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Design of Multi-target Directed Ligands as a Modern Approach for the Development of Innovative Drug Candidates for Alzheimer’s Disease

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Multi-Target Drug Design Using Chem-Bioinformatic Approaches

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multi-faceted pathogenesis. So far, the therapeutic paradigm “one-compound-one-target” has failed and despite enormous efforts to elucidate the pathophysiology of AD, the disease is still incurable, with all current medicines only being capable to slow up its progress and ameliorate the quality of life of the patients. The multiple factors involved in AD include amyloid aggregation to form insoluble neurotoxic plaques of Aβ, hyperphosphorylation of tau protein, oxidative stress, calcium imbalance, mitochondrial dysfunction, deterioration of synaptic transmission, and neuronal loss. These factors together accentuate changes in the central nervous system (CNS) homeostasis, starting a complex process of interconnected physiological damage, leading to cognitive and memory impairment and neuronal death. A recent approach for the rational design of new drug candidates, also called multi-target directed ligand (MTDL) approach, has gained increasing attention by many research groups, which have developed a variety of hybrid compounds acting simultaneously on diverse biological targets. In this chapter, we aimed to show some recent advances during the last decade and examples of the exploitation of MTDL approach in the rational design of novel drug candidate prototypes for the treatment of AD.

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References

  1. Bolognesi ML, Matera R, Minarini A, Rosini M, Melchiorre C (2009) Alzheimer’s disease: new approaches to drug discovery. Curr Opin Chem Biol 13:303–308. https://doi.org/10.1016/j.cbpa.2009.04.619

    Article  CAS  PubMed  Google Scholar 

  2. Youdim MBH, Buccafusco JJ (2005) Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 26:27–35. https://doi.org/10.1016/j.tips.2004.11.007

    Article  CAS  PubMed  Google Scholar 

  3. Thies W, Bleiler L (2011) 2011 Alzheimer’s disease facts and figures. Alzheimers Dement 7:208–244. https://doi.org/10.1016/j.jalz.2011.02.004

    Article  Google Scholar 

  4. Fraga CAM, Barreiro EJ (2008) New insights for multifactorial disease therapy: the challenge of the symbiotic drugs. Curr Drug Ther 3:1–13. https://doi.org/10.2174/157488508783331225

    Article  Google Scholar 

  5. Zhang H-Y (2005) One-compound-multiple-targets strategy to combat Alzheimer’s disease. FEBS Lett 579:5260–5264. https://doi.org/10.1016/j.febslet.2005.09.006

    Article  CAS  PubMed  Google Scholar 

  6. Rosini M, Simoni E, Bartolini M, Cavalli A, Ceccarini L, Pascu N, McClymont DW, Tarozzi A, Bolognesi ML, Minarini A, Tumiatti V, Andrisano V, Mellor IR, Melchiorre C (2008) Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA receptors in Alzheimer’s disease: a promising direction for the multi-target-directed ligands gold rush. J Med Chem 51:4381–4384. https://doi.org/10.1021/jm800577j

    Article  CAS  PubMed  Google Scholar 

  7. Möller HJ, Graeber MB (1998) The case described by Alois Alzheimer in 1911. Eur Arch Psychiatry Clin Neurosci 248:111–122. https://doi.org/10.1007/s004060050027

    Article  PubMed  Google Scholar 

  8. Sayeg N (2013) Aspectos socioeconômicos. http://www.alzheimermed.com.br/conceitos/aspectos

  9. Instituto Brasileiro de Geografia e Estastística (IBGE) (2010) Censo Demográfico 2010

    Google Scholar 

  10. Alzheimer’s Association (2012) 2012 Alzheimer’s disease facts and figures

    Google Scholar 

  11. Alzheimer’s Disease International (2012) Dementia: a public health priority. World Health Organization, Geneva, pp 1–102

    Google Scholar 

  12. Kalache A (1991) Ageing in developing countries. Crit Public Health 2:38–43. https://doi.org/10.1080/09581599108406812

    Article  Google Scholar 

  13. IBGE (2013) Censo 2000. http://www.ibge.gov.br/home/estatistica/populacao/%0Acenso2000/populacao/censo2000_populacao.pdf

  14. Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66:137–147. https://doi.org/10.1136/jnnp.66.2.137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen S-Y, Chen Y, Li Y-P, Chen S-H, Tan J-H, Ou T-M, Gu L-Q, Huang Z-S (2011) Design, synthesis, and biological evaluation of curcumin analogues as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 19:5596–5604. https://doi.org/10.1016/j.bmc.2011.07.033

    Article  CAS  PubMed  Google Scholar 

  16. Ray B, Lahiri DK (2009) Neuroinflammation in Alzheimer’s disease: different molecular targets and potential therapeutic agents including curcumin. Curr Opin Pharmacol 9:434–444. https://doi.org/10.1016/j.coph.2009.06.012

    Article  CAS  PubMed  Google Scholar 

  17. Viegas FPD, Simões MCR, da Rocha MD, Castelli MR, Moreira MS, Viegas C Jr (2011) Alzheimer’s disease: characterization, evolution and implications of the neuroinflammatory process. Rev Virtual Química 3:286–306. https://doi.org/10.5935/1984-6835.20110034

    Article  CAS  Google Scholar 

  18. Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frolich L (2004) Combination therapy in Alzheimer’s disease: a review of current evidence. CNS Drugs 18:827–844

    Article  CAS  Google Scholar 

  19. Starkov AA, Beal FM (2008) Portal to Alzheimer’s disease. Nat Med 14:1020–1021

    Article  CAS  Google Scholar 

  20. Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14:45–53. https://doi.org/10.1016/j.molmed.2007.12.002.Amyloid

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang J-Z, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68. https://doi.org/10.1111/j.1460-9568.2006.05226.x

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zetterberg H, Blennow K (2006) Plasma Aβ in Alzheimer’s disease – up or down? Neurology 5:638–639

    PubMed  Google Scholar 

  23. Campos HC, Divino M, Pereira F, Viegas D, Nicastro PC, Fossaluzza PC, Alberto C, Fraga M, Barreiro EJ, Viegas C Jr (2011) The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders I: Parkinson’s disease. CNS Neurol Disord Drug Targets 10:239–250

    Article  CAS  Google Scholar 

  24. Liu Q, Xie F, Rolston R, Moreira P, Nunomura A, Zhu X, Smith M, Perry G (2007) Prevention and treatment of Alzheimer disease and aging: antioxidants. Mini Rev Med Chem 7:171–180. https://doi.org/10.2174/138955707779802552

