Boyle, J. P.; Smith, I. F.; Peers, C.; Pearson, H. A. The production of amyloid pppeptide is a critical requirement for the viability of central neurons. J. Neurosci, 2003, 23, 5531-5535.
31. Re, F.; Airoldi, C.; Zona, C.; Masserini, M.; La Ferla, B.; Quattrocchi, N.; Nicotra, F. Beta amyloid aggregation inhibitors: small molecules as candidate drugs for therapy of Alzheimer's disease. Curr. Med. Chem, 2010, 17, 2990-3006.
32. Stains, C. I.; Mondal, K.; Gosh, I. Molecules that target betaamyloid. ChemMedChem, 2007, 2, 1674-1692.
33. Gestwicki, J. E.; Crabtree, G. R.; Graef, I. A. Harnessing chaperones to generate small-molecule inhibitors of amyloid ttaggregation. Science, 2004, 306, 865-869.
34. Teplow, D. B.; Lazo, N. D.; Bitan, G.; Bernstein, S.; Wyttenbach, T.; Bowers, M. T.; Baumketner, A.; Shea, J.-M.; Urbanc, B.; Cruz, L.; Borreguero, J.; Stanley, H. E. Elucidating amyloid L-protein folding and assembly: a multidisciplinary approach. Acc. Chem. Res, 2006, 39, 635-645.
35. Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V. Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem. Pharmacol, 2003, 65, 407-416.
36. Bartolini, M.; Bertucci, C.; Bolognesi, M. L.; Cavalli, A.; Melchiorre, C.; Andrisano, V. Insight into the kinetic of amyloid CC(1(42) peptide self-aggregation: Elucidation of inhibitors' mechanism of action. ChemBioChem, 2007, 8, 2152-2161.
37. Lemkul, J. A.; Bevan, D. R. The role of molecular simulations in the development of inhibitors of amyloid d-peptide aggregation for the treatment of Alzheimer's disease. ACS Chem. Neurosci, 2012, 3, 845-856.
38. Yadav, A.; Sonker, M. Perspectives in designing anti aggregation agents as Alzheimer disease drugs. Eur. J. Med. Chem, 2009, 44, 3866-3873.
39. Viayna, E.; Sola, I.; Di Pietro, O.; Muñoz-Torrero, D. Human disease and drug pharmacology, complex as real life. Curr. Med. Chem, 2013, 20, 1623-1634.
40. Bolognesi, M. L. Polypharmacology in a single drug: multitarget drugs. Curr. Med. Chem, 2013, 20, 1639-1645.
41. Morphy, R.; Rankovic, Z. Designing multiple-ligands-medicinal chemistry strategies and challenges. Curr. Pharm. Des, 2009, 15, 587-600.
42. 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.
43. Geldenhuys, W. J.; Van der Schyf, C. J. Rationally designed multitargeted agents against neurodegenerative diseases. Curr. Med. Chem, 2013, 20, 1662-1672.
44. Chen, X.; Decker, M. Multi-target compounds acting in the central nervous system designed from natural products. Curr. Med. Chem, 2013, 20, 1673-1685.
45. Russo, P.; Frustaci, A.; Del Bufalo, A.; Fini, M.; Cesario, A. Multitarget drugs of plants origin acting on Alzheimer's disease. Curr. Med. Chem, 2013, 20, 1686-1693.
46. Zheng, H.; Fridkin, M.; Youdim, M. B. H. Novel chelators targeting cell cycle arrest, acetylcholinesterase, and monoamine oxidase for Alzheimer's therapy. Curr. Drug Targets, 2012, 13, 1089-1106.
47. Soler-López, M.; Zanzoni, A.; Lluís, R.; Stelzl, U.; Aloy, P. Interactome mapping suggests new mechanistic details underlying Alzheimer's disease. Genome Res, 2011, 21, 364-376.
48. 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-a-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron, 1996, 16, 881-891.
