Recent Advancements in the Treatment of Alzheimer’s Disease: A Multitarget-directed Ligand Approach


Cite item

Full Text

Abstract

:Alzheimer's disease (AD) is a neurodegenerative disease and one of the leading causes of progressive dementia, affecting 50 million people worldwide. Many pathogenic processes, including amyloid β aggregation, tau hyperphosphorylation, oxidative stress, neuronal death, and deterioration of the function of cholinergic neurons, are associated with its progression. The one-compound-one-target treatment paradigm was unsuccessful in treating AD due to the multifaceted nature of Alzheimer's disease. The recent develop-ment of multitarget-directed ligand research has been explored to target the complemen-tary pathways associated with the disease. We aimed to find the key role and progress of MTDLs in treating AD; thus, we searched for the past ten years of literature on "Pub-Med", "ScienceDirect", "ACS" and "Bentham Science" using the keywords neurodegen-erative diseases, Alzheimer’s disease, and multitarget-directed ligands. The literature was further filtered based on the quality of work and relevance to AD. Thus, this review high-lights the current advancement and advantages of multitarget-directed ligands over tradi-tional single-targeted drugs and recent progress in their development to treat AD.

About the authors

Sumit Kumar

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli

Email: info@benthamscience.net

Amol Mahajan

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli

Email: info@benthamscience.net

Ramesh Ambatwar

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli

Email: info@benthamscience.net

Gopal Khatik

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli

Author for correspondence.
Email: info@benthamscience.net

References

  1. Patel, D.V.; Patel, N.R.; Kanhed, A.M.; Teli, D.M.; Patel, K.B.; Gandhi, P.M.; Patel, S.P.; Chaudhary, B.N.; Shah, D.B.; Prajapati, N.K.; Patel, K.V.; Yadav, M.R. Further studies on triazinoindoles as potential novel multitarget-directed anti-Alzheimer’s agents. ACS Chem. Neurosci., 2020, 11(21), 3557-3574. doi: 10.1021/acschemneuro.0c00448 PMID: 33073564
  2. Blaikie, L.; Kay, G.; Kong, T.L.P. Current and emerging therapeutic targets of Alzheimer’s disease for the design of multi-target directed ligands. MedChemComm, 2019, 10(12), 2052-2072. doi: 10.1039/C9MD00337A PMID: 32206241
  3. Uddin, M.S.; Kabir, M.T.; Jeandet, P.; Mathew, B.; Ashraf, G.M.; Perveen, A.; Bin-Jumah, M.N.; Mousa, S.A.; Abdel-Daim, M.M. Novel anti-Alzheimer’s therapeutic molecules targeting amyloid precursor protein processing. Oxid. Med. Cell. Longev., 2020, 2020, 1-19. doi: 10.1155/2020/7039138 PMID: 32411333
  4. Castanho, I.; Lunnon, K. Epigenetic Processes in Alzheimer’s Disease. In: Chromatin Signaling and Neurological Disorders; Elsevier Inc., 2019; pp. 153-180. doi: 10.1016/B978-0-12-813796-3.00008-0
  5. Pérez-Areales, F.J.; Garrido, M.; Aso, E.; Bartolini, M.; De Simone, A.; Espargaró, A.; Ginex, T.; Sabate, R.; Pérez, B.; Andrisano, V.; Puigoriol-Illamola, D.; Pallàs, M.; Luque, F.J.; Loza, M.I.; Brea, J.; Ferrer, I.; Ciruela, F.; Messeguer, A.; Muñoz-Torrero, D. Centrally active multitarget anti-Alzheimer agents derived from the antioxidant lead CR-6. J. Med. Chem., 2020, 63(17), 9360-9390. doi: 10.1021/acs.jmedchem.0c00528 PMID: 32706255
  6. Pasieka, A.; Panek, D.; Szałaj, N.; Espargaró, A.; Więckowska, A.; Malawska, B.; Sabaté, R.; Bajda, M. Dual inhibitors of amyloid-β and tau aggregation with amyloid-β disaggregating properties: Extended in cellulo, in silico, and kinetic studies of multifunctional anti-Alzheimer’s agents. ACS Chem. Neurosci., 2021, 12(11), 2057-2068. doi: 10.1021/acschemneuro.1c00235 PMID: 34019757
  7. Zhao, J.; Shi, Q.; Tian, H.; Li, Y.; Liu, Y.; Xu, Z.; Robert, A.; Liu, Q.; Meunier, B. TDMQ20, a specific copper chelator, reduces memory impairments in Alzheimer’s disease mouse models. ACS Chem. Neurosci., 2021, 12(1), 140-149. doi: 10.1021/acschemneuro.0c00621 PMID: 33322892
  8. Pawge, G.; Khatik, G.L. p53 regulated senescence mechanism and role of its modulators in age-related disorders. Biochem. Pharmacol., 2021, 190, 114651. doi: 10.1016/j.bcp.2021.114651 PMID: 34118220
  9. Alzheimer’s disease facts and figures. Alzheimers Dement., 2022, 18(4), 700-789. doi: 10.1002/alz.12638 PMID: 35289055