    Article  CAS  PubMed  Google Scholar 

  25. Legg K (2011) Neurodegenerative diseases: an alternative path to reduce neuroinflammation. Nat Rev Drug Discov 10:901. https://doi.org/10.1038/nrd3607

    Article  CAS  PubMed  Google Scholar 

  26. Gaggelli E, Kozlowski H, Valensin D, Valensin G (2006) Copper homeostasis and neurodegenerative disorders (Alzheimer’s, prion, and Parkinson’s diseases and amyotrophic lateral sclerosis). Chem Rev 106:1995–2044. https://doi.org/10.1021/cr040410w

    Article  CAS  PubMed  Google Scholar 

  27. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WST, Hampel H, Hull M, Landreth G, Lue LF, Mrak R, Mackenzie IR, Mcgeer PL, Banion MKO, Pachter J, Pasinetti G, Salaman CP, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Coray TW (2000) Inflammation and Alzheimer’ s disease. Neurobiol Aging 21:383–421

    Article  CAS  Google Scholar 

  28. Heneka MT, O’Banion MK (2007) Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184:69–91. https://doi.org/10.1016/j.jneuroim.2006.11.017

    Article  CAS  PubMed  Google Scholar 

  29. Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J (2008) Inflammaging as a prodrome to Alzheimer’s disease. J Neuroinflammation 5:51. https://doi.org/10.1186/1742-2094-5-51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kamal MA, Greig NH, Reale M (2009) Anti-inflammatory properties of acetylcholinesterase inhibitors administred in Alzheimer’s disease. Anti-Inflammatory Anti-Allergy Agents Med Chem 8:85–100

    Article  CAS  Google Scholar 

  31. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M (2010) Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 9:702–716. https://doi.org/10.1016/S1474-4422(10)70119-8

    Article  CAS  PubMed  Google Scholar 

  32. Piau A, Nourhashémi F, Hein C, Caillaud C, Vellas B (2011) Progress in the development of new drugs in Alzheimer’s disease. J Nutr Health Aging 15:45–57. https://doi.org/10.1007/s12603-011-0012-x

    Article  CAS  PubMed  Google Scholar 

  33. Cavalli A, Bolognesi ML, Mìnarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 51:347–372. https://doi.org/10.1021/jm7009364

    Article  CAS  PubMed  Google Scholar 

  34. Samadi A, Valderas C, Ríos CDL, Bastida A, Chioua M, González-Lafuente L, Colmena I, Gandía L, Romero A, Del Barrio L, Martín-De-Saavedra MD, López MG, Villarroya M, Marco-Contelles J (2011) Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles. Bioorg Med Chem 19:122–133. https://doi.org/10.1016/j.bmc.2010.11.040

    Article  CAS  PubMed  Google Scholar 

  35. Bolognesi ML, Cavalli A, Valgimigli L, Bartolini M, Rosini M, Andrisano V, Recanatini M, Melchiorre C (2007) Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer’s disease. J Med Chem 50:6446–6449. https://doi.org/10.1021/jm701225u

    Article  CAS  PubMed  Google Scholar 

  36. Cavalli A, Bolognesi ML, Capsoni S, Andrisano V, Bartolini M, Margotti E, Cattaneo A, Recanatini M, Melchiorre C (2007) A small molecule targeting the multifactorial nature of Alzheimer’s disease. Angew Chem Int Ed 46:3689–3692. https://doi.org/10.1002/anie.200700256

    Article  CAS  Google Scholar 

  37. Shan WJ, Huang L, Zhou Q, Meng FC, Li XS (2011) Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant, inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation. Eur J Med Chem 46:5885–5893. https://doi.org/10.1016/j.ejmech.2011.09.051

    Article  CAS  PubMed  Google Scholar 

  38. Jiang H, Wang X, Huang L, Luo Z, Su T, Ding K, Li X (2011) Benzenediol-berberine hybrids: multifunctional agents for Alzheimer’s disease. Bioorg Med Chem 19:7228–7235. https://doi.org/10.1016/j.bmc.2011.09.040

    Article  CAS  PubMed  Google Scholar 

  39. Fernández-Bachiller MI, Pérez C, González-Muñoz GC, Conde S, López MG, Villarroya M, García AG, Rodríguez-Franco MI (2010) Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimers disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J Med Chem 53:4927–4937. https://doi.org/10.1021/jm100329q

    Article  CAS  PubMed  Google Scholar 

  40. Bolognesi ML, Cavalli A, Melchiorre C (2009) Memoquin: a multi-target – directed ligand as an innovative therapeutic opportunity for Alzheimer’s disease. Neurotherapeutics 6:152–162

    Article  CAS  Google Scholar 

  41. Bolognesi ML, Cavalli A, Bergamini C, Fato R, Lenaz G, Rosini M, Bartolini M, Andrisano V, Melchiorre C (2009) Toward a rational design of multitarget-directed antioxidants: merging memoquin and lipoic acid molecular frameworks. J Med Chem 52:7883–7886. https://doi.org/10.1021/jm901123n

    Article  CAS  PubMed  Google Scholar 

  42. Bolognesi ML, Bartolini M, Tarozzi A, Morroni F, Lizzi F, Milelli A, Minarini A, Rosini M, Hrelia P, Andrisano V, Melchiorre C (2011) Multitargeted drugs discovery: balancing anti-amyloid and anticholinesterase capacity in a single chemical entity. Bioorg Med Chem Lett 21:2655–2658. https://doi.org/10.1016/j.bmcl.2010.12.093

    Article  CAS  PubMed  Google Scholar 

  43. Simoni E, Daniele S, Bottegoni G, Pizzirani D, Trincavelli ML, Goldoni L, Tarozzo G, Reggiani A, Martini C, Piomelli D, Melchiorre C, Rosini M, Cavalli A (2012) Combining galanthamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer’s disease. J Med Chem 55:9708–9721. https://doi.org/10.1021/jm3009458

    Article  CAS  PubMed  Google Scholar 

  44. Rook Y, Schmidtke KU, Gaube F, Schepmann D, Wünsch B, Heilmann J, Lehmann J, Winckler T (2010) Bivalent β-carbolines as potential multitarget anti-Alzheimer agents. J Med Chem 53:3611–3617. https://doi.org/10.1021/jm1000024

    Article  CAS  PubMed  Google Scholar 

  45. Rizzo S, Tarozzi A, Bartolini M, Da Costa G, Bisi A, Gobbi S, Belluti F, Ligresti A, Allarà M, Monti J, Andrisano V, Di Marzo V, Hrelia P, Rampa A (2012) 2-Arylbenzofuran-based molecules as multipotent Alzheimer’s disease modifying agents. Eur J Med Chem 58:519–532. https://doi.org/10.1016/j.ejmech.2012.10.045