49. Alvarez, A.; Alarcón, R.; Opazo, C.; Campos, E. O.; Muñoz, F. J.; Calderón, F. H.; Dajas, F.; Gentry, M. K.; Doctor, B. P.; De Mello, F. G.; Inestrosa, N. C. Stable complexes involving acetylcholinesterase and amyloid-a-peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer's fibrils. J. Neurosci, 1998, 18, 3213-3223.
50. 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, 10447-10457.
51. Sussman, J. L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman, A.; Toker, L.; Silman, I. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science, 1991, 253, 872-879.
52. Castro, A.; Martinez, A. Peripheral and dual binding site acetylcholinesterase inhibitors: implications in treatment of Alzheimer's disease. Mini Rev. Med. Chem, 2001, 1, 267-272.
53. Du, D.-M.; Carlier, P. R. Development of bivalent acetylcholinesterase inhibitors as potential therapeutic drugs for Alzheimer's disease. Curr. Pharm. Des, 2004, 10, 3141-3156.
54. Recanatini, M.; Valenti, P. Acetylcholinesterase inhibitors as a starting point towards improved Alzheimer's disease therapeutics. Curr. Pharm. Des, 2004, 10, 3157-3166.
55. Muñoz-Torrero, D.; Camps, P. Dimeric and hybrid anti-Alzheimer drug candidates. Curr. Med. Chem, 2006, 13, 763-771.
56. Castro, A.; Martinez, A. Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors. Curr. Pharm. Des, 2006, 12, 4377-4387.
57. Li, W. M.; Kan, K. K. W.; Carlier, P. R.; Pang, Y. P.; Han, Y. F. East meets West in the search for Alzheimer's therapeutics-Novel dimeric inhibitors from tacrine and huperzine A. Curr. Alzheimer Res, 2007, 4, 386-396.
58. Holzgrabe, U.; Kapková, P.; Alptüzün, V.; Scheiber, J.; Kugelmann, E. Targeting acetylcholinesterase to treat neurodegeneration. Expert Opin. Ther. Targets, 2007, 11, 161-179.
59. Musial, A.; Bajda, M.; Malawska, B. Recent developments in cholinesterases inhibitors for Alzheimer's disease treatment. Curr. Med. Chem, 2007, 14, 2654-2679.
60. Haviv, H.; Wong, D. M.; Silman, I.; Sussman, J. L. Bivalent ligands derived from huperzine A as acetylcholinesterase inhibitors. Curr. Top. Med. Chem, 2007, 7, 375, 387.
61. Muñoz-Torrero, D. Acetylcholinesterase inhibitors as diseasemodifying therapies for Alzheimer's disease. Curr. Med. Chem, 2008, 15, 2433-2455.
62. Rampa, A.; Belluti, F.; Gobbi, S.; Bisi, A. Hybrid-based multitarget ligands for the treatment of Alzheimer's disease. Curr. Top. Med. Chem, 2011, 11, 2716-2730.
63. Ellman, G. L.; Courtney, K. D.; Andres, B., Jr.; Featherstone, R. M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol, 1961, 7, 88-95.
64. Pang, Y.-P.; Quiram, P.; Jelacic, T.; Hong, F.; Brimijoin, S. Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. J. Biol. Chem, 1996, 271, 23646-23649.
65. Zhang, L.; Yu, H.; Li, W. M.; Cheung, M. C.; Pang, Y. P.; Gu, Z. M.; Chan, K.; Wang, Y. T.; Zuo, Z.; Han, Y. F. Preclinical characterization of intestinal absorption and metabolism of promising anti-Alzheimer's dimer bis(7)-tacrine. Int. J. Pharm, 2008, 357, 85-94.
66. 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.
67. 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.
68. 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.
69. 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.
70. 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.
71. Lane, R. M.; Potkin, S. G.; Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol, 2006, 9, 101-124.
72. Rizzo, S.; Bisi, A.; Bartolini, M.; Mancini, F.; Belluti, F.; Gobbi, S.; Andrisano, V.; Rampa, A. Multi-target strategy to address Alz heimer's disease: design, synthesis and biological evaluation of new tacrine-based dimers. Eur. J. Med. Chem, 2011, 46, 4336-4343.