    Article  CAS  PubMed  Google Scholar 

  46. Piazzi L, Cavalli A, Colizzi F, Belluti F, Bartolini M, Mancini F, Recanatini M, Andrisano V, Rampa A (2008) Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorg Med Chem Lett 18:423–426. https://doi.org/10.1016/j.bmcl.2007.09.100

    Article  CAS  PubMed  Google Scholar 

  47. Jackson S, Ham RJ, Wilkinson D (2004) The safety and tolerability of donepezil in patients with Alzheimer’s disease. Br J Clin Pharmacol 58:1–8. https://doi.org/10.1111/j.1365-2125.2004.01848.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sugimoto H, Ogura H, Arai Y, Iimura Y, Yamanishi Y (2002) Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn J Pharmacol 89:7–20. https://doi.org/10.1254/jjp.89.7

    Article  CAS  PubMed  Google Scholar 

  49. Wu M-Y, Esteban G, Brogi S, Shionoya M, Wang L, Campiani G, Unzeta M, Inokuchi T, Butini S, Marco-Contelles J (2015) Donepezil-like multifunctional agents: design, synthesis, molecular modeling and biological evaluation. Eur J Med Chem 121:1–16. https://doi.org/10.1016/j.ejmech.2015.10.001

    Article  CAS  Google Scholar 

  50. Pudlo M, Luzet V, Ismaïli L, Tomassoli I, Iutzeler A, Refouvelet B (2014) Quinolone–benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease. Bioorg Med Chem 22:2496–2507. https://doi.org/10.1016/j.bmc.2014.02.046

    Article  CAS  PubMed  Google Scholar 

  51. Samadi A, Chioua M, Bolea I, De Los Ríos C, Iriepa I, Moraleda I, Bastida A, Esteban G, Unzeta M, Gálvez E, Marco-Contelles J (2011) Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease. Eur J Med Chem 46:4665–4668. https://doi.org/10.1016/j.ejmech.2011.05.048

    Article  CAS  PubMed  Google Scholar 

  52. Bolea I, Juárez-Jiménez J, de los Rıos C, Chioua M, Pouplana R, Luque FJ, Unzeta M, Marco-Contelles J, Samadi A (2011) Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1 H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer. J Med Chem 54:8251–8270. https://doi.org/10.1021/jm200853t

    Article  CAS  PubMed  Google Scholar 

  53. Huang L, Lu C, Sun Y, Mao F, Luo Z, Su T, Jiang H, Shan W, Li X (2012) Multitarget-directed benzylideneindanone derivatives: anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer’s disease. J Med Chem 55:8483–8492. https://doi.org/10.1021/jm300978h

    Article  CAS  PubMed  Google Scholar 

  54. De Ferrari GV, Canales M, Shin I, Weiner LM, Silman I, Inestrosa NC (2001) A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry 40:10447–10457

    Article  Google Scholar 

  55. Guzior N, Bajda M, Rakoczy J, Brus B, Gobec S, Malawska B (2015) Isoindoline-1,3-dione derivatives targeting cholinesterases: design, synthesis and biological evaluation of potential anti-Alzheimer’s agents. Bioorg Med Chem 23:1629–1637. https://doi.org/10.1016/j.bmc.2015.01.045

    Article  CAS  PubMed  Google Scholar 

  56. Więckowska A, Więckowski K, Bajda M, Brus B, Sałat K, Czerwińska P, Gobec S, Filipek B, Malawska B (2015) Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with β-amyloid anti-aggregation properties and beneficial effects on memory in vivo. Bioorg Med Chem 23:2445–2457. https://doi.org/10.1016/j.bmc.2015.03.051

    Article  CAS  PubMed  Google Scholar 

  57. Wang L, Esteban G, Ojima M, Bautista-Aguilera OM, Inokuchi T, Moraleda I, Iriepa I, Samadi A, Youdim MBH, Romero A, Soriano E, Herrero R, Fernández Fernández AP, Ricardo-Martínez-Murillo, Marco-Contelles J, Unzeta M (2014) Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer’s disease. Eur J Med Chem 80:543–561. https://doi.org/10.1016/j.ejmech.2014.04.078

    Article  CAS  PubMed  Google Scholar 

  58. Bautista-Aguilera OM, Esteban G, Bolea I, Nikolic K, Agbaba D, Moraleda I, Iriepa I, Samadi A, Soriano E, Unzeta M, Marco-Contelles J (2014) 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 75:82–95. https://doi.org/10.1016/j.ejmech.2013.12.028

    Article  CAS  PubMed  Google Scholar 

  59. Bautista-Aguilera OM, Samadi A, Chioua M, Nikolic K, Filipic S, Agbaba D, Soriano E, de Andrés L, Rodríguez-Franco MI, Alcaro S, Ramsay RR, Ortuso F, Yañez M, Marco-Contelles J (2014) N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1 H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor. J Med Chem 57:10455–10463. https://doi.org/10.1021/jm501501a

    Article  CAS  PubMed  Google Scholar 

  60. Yerdelen KO, Koca M, Anil B, Sevindik H, Kasap Z, Halici Z, Turkaydin K, Gunesacar G (2015) Synthesis of donepezil-based multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 25:5576–5582. https://doi.org/10.1016/j.bmcl.2015.10.051

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  62. Castañeda-Arriaga R, Alvarez-Idaboy JR (2014) Lipoic acid and dihydrolipoic acid. A comprehensive theoretical study of their antioxidant activity supported by available experimental kinetic data. J Chem Inf Model 54:1642–1652. https://doi.org/10.1021/ci500213p

    Article  CAS  PubMed  Google Scholar 

  63. Rosini M, Simoni E, Bartolini M, Tarozzi A, Matera R, Milelli A, Hrelia P, Andrisano V, Bolognesi ML, Melchiorre C (2011) Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer’s disease. Eur J Med Chem 46:5435–5442. https://doi.org/10.1016/j.ejmech.2011.09.001

    Article  CAS  PubMed  Google Scholar 

  64. Prezzavento O, Arena E, Parenti C, Pasquinucci L, Aricò G, Scoto GM, Grancara S, Toninello A, Ronsisvalle S (2013) Design and synthesis of new bifunctional sigma-1 selective ligands with antioxidant activity. J Med Chem 56:2447–2455. https://doi.org/10.1021/jm3017893