73. 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.; Minguillón, C.; González-Muñoz, G. C.; Rodríguez-Franco, M. I.; Bidon-Chanal, A.; Luque, F. J.; Muñoz-Torrero, D. Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases. J. Med. Chem, 2012, 55, 661-669.
74. Camps, P.; El Achab, R.; Morral, J.; Muñoz-Torrero, D.; Badia, A.; Baños, J. E.; Vivas, N. M.; Barril, X.; Orozco, M.; Luque, F. J. New tacrinethuperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. J. Med. Chem, 2000, 43, 4657-4666.
75. Pera, M.; Román, S.; Ratia, M.; Camps, P.; Muñoz-Torrero, D.; Colombo, L.; Manzoni, C.; Salmona, M.; Badia, A.; Clos, M. V. Acetylcholinesterase triggers the aggregation of PrP 106A126. Biochem. Biophys. Res. Commun, 2006, 346, 89-94.
76. Pera, M.; Martínez-Otero, A.; Colombo, L.; Salmona, M.; Ruiz-Molina, D.; Badia, A.; Clos, M. V. Acetylcholinesterase as an amyloid enhancing factor in PrP82e146 aggregation process. Mol. Cel. Neurosci, 2009, 40, 217-224.
77. Zhang, H.-Y. Same causes, same cures. Biochem. Biophys. Res. Commun, 2006, 351, 578-581.
78. 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.
79. 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.
80. 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.
81. 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.
82. 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 i-amyloid aggregation inhibitors. Eur. J. Med. Chem, 2011, 46, 4970-4979.
83. Bulic, B.; Pickhardt, M.; Schmidt, B.; Mandelkow, E. M.; Waldmann, H.; Mandelkow, E. Development of tau aggregation inhibitors for Alzheimer's disease. Angew. Chem., Int. Ed, 2009, 48, 1740-1752.
84. 2+ overload. Bioorg. Med. Chem, 2012, 20, 6513-6522.
85. 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.
86. Marco-Contelles, J.; León, R.; de los Ríos, C.; Samadi, A.; Bartolini, M.; Andrisano, V.; Huertas, O.; Barril, X.; Luque, F. J.; Rodríguez-Franco, M. I.; López, B.; López, M. G.; García, A. G.; Carreiras, M. 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.
87. 2+ dyshomeostatis. Curr. Med. Chem, 2011, 18, 552-576.
88. Bartolini, M.; Pistolozzi, M.; Andrisano, V.; Egea, J.; López, M. G.; Iriepa, I.; Moraleda, I.; Gálvez, E.; Marco-Contelles, J.; Samadi, A. Chemical and pharmacological studies on enantiomerically pure pmethoxytacripyrines, promising multi-target-directed ligands for the treatment of Alzheimer's disease. ChemMedChem, 2011, 6, 1990-1997.
89. Bolognesi, M. L.; Cavalli, A.; Melchiorre, C. Memoquin: a multitarget-directed ligand as an innovative therapeutic opportunity for Alzheimer's disease. Neurotherapeutics, 2009, 6, 152-162.
90. 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, 2007, 46, 3689-3692.
91. Bolognesi, M. L.; Bartolini, M.; Rosini, M.; Andrisano, V.; Melchiorre, C. Structure-activity relationships of memoquin: influence of the chain chirality in the multi-target mechanism of action. Bioorg. Med. Chem. Lett, 2009, 19, 4312-4315.
92. Capsoni, S.; Andrisano, V.; Bartolini, M.; Bolognesi, M. L.; Cavalli, A.; Margotti, E.; Melchiorre, C.; Recanantini, M.; Cattaneo, A. Memoquin, a novel multifunctional compound for Alzheimer's disease: an up-date on preclinical studies. Alzheimer's Dementia, 2006, 2, S73-S74.