    Article  CAS  PubMed  Google Scholar 

  65. Fava A, Pirritano D, Plastino M, Cristiano D, Puccio G, Colica C, Ermio C, De Bartolo M, Mauro G, Bosco D (2013) The effect of lipoic acid therapy on cognitive functioning in patients with Alzheimer’s disease. J Neurodegener Dis 2013:7. https://doi.org/10.1155/2013/454253

    Article  CAS  Google Scholar 

  66. Estrada M, Pérez C, Soriano E, Laurini E, Romano M, Pricl S, Morales-García JA, Pérez-Castillo A, Rodríguez-Franco MI (2016) New neurogenic lipoic-based hybrids as innovative Alzheimer’s drugs with σ-1 agonism and β-secretase inhibition. Future Med Chem 8:1191–1207. https://doi.org/10.4155/fmc-2016-0036

    Article  CAS  PubMed  Google Scholar 

  67. Dias KST, de Paula CT, dos Santos T, Souza INO, Boni MS, Guimarães MJR, da Silva FMR, Castro NG, Neves GA, Veloso CC, Coelho MM, de Melo ISF, Giusti FCV, Giusti-Paiva A, da Silva ML, Dardenne LE, Guedes IA, Pruccoli L, Morroni F, Tarozzi A, Viegas C (2017) Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer’s disease. Eur J Med Chem 130:440–457. https://doi.org/10.1016/j.ejmech.2017.02.043

    Article  CAS  PubMed  Google Scholar 

  68. Xu W, Wang X-B, Wang Z-M, Wu J-J, Li F, Wang J, Kong L-Y (2016) Synthesis and evaluation of donepezil–ferulic acid hybrids as multi-target-directed ligands against Alzheimer’s disease. Med Chem Commun 7:990–998. https://doi.org/10.1039/C6MD00053C

    Article  CAS  Google Scholar 

  69. Wang J, Wang Z-M, Li X-M, Li F, Wu J-J, Kong L-Y, Wang X-B (2016) Synthesis and evaluation of multi-target-directed ligands for the treatment of Alzheimer’s disease based on the fusion of donepezil and melatonin. Bioorg Med Chem 24:4324–4338. https://doi.org/10.1016/j.bmc.2016.07.025

    Article  CAS  PubMed  Google Scholar 

  70. Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W, Tan Z, Deng Y (2014) Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 76:314–331. https://doi.org/10.1016/j.ejmech.2014.02.045

    Article  CAS  PubMed  Google Scholar 

  71. Farina R, Pisani L, Catto M, Nicolotti O, Gadaleta D, Denora N, Soto-Otero R, Mendez-Alvarez E, Passos CS, Muncipinto G, Altomare CD, Nurisso A, Carrupt P-A, Carotti A (2015) Structure-based design and optimization of multitarget-directed 2 H-Chromen-2-one derivatives as potent inhibitors of monoamine oxidase B and cholinesterases. J Med Chem 58:5561–5578. https://doi.org/10.1021/acs.jmedchem.5b00599

    Article  CAS  Google Scholar 

  72. Claeysen S, Bockaert J, Giannoni P (2015) Serotonin: a new hope in Alzheimer’s disease? ACS Chem Neurosci 6:940–943. https://doi.org/10.1021/acschemneuro.5b00135

    Article  CAS  PubMed  Google Scholar 

  73. Van der Schyf CJ (2016) Psychotropic drug development strategies that target neuropsychiatric etiologies in Alzheimer’s and Parkinson’s diseases. Drug Dev Res 77:458–468. https://doi.org/10.1002/ddr.21368

    Article  CAS  PubMed  Google Scholar 

  74. Lecoutey C, Hedou D, Freret T, Giannoni P, Gaven F, Since M, Bouet V, Ballandonne C, Corvaisier S, Malzert Fréon A, Mignani S, Cresteil T, Boulouard M, Claeysen S, Rochais C, Dallemagne P (2014) Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer’s disease treatment. Proc Natl Acad Sci U S A 111:E3825–E3830. https://doi.org/10.1073/pnas.1410315111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rochais C, Lecoutey C, Gaven F, Giannoni P, Hamidouche K, Hedou D, Dubost E, Genest D, Yahiaoui S, Freret T, Bouet V, Dauphin F, Sopkova de Oliveira Santos J, Ballandonne C, Corvaisier S, Malzert-Fréon A, Legay R, Boulouard M, Claeysen S, Dallemagne P (2015) Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT 4 R) agonist activities as potential agents against Alzheimer’s disease: the design of donecopride. J Med Chem 58:3172–3187. https://doi.org/10.1021/acs.jmedchem.5b00115

    Article  CAS  PubMed  Google Scholar 

  76. Mishra CB, Kumari S, Manral A, Prakash A, Saini V, Lynn AM, Tiwari M (2017) Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur J Med Chem 125:736–750. https://doi.org/10.1016/j.ejmech.2016.09.057

    Article  CAS  PubMed  Google Scholar 

  77. Pereira JD, Caricati-Neto A, Miranda-Ferreira R, Smaili SS, Godinho RO, Rios CDL, Léon R, Villaroya M, Samadi A, Marco-Contelles J, Jurkiewicz NH, Garcia AG, Jurkiewicz A (2011) Effects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity. Eur J Pharmacol 660:411–419. https://doi.org/10.1016/j.ejphar.2011.03.042

    Article  CAS  PubMed  Google Scholar 

  78. Tumiatti V, Minarini A, Bolognesi ML, Milelli A, Rosini M, Melchiorre C (2010) Tacrine derivatives and Alzheimer’s disease. Curr Med Chem 17:1825–1838

    Article  CAS  Google Scholar 

  79. Marco-Contelles J, León R, López MG, García AG, Villarroya M (2006) Synthesis and biological evaluation of new 4H-pyrano[2,3-b]quinoline derivatives that block acetylcholinesterase and cell calcium signals, and cause neuroprotection against calcium overload and free radicals. Eur J Med Chem 41:1464–1469. https://doi.org/10.1016/j.ejmech.2006.06.016

    Article  CAS  PubMed  Google Scholar 

  80. Minarini A, Milelli A, Tumiatti V, Rosini M, Simoni E, Bolognesi ML, Andrisano V, Bartolini M, Motori E, Angeloni C, Hrelia S (2012) Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer’s disease treatment. Neuropharmacology 62:997–1003. https://doi.org/10.1016/j.neuropharm.2011.10.007

    Article  CAS  PubMed  Google Scholar 

  81. Fang L, Kraus B, Lehmann J, Heilmann J, Zhang Y, Decker M (2008) Design and synthesis of tacrine-ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates. Bioorg Med Chem Lett 18:2905–2909. https://doi.org/10.1016/j.bmcl.2008.03.073