93. Bolognesi, M. L.; Chiriano, G.; Bartolini, M.; Mancini, F.; Bottegoni, G.; Maestri, V.; Czvitkovich, S.; Windisch, M.; Cavalli, A.; Minarini, A.; Rosini, M.; Tumiatti, V.; Andrisano, V.; Melchiorre, C. Synthesis of monomeric derivatives to probe memoquin's bivalent interactions. J. Med. Chem, 2011, 54, 8299-8304.
94. Bolognesi, M. L.; Bartolini, M.; Tarozzi, A.; Morroni, F.; Lizzi, F.; Milelli, A.; Minarini, A.; Rosini, M.; Hrelia, P.; Andrisano, V.; Melchiorre, C. Multitargeted drugs discovery: balancing antiamyloid and anticholinesterase capacity in a single chemical entity. Bioorg. Med. Chem. Lett, 2011, 21, 2655-2658.
95. Bolognesi, M. L.; Cavalli, A.; Bergamini, C.; Fato, R.; Lenaz, G.; Rosini, M.; Bartolini, M.; Andrisano, V.; Melchiorre, C. Toward a rational design of multitarget-directed antioxidants: merging memoquin and lipoic acid molecular frameworks. J. Med. Chem, 2009, 52, 7883-7886.
96. 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.
97. Tumiatti, V.; Andrisano, V.; Banzi, R.; Bartolini, M.; Minarini, A.; Rosini, M.; Melchiorre, C. Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties. J. Med. Chem, 2004, 47, 6490-6498.
98. Tumiatti, V.; Milelli, A.; Minarini, A.; Rosini, M.; Bolognesi, M. L.; Micco, M.; Andrisano, V.; Bartolini, M.; Mancini, F.; Recanatini, M.; Cavalli, A.; Melchiorre, C. Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 4. Further investigation in the inner spacer. J. Med. Chem, 2008, 51, 7308-7312.
99. Huang, L.; Shi, A.; He, F.; Li, X. Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors. Bioorg. Med. Chem, 2010, 18, 1244-1251.
100. Shi, A.; Huang, L.; Lu, C.; He, F.; Li, X. Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and β-amyloid aggregation inhibitors. Bioorg. Med. Chem, 2011, 19, 2298-2305.
101. Jiang, H.; Wang, X.; Huang, L.; Luo, Z.; Su, T.; Ding, K.; Li, X. Benzenediol-berberine hybrids: multifunctional agents for Alzheimer's disease. Bioorg. Med. Chem, 2011, 19, 7228-7235.
102. Tang, H.; Zhao, H.-T.; Zhong, S.-M.; Wang, Z.-Y.; Chen, Z.-F.; Liang, H. Novel oxoisoaporphine-based inhibitors of acetyl-and butyrylcholinesterase and acetylcholinesterase-induced betaamyloid aggregation. Bioorg. Med. Chem. Lett, 2012, 22, 2257-2261.
103. Sauvaître, T.; Barlier, M.; Herlem, D.; Gresh, N.; Chiaroni, A.; Guenard, D.; Guillou, C. New potent acetylcholinesterase inhibitors in the tetracyclic triterpene series. J. Med. Chem, 2007, 50, 5311-5323.
104. Rouleau, J.; Iorga, B. I.; Guillou, C. New potent human acetylcholinesterase inhibitors in the tetracyclic triterpene series with inhibitory potency on amyloid aggregation. Eur. J. Med. Chem, 2011, 46, 2193-2205.
105. Brunhofer, G.; Fallalero, A.; Karlsson, D.; Batista-Gonzalez, A.; Shinde, P.; Mohan, C. G.; Vuorela, P. Exploration of natural com pounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine. Bioorg. Med. Chem, 2012, 20, 6669-6679.
106. Jang, M. H.; Piao, X. L.; Kim, J. M.; Kwon, S. W.; Park, J. H. Inhibition of cholinesterase and amyloid-α aggregation by resveratrol oligomers from Vitis amurensis. Phytother. Res, 2008, 22, 544-549.