    Article  CAS  PubMed  Google Scholar 

  82. Marco-contelles J, Leo R, Ri DL, Samadi A, Bartolini M, Andrisano V, Huertas O, Barril X, Luque FJ, Rodri MI, Lo MG, Garci AG, Villarroya M (2009) Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease. J Med Chem 52:2724–2732. https://doi.org/10.1021/jm801292b

    Article  CAS  PubMed  Google Scholar 

  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 (2012) Design, synthesis and pharmacological evaluation of novel tacrine–caffeic acid hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg Med Chem Lett 22:6498–6502. https://doi.org/10.1016/j.bmcl.2012.08.036

    Article  CAS  PubMed  Google Scholar 

  84. Wang Y, Wang F, Yu JP, Jiang FC, Guan XL, Wang CM, Li L, Cao H, Li MX, Chen JG (2012) Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca2+ overload. Bioorg Med Chem 20:6513–6522. https://doi.org/10.1016/j.bmc.2012.08.040

    Article  CAS  PubMed  Google Scholar 

  85. Lan J-S, Xie S-S, Li S-Y, Pan L-F, Wang X-B, Kong L-Y (2014) Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 22:6089–6104. https://doi.org/10.1016/j.bmc.2014.08.035

    Article  CAS  PubMed  Google Scholar 

  86. Mourad Chioua J, Pérez-Peña N, García-Font I, Moraleda II, Elena Soriano J (2015) Pyranopyrazolotacrines as nonneurotoxic, Aβ-anti-aggregating and neuroprotective agents for Alzheimer’s disease. Future Med Chem 7:845–855. https://doi.org/10.4155/fmc.15.35

    Article  CAS  PubMed  Google Scholar 

  87. Fu Y, Mu Y, Lei H, Wang P, Li X, Leng Q, Han L, Qu X, Wang Z, Huang X (2016) Design, synthesis and evaluation of novel tacrine-ferulic acid hybrids as multifunctional drug candidates against Alzheimer’s disease. Molecules 21:1338. https://doi.org/10.3390/molecules21101338

    Article  CAS  PubMed Central  Google Scholar 

  88. Benchekroun M, Romero A, Egea J, León R, Michalska P, Buendía I, Jimeno ML, Jun D, Janockova J, Sepsova V, Soukup O, Bautista-Aguilera OM, Refouvelet B, Ouari O, Marco-Contelles J, Ismaili L (2016) The antioxidant additive approach for Alzheimer’s disease therapy: new ferulic (lipoic) acid plus melatonin modified tacrines as cholinesterases inhibitors, direct antioxidants, and nuclear factor (erythroid-derived 2)-like 2 activators. J Med Chem 59:9967–9973. https://doi.org/10.1021/acs.jmedchem.6b01178

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  90. Wang X-Q, Xia C-L, Chen S-B, Tan J-H, Ou T-M, Huang S-L, Li D, Gu L-Q, Huang Z-S (2015) Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 89:349–361. https://doi.org/10.1016/j.ejmech.2014.10.018

    Article  CAS  PubMed  Google Scholar 

  91. Anand P, Singh B, Singh N (2012) A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease. Bioorg Med Chem 20:1175–1180. https://doi.org/10.1016/j.bmc.2011.12.042

    Article  CAS  PubMed  Google Scholar 

  92. Patil PO, Bari SB, Firke SD, Deshmukh PK, Donda ST, Patil DA (2013) A comprehensive review on synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for depression and Alzheimer’s disease. Bioorg Med Chem 21:2434–2450. https://doi.org/10.1016/j.bmc.2013.02.017

    Article  CAS  PubMed  Google Scholar 

  93. Chimenti F, Secci D, Bolasco A, Chimenti P, Bizzarri B, Granese A, Carradori S, Yáñez M, Orallo F, Ortuso F, Alcaro S (2009) Synthesis, molecular modeling, and selective inhibitory activity against human monoamine oxidases of 3-carboxamido-7-substituted coumarins. J Med Chem 52:1935–1942. https://doi.org/10.1021/jm801496u

    Article  CAS  PubMed  Google Scholar 

  94. Catto M, Nicolotti O, Leonetti F, Carotti A, Favia AD, Soto-Otero R, Méndez-Álvarez E, Carotti A (2006) Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches. J Med Chem 49:4912–4925. https://doi.org/10.1021/jm060183l

    Article  CAS  Google Scholar 

  95. Xie SS, Wang X, Jiang N, Yu W, Wang KDG, Lan JS, Li ZR, Kong LY (2015) Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer’s disease. Eur J Med Chem 95:153–165. https://doi.org/10.1016/j.ejmech.2015.03.040

    Article  CAS  PubMed  Google Scholar 

  96. Boulebd H, Ismaili L, Bartolini M, Bouraiou A, Andrisano V, Martin H, Bonet A, Moraleda I, Iriepa I, Chioua M, Belfaitah A, Marco-Contelles J (2016) Imidazopyranotacrines as non-hepatotoxic, selective acetylcholinesterase inhibitors, and antioxidant agents for Alzheimer’s disease therapy. Molecules 21:400. https://doi.org/10.3390/molecules21040400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Spilovska K, Korabecny J, Horova A, Musilek K, Nepovimova E, Drtinova L, Gazova Z, Siposova K, Dolezal R, Jun D, Kuca K (2015) 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 24:2645–2655. https://doi.org/10.1007/s00044-015-1316-x

    Article  CAS  Google Scholar 

  98. Martins C, Carreiras MC, León R, De Los Ríos C, Bartolini M, Andrisano V, Iriepa I, Moraleda I, Gálvez E, García M, Egea J, Samadi A, Chioua M, Marco-Contelles J (2011) Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues. Eur J Med Chem 46:6119–6130. https://doi.org/10.1016/j.ejmech.2011.09.038

    Article  CAS  PubMed  Google Scholar 

  99. Chen Y, Lin H, Zhu J, Gu K, Li Q, He S, Lu X, Tan R, Pei Y, Wu L, Bian Y, Sun H (2017) Design, synthesis, in vitro and in vivo evaluation of tacrine–cinnamic acid hybrids as multi-target acetyl- and butyrylcholinesterase inhibitors against Alzheimer’s disease. RSC Adv 7:33851–33867. https://doi.org/10.1039/C7RA04385F

    Article  CAS  Google Scholar 

  100. Jeřábek J, Uliassi E, Guidotti L, Korábečný J, Soukup O, Sepsova V, Hrabinova M, Kuča K, Bartolini M, Peña-Altamira LE, Petralla S, Monti B, Roberti M, Bolognesi ML (2017) Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer’s disease. Eur J Med Chem 127:250–262. https://doi.org/10.1016/j.ejmech.2016.12.048