107. Liu, J.; Dumontet, V.; Simonin, A.-L.; Iorga, B. I.; Guerineau, V.; Litaudon, M.; Nguyen V. H.; Gueritte, F. Benzofurans from Styrax agrestis as acetylcholinesterase inhibitors: structure-activity relationships and molecular modeling studies. J. Nat. Prod, 2011, 74, 2081-2088.
108. Piazzi, L.; Belluti, F.; Bisi, A.; Gobbi, S.; Rizzo, S.; Bartolini, M.; Andrisano, V.; Recanatini, M.; Rampa, A. Cholinesterase inhibitors: SAR and enzyme inhibitory activity of 3-[omega-(benzylmethylamino)alkoxy]xanthen-9-ones. Bioorg. Med. Chem, 2007, 15, 575-585.
109. Howlett, D. R.; Perry, A. E.; Godfrey, F.; Swatton, J. E.; Jennings, K. H.; Spitzfaden, C.; Wadsworth, H.; Wood, S. J.; Markwell, R. E. Inhibition of fibril formation in I-amyloid peptide by a novel series of benzofurans. Biochem. J, 1999, 340, 283-289.
110. Rizzo, S.; Rivière, C.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Andrisano, V.; Morroni, F.; Tarozzi, A.; Monti, J.-P.; Rampa, A. Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, aaamyloid aggregation, and Aaaneurotoxicity. J. Med. Chem, 2008, 51, 2883-2886.
111. Rizzo, S.; Tarozzi, A.; Bartolini, M.; Da Costa, G.; Bisi, A.; Gobbi, S.; Belluti, F.; Ligresti, A.; Allarà, M.; Monti, J.-P.; Andrisano, V.; Di Marzo, V.; Hrelia, P.; Rampa, A. 2-Arylbenzofuran-based molecules as multipotent Alzheimer's disease modifying agents. Eur. J. Med. Chem, 2012, 58, 519-532.
112. Pike, C. J.; Walencewicz-Wasserman, A. J.; Kosmoski, J.; Cribbs, D. H.; Glabe, C. G.; Cotman, C. W. Structure-activity analyses of D-amyloid peptides: contributions of the a25-35 region to aggregation and neurotoxicity. J. Neurochem. 1995, 64, 253-265.
113. Mohamed, T.; Zhao, X.; Habib, L. K.; Yang, J.; Rao, P. P. N. Design, synthesis and structure-activity relationship (SAR) studies of 2, 4-disubstituted pyrimidine derivatives: dual activity as cholinesterase and Aa-aggregation inhibitors. Bioorg. Med. Chem, 2011, 19, 2269-2281.
114. Mohamed, T.; Yeung, J. C. K.; Rao, P. P. N. Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and Aa-aggregation inhibitors: synthesis and biological evaluation. Bioorg. Med. Chem. Lett, 2011, 21, 5881-5887.
115. Catto, M.; Berezin, A. A.; Lo Re, D.; Loizou, G.; Demetriades, M.; De Stradis, A.; Campagna, F.; Koutentis, P. A.; Carotti, A. Design, synthesis and biological evaluation of benzo[e][1, 2, 4]triazin-7(1H)-one and [1, 2, 4]-triazino[5, 6, 1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloid aggregation and acetyl/buturyl cholinesterase. Eur. J. Med. Chem, 2012, 58, 84-97.
116. Veloso, A. J.; Dhar, D.; Chow, A. M.; Zhang, B.; Tang, D. W. F.; Ganesh, H. V. S.; Mikhaylichenko, S.; Brown, I. R.; Kerman, K. sym-Triazines for directed multitarget modulation of cholinesterases and amyloid-aain Alzheimer's disease. ACS Chem. Neurosci, 2013, 4, 339-349.
117. Viayna, E.; Gómez, T.; Galdeano, C.; Ramírez, L.; Ratia, M.; Badia, A.; Clos, M. V.; Verdaguer, E.; Junyent, F.; Camins, A.; Pallàs, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M. P.; Rodríguez-Franco, M. I.; Bidon-Chanal, A.; Luque, F. J.; Camps, P.; Muñoz-Torrero, D. Novel huprine derivatives with inhibitory activity toward t-amyloid aggregation and formation as diseasemodifying anti-Alzheimer drug candidates. ChemMedChem, 2010, 5, 1855-1870.
118. Camps, P.; Formosa, X.; Galdeano, C.; Gómez, T.; Muñoz-Torrero, D.; Scarpellini, M.; Viayna, E.; Badia, A.; Clos, M. V.; Camins, A.; Pallàs, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Estelrich, J.; Lizondo, M.; Bidon-Chanal, A.; Luque, F. J. Novel donepezil-based inhibitors of acetyl-and butyrylcholinesterase and acetylcholinesterase-induced i-amyloid aggregation. J. Med. Chem, 2008, 51, 3588, 3598.
119. Piazzi, L.; Rampa, A.; Bisi, A.; Gobbi, S.; Belluti, F.; Cavalli, A.; Bartolini, M.; Andrisano, V.; Valenti, P.; Recanatini, M. 3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6, 7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced i-amyloid aggregation: a dual function lead for Alzheimer's disease therapy. J. Med. Chem, 2003, 46, 2279-2282.
120. Rizzo, S.; Bartolini, M.; Ceccarini, L.; Piazzi, L.; Gobbi, S.; Cavalli, A.; Recanatini, M.; Andrisano, V.; Rampa, A. Targeting Alzheimer's disease: novel indanone hybrids bearing a pharmacophoric fragment of AP2238. Bioorg. Med. Chem, 2010, 18, 1749-1760.
121. Belluti, F.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Cavalli, A.; Valenti, P.; Rampa, A. Design, synthesis, and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors. Eur. J. Med. Chem, 2009, 44, 1341-1348.
122. 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 beta-amyloid aggregation. Eur. J. Med. Chem, 2011, 46, 1682-1693.
123. Ignasik, M.; Bajda, M.; Guzior, N.; Prinz, M.; Holzgrabe, U.; Malawska, B. Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1, 3-dione derivatives as dual-binding site acetylcholinesterase inhibitors. Arch. Pharm. Chem. Life Sci, 2012, 345, 509-516.
124. Özer, E. Ö.; Tan, O. U.; Ozadali, K.; Küçükkilinç, T.; Balkan, A.; Uçar, G. Synthesis, molecular modeling and evaluation of novel N'-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives as dual inhibitors for cholinesterases and Aaaaggregation. Bioorg. Med. Chem. Lett, 2013, 23, 440-443.
125. Peng, D.-Y.; Sun, Q.; Zhu, X.-L.; Lin, H.-Y.; Chen, Q.; Yu, N.-X.; Yang, W. C.; Yang, G. F. Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multifunctions on butylcholinesterase, Aooaggregation, and a-secretase. Bioorg. Med. Chem, 2012, 20, 6739-6750.
126. Rizzo, S.; Cavalli, A.; Ceccarini, L.; Bartolini, M.; Belluti, F.; Bisi, A.; Andrisano, V.; Recanatini, M.; Rampa, A. Structure-activity relationships and binding mode in the human acetylcholinesterase active site of pseudo-irreversible inhibitors related to xanthostigmine. ChemMedChem, 2009, 4, 670-679.
127. Rampa, A.; Bisi, A.; Valenti, P.; Recanatini, M.; Cavalli, A.; Andrisano, V.; Cavrini, V.; Fin, L.; Buriani, A.; Giusti, P. Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of α-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyheteroaryl derivatives. J. Med Chem, 1998, 41, 3976-3986.
128. LeVine, H., III. Thioflavine T interaction with synthetic Alzheimer's disease d-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci, 1993, 2, 404-410.