    Article  CAS  PubMed  Google Scholar 

  101. Teponnou GAK, Joubert J, Malan SF (2017) Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target agents for Alzheimer’s disease therapy. Open Med Chem J 11:24–37. https://doi.org/10.2174/1874104501711010024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Viegas C, Bolzani VDS, Barreiro EJ, Fraga CAM (2005) New anti-Alzheimer drugs from biodiversity: the role of the natural acetylcholinesterase inhibitors. Mini Rev Med Chem 5:915–926. https://doi.org/10.2174/138955705774329546

    Article  CAS  PubMed  Google Scholar 

  103. Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli A, Bartolini M, Andrisano V, Valenti P, Recanatini M (2003) 3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6,7-dimethoxy-2 H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation: a dual function lead for Alzheimer’s disease therapy. J Med Chem 46:2279–2282. https://doi.org/10.1021/jm0340602

    Article  CAS  PubMed  Google Scholar 

  104. Piazzi L, Cavalli A, Belluti F, Bisi A, Gobbi S, Rizzo S, Bartolini M, Andrisano V, Recanatini M, Rampa A (2007) Extensive SAR and computational studies of 3-{4-[(benzylmethylamino)methyl]phenyl}-6,7-dimethoxy-2 H-2-chromenone (AP2238) derivatives. J Med Chem 50:4250–4254. https://doi.org/10.1021/jm070100g

    Article  CAS  PubMed  Google Scholar 

  105. Rizzo S, Bartolini M, Ceccarini L, Piazzi L, Gobbi S, Cavalli A, Recanatini M, Andrisano V, Rampa A (2010) Targeting Alzheimer’s disease: novel indanone hybrids bearing a pharmacophoric fragment of AP2238. Bioorg Med Chem 18:1749–1760. https://doi.org/10.1016/j.bmc.2010.01.071

    Article  CAS  PubMed  Google Scholar 

  106. López-Iglesias B, Pérez C, Morales-García JA, Alonso-Gil S, Pérez-Castillo A, Romero A, López MG, Villarroya M, Conde S, Rodríguez-Franco MI (2014) New melatonin-N, N-dibenzyl(N-methyl)amine hybrids: potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer’s disease. J Med Chem 57:3773–3785. https://doi.org/10.1021/jm5000613

    Article  CAS  PubMed  Google Scholar 

  107. Luo XT, Wang CM, Liu Y, Huang ZG (2015) New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer’s disease. Eur J Med Chem 103:302–311. https://doi.org/10.1016/j.ejmech.2015.08.052

    Article  CAS  PubMed  Google Scholar 

  108. Lu C, Guo Y, Yan J, Luo Z, Luo H, Yan M, Huang L, Li X (2013) Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer’s disease. J Med Chem 56:5843–5859. https://doi.org/10.1021/jm400567s

    Article  CAS  PubMed  Google Scholar 

  109. Pan L-F, Wang X-B, Xie S-S, Li S-Y, Kong L-Y (2014) Multitarget-directed resveratrol derivatives: anti-cholinesterases, anti-β-amyloid aggregation and monoamine oxidase inhibition properties against Alzheimer’s disease. Med Chem Commun 5:609. https://doi.org/10.1039/c3md00376k

    Article  CAS  Google Scholar 

  110. Pan W, Hu K, Bai P, Yu L, Ma Q, Li T, Zhang X, Chen C, Peng K, Liu W, Sang Z (2016) Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 26:2539–2543. https://doi.org/10.1016/j.bmcl.2016.03.086

    Article  CAS  PubMed  Google Scholar 

  111. Pérez-Areales FJ, Di Pietro O, Espargaró A, Vallverdú-Queralt A, Galdeano C, Ragusa IM, Viayna E, Guillou C, Clos MV, Pérez B, Sabaté R, Lamuela-Raventós RM, Luque FJ, Muñoz-Torrero D (2014) Shogaol–huprine hybrids: dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties. Bioorg Med Chem 22:5298–5307. https://doi.org/10.1016/j.bmc.2014.07.053

    Article  CAS  PubMed  Google Scholar 

  112. Viayna E, Sola I, Bartolini M, De Simone A, Tapia-Rojas C, Serrano FG, Sabaté R, Juárez-Jiménez J, Pérez B, Luque FJ, Andrisano V, Clos MV, Inestrosa NC, Muñoz-Torrero D (2014) Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents. J Med Chem 57:2549–2567. https://doi.org/10.1021/jm401824w

    Article  CAS  PubMed  Google Scholar 

  113. Saura J, Luque JM, Cesura AM, Huber G, Lgffler J (1994) Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 62:15–30

    Article  CAS  Google Scholar 

  114. Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi RE, Inestrosa NC, Bush AI (2002) Metalloenzyme-like activity of Alzheimer’s disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J Biol Chem 277:40302–40308. https://doi.org/10.1074/jbc.M206428200

    Article  CAS  Google Scholar 

  115. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24:R453–R462. https://doi.org/10.1016/j.cub.2014.03.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Huang M, Xie S-S, Jiang N, Lan J-S, Kong L-Y, Wang X-B (2015) Multifunctional coumarin derivatives: monoamine oxidase B (MAO-B) inhibition, anti-β-amyloid (Aβ) aggregation and metal chelation properties against Alzheimer’s disease. Bioorg Med Chem Lett 25:508–513. https://doi.org/10.1016/j.bmcl.2014.12.034

    Article  CAS  PubMed  Google Scholar 

  117. Li Y, Qiang X, Luo L, Li Y, Xiao G, Tan Z, Deng Y (2016) Synthesis and evaluation of 4-hydroxyl aurone derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 24:2342–2351. https://doi.org/10.1016/j.bmc.2016.04.012

    Article  CAS  PubMed  Google Scholar 

  118. Li Y, Qiang X, Li Y, Yang X, Luo L, Xiao G, Cao Z, Tan Z, Deng Y (2016) Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 26:2035–2039. https://doi.org/10.1016/j.bmcl.2016.02.079

    Article  CAS  PubMed  Google Scholar 

  119. Liu Q, Qiang X, Li Y, Sang Z, Li Y, Tan Z, Deng Y (2015) Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 23:911–923. https://doi.org/10.1016/j.bmc.2015.01.042

    Article  CAS  PubMed  Google Scholar 

  120. Shaik JB, Palaka BK, Penumala M, Kotapati KV, Devineni SR, Eadlapalli S, Darla MM, Ampasala DR, Vadde R, Amooru GD (2016) Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents. Eur J Med Chem 107:219–232. https://doi.org/10.1016/j.ejmech.2015.10.046