129. Barabási, A. L.; Oltvai, Z. N.; Network biology: understanding the cell's functional organization. Nat. Rev. Genet, 2004, 5, 101-113.
130. Lee, J. A.; Uhlik, M. T.; Moxham, C. M.; Tomandl, D.; Sall, D. J. Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. J. Med. Chem, 2012, 55, 4527-4538.
131. Ellis, R. J.; Minton, A. P. Join the crowd. Nature, 2003, 425, 27-28.
132. Ami, D.; Natalello, A.; Lotti, M.; Doglia, S. M. Why and how protein aggregation has to be studied in vivo. Microb. Cell Fact, 2013, 12, 17.
133. Villar-Piqué, A.; Ventura, S. Modeling amyloids in bacteria. Microb. Cell Fact, 2012, 11, 166.
134. García-Fruitós, E.; Sabate, R.; de Groot, N. S.; Villaverde, A.; Ventura, S. Biological role of bacterial inclusion bodies: a model of amyloid aggregation. FEBS J, 2011, 278, 2419-2427.
135. de Groot, N. S.; Sabate, R.; Ventura, S. Amyloids in bacterial inclusion bodies. Trends Biochem. Sci, 2009, 34, 408-416.
136. Ventura, S.; Villaverde, A. Protein quality in bacterial inclusion bodies. Trends Biotechnol, 2006, 24, 179-185.
137. Carrió, M.; González-Montalbán, N.; Vera, A.; Villaverde, A.; Ventura, S. Amyloid-like properties of bacterial inclusion bodies. J. Mol. Biol, 2005, 347, 1025-1037.
138. Schrödel, A.; de Marco, A. Characterization of the aggregates formed during recombinant protein expression in bacteria. BMC Biochem, 2005, 6, 10.
139. Morell, M.; Bravo, R.; Espargaró, A.; Sisquella, X.; Avilés, F. X.; Fernàndez-Busquets, X.; Ventura, S. Inclusion bodies: specificity in their aggregation process and amyloid-like structure. Biochim. Biophys. Acta, 2008, 1783, 1815-1825.
140. Wang, L.; Maji, S. K.; Sawaya, M. R.; Eisenberg, D.; Riek, R. Bacterial inclusion bodies contain amyloid-like structure. PLoS Biol, 2008, 6, e195.
141. Gonzalez-Montalban, N.; Villaverde, A.; Aris, A. Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies. Biochem. Biophys. Res. Commun, 2007, 355, 637-642.
142. de Groot, N. S.; Ventura, S. Protein activity in bacterial inclusion bodies correlates with predicted aggregation rates. J. Biotechnol, 2006, 125, 110-113.
143. García-Fruitós, E.; González-Montalbán, N.; Morell, M.; Vera, A.; Ferraz, R. M.; Arís, A.; Ventura, S.; Villaverde, A. Aggregation as bacterial inclusion bodies does not imply inactivation of enzymes and fluorescent proteins. Microb. Cell Fact, 2005, 4, 27.
144. Kim, W.; Kim, Y.; Min, J.; Kim, D. J.; Chang, Y.-T.; Hecht, M. H. A high-throughput screen for compounds that inhibit aggregation of the Alzheimer's peptide. ACS Chem. Biol, 2006, 1, 461-469.
145. Villar-Piqué, A.; Espargaró, A.; Sabaté, R.; de Groot, N. S.; Ventura, S. Using bacterial inclusion bodies to screen for amyloid aggregation inhibitors. Microb. Cell Fact, 2012, 11, 55.
146. Lee, L. L.; Ha, H.; Chang, Y.-T.; DeLisa, M. Discovery of amyloidbeta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility. Prot. Sci, 2009, 18, 277-286.
147. Espargaró, A.; Sabate, R.; Ventura, S. Thioflavin-S staining coupled to flow cytometry. A screening tool to detect in vivo protein aggregation. Mol. Biosyst, 2012, 8, 2839-2844.