    Article  CAS  PubMed  Google Scholar 

  121. Lan J-S, Ding Y, Liu Y, Kang P, Hou J-W, Zhang X-Y, Xie S-S, Zhang T (2017) Design, synthesis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease. Eur J Med Chem 139:48–59. https://doi.org/10.1016/j.ejmech.2017.07.055

    Article  CAS  PubMed  Google Scholar 

  122. Puksasook T, Kimura S, Tadtong S, Jiaranaikulwanitch J, Pratuangdejkul J, Kitphati W, Suwanborirux K, Saito N, Nukoolkarn V (2017) Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer’s disease. J Nat Med 71:1–18. https://doi.org/10.1007/s11418-017-1097-2

    Article  CAS  Google Scholar 

  123. Yang H-L, Cai P, Liu Q-H, Yang X-L, Fang S-Q, Tang Y-W, Wang C, Wang X-B, Kong L-Y (2017) Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer’s disease. Bioorg Med Chem 25(21):5917–5928. https://doi.org/10.1016/j.bmc.2017.08.048

    Article  CAS  PubMed  Google Scholar 

  124. Prati F, De Simone A, Bisignano P, Armirotti A, Summa M, Pizzirani D, Scarpelli R, Perez DI, Andrisano V, Perez-Castillo A, Monti B, Massenzio F, Polito L, Racchi M, Favia AD, Bottegoni G, Martinez A, Bolognesi ML, Cavalli A (2015) Multitarget drug discovery for Alzheimer’s disease: triazinones as BACE-1 and GSK-3β inhibitors. Angew Chem Int Ed 54:1578–1582. https://doi.org/10.1002/anie.201410456

    Article  CAS  Google Scholar 

  125. Kumar J, Meena P, Singh A, Jameel E, Maqbool M, Mobashir M, Shandilya A, Tiwari M, Hoda N, Jayaram B (2016) Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer’s disease therapies. Eur J Med Chem 119:260–277. https://doi.org/10.1016/j.ejmech.2016.04.053

    Article  CAS  PubMed  Google Scholar 

  126. Liao S, Deng H, Huang S, Yang J, Wang S, Yin B, Zheng T, Zhang D, Liu J, Gao G, Ma J, Deng Z (2015) Design, synthesis and evaluation of novel 5,6,7-trimethoxyflavone–6-chlorotacrine hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 25:1541–1545. https://doi.org/10.1016/j.bmcl.2015.02.015

    Article  CAS  PubMed  Google Scholar 

  127. Sang Z, Li Y, Qiang X, Xiao G, Liu Q, Tan Z, Deng Y (2015) Multifunctional scutellarin–rivastigmine hybrids with cholinergic, antioxidant, biometal chelating and neuroprotective properties for the treatment of Alzheimer’s disease. Bioorg Med Chem 23:668–680. https://doi.org/10.1016/j.bmc.2015.01.005

    Article  CAS  PubMed  Google Scholar 

  128. González-Naranjo P, Pérez-Macias N, Campillo NE, Pérez C, Arán VJ, Girón R, Sánchez-Robles E, Martín MI, Gómez-Cañas M, García-Arencibia M, Fernández-Ruiz J, Páez JA (2014) Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer’s disease. Eur J Med Chem 73:56–72. https://doi.org/10.1016/j.ejmech.2013.11.026

    Article  CAS  PubMed  Google Scholar 

  129. Greig NH, Lahiri DK, Sambamurti K (2002) Butyrylcholinesterase: an important new target in Alzheimers disease therapy. Int Psychogeriatr 14:77–91. https://doi.org/10.1017/S1041610203008676

    Article  PubMed  Google Scholar 

  130. Mesulam M, Guillozet A, Shaw P, Quinn B (2002) Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain. Neurobiol Dis 9:88–93. https://doi.org/10.1006/nbdi.2001.0462

    Article  CAS  PubMed  Google Scholar 

  131. Digiacomo M, Chen Z, Wang S, Lapucci A, Macchia M, Yang X, Chu J, Han Y, Pi R, Rapposelli S (2015) Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD. Bioorg Med Chem Lett 25:807–810. https://doi.org/10.1016/j.bmcl.2014.12.084

    Article  CAS  PubMed  Google Scholar 

  132. Estrada M, Herrera-Arozamena C, Pérez C, Viña D, Romero A, Morales-García JA, Pérez-Castillo A, Rodríguez-Franco MI (2016) New cinnamic – N-benzylpiperidine and cinnamic – N,N-dibenzyl(N-methyl)amine hybrids as Alzheimer-directed multitarget drugs with antioxidant, cholinergic, neuroprotective and neurogenic properties. Eur J Med Chem 121:376–386. https://doi.org/10.1016/j.ejmech.2016.05.055

    Article  CAS  PubMed  Google Scholar 

  133. Chen Z, Digiacomo M, Tu Y, Gu Q, Wang S, Yang X, Chu J, Chen Q, Han Y, Chen J, Nesi G, Sestito S, Macchia M, Rapposelli S, Pi R (2017) Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer’s disease. Eur J Med Chem 125:784–792. https://doi.org/10.1016/j.ejmech.2016.09.052

    Article  CAS  PubMed  Google Scholar 

  134. Wang Z, Li W, Wang Y, Li XX, Huang L, Li XX (2016) Design, synthesis and evaluation of clioquinol–ebselen hybrids as multi-target-directed ligands against Alzheimer’s disease. RSC Adv 6:7139–7158. https://doi.org/10.1039/C5RA26797H

    Article  CAS  Google Scholar 

  135. Wang Z-M, Xie S-S, Li X-M, Wu J-J, Wang X-B, Kong L-Y (2015) Multifunctional 3-Schiff base-4-hydroxycoumarin derivatives with monoamine oxidase inhibition, anti-β-amyloid aggregation, metal chelation, antioxidant and neuroprotection properties against Alzheimer’s disease. RSC Adv 5:70395–70409. https://doi.org/10.1039/C5RA13594J

    Article  CAS  Google Scholar 

  136. Wang Z, Wang Y, Wang B, Li W, Huang L, Li X (2015) Design, synthesis, and evaluation of orally available clioquinol-moracin M hybrids as multitarget-directed ligands for cognitive improvement in a rat model of neurodegeneration in Alzheimer’s disease. J Med Chem 58:8616–8637. https://doi.org/10.1021/acs.jmedchem.5b01222

    Article  CAS  PubMed  Google Scholar 

  137. Maqbool M, Manral A, Jameel E, Kumar J, Saini V, Shandilya A, Tiwari M, Hoda N, Jayaram B (2016) Development of cyanopyridine–triazine hybrids as lead multitarget anti-Alzheimer agents. Bioorg Med Chem 24:2777–2788. https://doi.org/10.1016/j.bmc.2016.04.041

    Article  CAS  PubMed  Google Scholar 

  138. Sheng R, Tang L, Jiang L, Hong L, Shi Y, Zhou N, Hu Y (2016) Novel 1-phenyl-3-hydroxy-4-pyridinone derivatives as multifunctional agents for the therapy of Alzheimer’s disease. ACS Chem Neurosci 7:69–81. https://doi.org/10.1021/acschemneuro.5b00224

    Article  CAS  PubMed  Google Scholar 

  139. Tang H, Wei Y, Zhang C, Ning F, Qiao W, Huang S, Ma L (2009) Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase. Eur J Med Chem 44:2523–2532. https://doi.org/10.1016/j.ejmech.2009.01.021

    Article  CAS  PubMed  Google Scholar 

  140. Wei S, Chen W, Qin J, Huangli Y, Wang L, Shen Y, Tang H (2016) Multitarget-directed oxoisoaporphine derivatives: anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced autophagy activity against Alzheimer’s disease. Bioorg Med Chem 24:6031–6039. https://doi.org/10.1016/j.bmc.2016.09.061

    Article  CAS  PubMed  Google Scholar 

  141. Ignasik M, Bajda M, Guzior N, Prinz M, Holzgrabe U, Malawska B (2012) Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors. Arch Pharm (Weinheim) 345:509–516. https://doi.org/10.1002/ardp.201100423

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Li X, Wang H, Lu Z, Zheng X, Ni W, Zhu J, Fu Y, Lian F, Zhang N, Li J, Zhang H, Mao F (2016) Development of multifunctional pyrimidinylthiourea derivatives as potential anti-Alzheimer agents. J Med Chem 59:8326–8344. https://doi.org/10.1021/acs.jmedchem.6b00636

    Article  CAS  PubMed  Google Scholar 

  144. De Simone A, Bartolini M, Baschieri A, Apperley KYP, Chen HH, Guardigni M, Montanari S, Kobrlova T, Soukup O, Valgimigli L, Andrisano V, Keillor JW, Basso M, Milelli A (2017) Hydroxy-substituted trans-cinnamoyl derivatives as multifunctional tools in the context of Alzheimer’s disease. Eur J Med Chem 139:378–389. https://doi.org/10.1016/j.ejmech.2017.07.058

    Article  CAS  PubMed  Google Scholar 

  145. Ozadali-Sari K, Tüylü Küçükkılınç T, Ayazgok B, Balkan A, Unsal-Tan O (2017) Novel multi-targeted agents for Alzheimer’s disease: synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles. Bioorg Chem 72:208–214. https://doi.org/10.1016/j.bioorg.2017.04.018

    Article  CAS  PubMed  Google Scholar 

  146. Cornec AS, Monti L, Kovalevich J, Makani V, James MJ, Vijayendran KG, Oukoloff K, Yao Y, Lee VMY, Trojanowski JQ, Smith AB, Brunden KR, Ballatore C (2017) Multitargeted imidazoles: potential therapeutic leads for Alzheimer’s and other neurodegenerative diseases. J Med Chem 60:5120–5145. https://doi.org/10.1021/acs.jmedchem.7b00475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Košak U, Knez D, Brus B, Pišlar A, Kos J, Gobec S, Coquelle N, Colletier JP, Nachon F, Brazzolotto X (2017) N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: potential multifunctional anti-Alzheimer’s agents. Bioorg Med Chem 25:633–645. https://doi.org/10.1016/j.bmc.2016.11.032

    Article  CAS  PubMed  Google Scholar 

  148. Sang Z, Pan W, Wang K, Ma Q, Yu L, Yang Y, Bai P, Leng C, Xu Q, Li X, Tan Z, Liu W (2017) Design, synthesis and evaluation of novel ferulic acid-O-alkylamine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 130:379–392. https://doi.org/10.1016/j.ejmech.2017.02.039

    Article  CAS  PubMed  Google Scholar 

  149. Mohamed T, Rao PPN (2017) 2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: development and structure-activity relationship (SAR) studies. Eur J Med Chem 126:823–843. https://doi.org/10.1016/j.ejmech.2016.12.005

    Article  CAS  PubMed  Google Scholar 

  150. Sang Z, Pan W, Wang K, Ma Q, Yu L, Liu W (2017) Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease. Bioorg Med Chem 25:3006–3017. https://doi.org/10.1016/j.bmc.2017.03.070

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are greatul to the Brazilian Agencies CNPq (#454088/2014-0, #400271/2014-1, #310082/2016-1), FAPEMIG (#CEX-APQ-00241-15), FINEP, INCT-INOFAR (#465.249/2014-0), PRPPG-UNIFAL, and CAPES for financial support and fellowships.

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Authors and Affiliations

  1. PeQuiM, Laboratory of Research in Medicinal Chemistry, Institute of Chemistry, Federal University of Alfenas, Alfenas, Brazil

    Cindy Juliet Cristancho Ortiz, Matheus de Freitas Silva, Vanessa Silva Gontijo, Flávia Pereira Dias Viegas, Kris Simone Tranches Dias & Claudio Viegas Jr.

  2. Programa de Pós-Graduação em Química, Federal University of Alfenas, Alfenas, Brazil

    Cindy Juliet Cristancho Ortiz, Matheus de Freitas Silva, Vanessa Silva Gontijo & Claudio Viegas Jr.

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  1. Cindy Juliet Cristancho Ortiz
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  2. Matheus de Freitas Silva
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  3. Vanessa Silva Gontijo
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  4. Flávia Pereira Dias Viegas
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  5. Kris Simone Tranches Dias
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  6. Claudio Viegas Jr.
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Correspondence to Claudio Viegas Jr. .

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  1. Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India

    Kunal Roy

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Ortiz, C.J.C., de Freitas Silva, M., Gontijo, V.S., Viegas, F.P.D., Dias, K.S.T., Viegas, C. (2018). Design of Multi-target Directed Ligands as a Modern Approach for the Development of Innovative Drug Candidates for Alzheimer’s Disease. In: Roy, K. (eds) Multi-Target Drug Design Using Chem-Bioinformatic Approaches. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/7653_2018_2

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  • DOI: https://doi.org/10.1007/7653_2018_2

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  • Print ISBN: 978-1-4939-8732-0

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