  10. Roggo, S. Inhibition of BACE, a promising approach to Alzheimer’s disease therapy. Curr. Top. Med. Chem., 2002, 2(4), 359-370. doi: 10.2174/1568026024607490 PMID: 11966460
  11. 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(3), 347-372. doi: 10.1021/jm7009364 PMID: 18181565
  12. Campora, M.; Francesconi, V.; Schenone, S.; Tasso, B.; Tonelli, M. Journey on naphthoquinone and anthraquinone derivatives: New insights in Alzheimer’s disease. Pharmaceuticals., 2021, 14(1), 33. doi: 10.3390/ph14010033 PMID: 33466332
  13. Uddin, M.S.; Kabir, M.T.; Rahman, M.M.; Mathew, B.; Shah, M.A.; Ashraf, G.M. TV 3326 for Alzheimer’s dementia: A novel multimodal ChE and MAO inhibitors to mitigate Alzheimer’s-like neuropathology. J. Pharm. Pharmacol., 2020, 72(8), 1001-1012. doi: 10.1111/jphp.13244 PMID: 32149402
  14. Morsy, A.; Trippier, P.C. Current and emerging pharmacological targets for the treatment of Alzheimer’s disease. J. Alzheimers Dis., 2019, 72(s1), S145-S176. doi: 10.3233/JAD-190744 PMID: 31594236
  15. Uddin, M.S.; Ashraf, G.M.; Mamun, A.A.; Mathew, B. Toxic tau: Structural origins of tau aggregation in Alzheimer’s disease. Neural Regen. Res., 2020, 15(8), 1417-1420. doi: 10.4103/1673-5374.274329 PMID: 31997800
  16. Arnsten, A.F.T.; Datta, D.; Del Tredici, K.; Braak, H. Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer’s disease. Alzheimers Dement., 2021, 17(1), 115-124. doi: 10.1002/alz.12192 PMID: 33075193
  17. Evans, P.H. Free radicals in brain metabolism and pathology. Br. Med. Bull., 1993, 49(3), 577-587. doi: 10.1093/oxfordjournals.bmb.a072632 PMID: 8221024
  18. Samanta, S.; Rajasekhar, K.; Babagond, V.; Govindaraju, T. Small molecule inhibits metal-dependent and -independent multifaceted toxicity of Alzheimer’s disease. ACS Chem. Neurosci., 2019, 10(8), 3611-3621. doi: 10.1021/acschemneuro.9b00216 PMID: 31140779
  19. Huang, W.J.; Zhang, X.; Chen, W.W. Role of oxidative stress in Alzheimer’s disease. Biomed. Rep., 2016, 4(5), 519-522. doi: 10.3892/br.2016.630 PMID: 27123241
  20. Misrani, A.; Tabassum, S.; Yang, L. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease. Front. Aging Neurosci., 2021, 13, 617588. doi: 10.3389/fnagi.2021.617588 PMID: 33679375
  21. Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: Targeting the cholinergic system. Curr. Neuropharmacol., 2016, 14(1), 101-115. doi: 10.2174/1570159X13666150716165726 PMID: 26813123
  22. Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Khachaturian, A.S.; Vergallo, A.; Farlow, M.R.; Snyder, P.J.; Giacobini, E.; Khachaturian, Z.S. Revisiting the cholinergic hypothesis in Alzheimer’s disease: Emerging evidence from translational and clinical research. J. Prev. Alzheimers Dis., 2019, 6(1), 2-15. PMID: 30569080
  23. Soma, S.; Suematsu, N.; Sato, A.Y.; Tsunoda, K.; Bramian, A.; Reddy, A.; Takabatake, K.; Karube, F.; Fujiyama, F.; Shimegi, S. Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory. Neurobiol. Learn. Mem., 2021, 183, 107484. doi: 10.1016/j.nlm.2021.107484 PMID: 34175450
  24. Chaney, A.M.; Lopez-Picon, F.R.; Serrière, S.; Wang, R.; Bochicchio, D.; Webb, S.D.; Vandesquille, M.; Harte, M.K.; Georgiadou, C.; Lawrence, C.; Busson, J.; Vercouillie, J.; Tauber, C.; Buron, F.; Routier, S.; Reekie, T.; Snellman, A.; Kassiou, M.; Rokka, J.; Davies, K.E.; Rinne, J.O.; Salih, D.A.; Edwards, F.A.; Orton, L.D.; Williams, S.R.; Chalon, S.; Boutin, H. Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: A collaborative multi-modal study. Theranostics, 2021, 11(14), 6644-6667. doi: 10.7150/thno.56059 PMID: 34093845
  25. Oddo, S.; LaFerla, F.M. The role of nicotinic acetylcholine receptors in Alzheimer’s disease. J. Physiol. Paris, 2006, 99(2-3), 172-179. doi: 10.1016/j.jphysparis.2005.12.080 PMID: 16448808
  26. Prati, F.; De Simone, A.; Bisignano, P.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Perez, D.I.; Andrisano, V.; Perez-Castillo, A.; Monti, B.; Massenzio, F.; Polito, L.; Racchi, M.; Favia, A.D.; Bottegoni, G.; Martinez, A.; Bolognesi, M.L.; Cavalli, A. Multitarget drug discovery for Alzheimer’s disease: triazinones as BACE-1 and GSK-3β inhibitors. Angew. Chem. Int. Ed., 2015, 54(5), 1578-1582. doi: 10.1002/anie.201410456 PMID: 25504761
  27. Guan, Z. Cross-talk between oxidative stress and modifications of cholinergic and glutaminergic receptors in the pathogenesis of Alzheimer’s disease. Acta Pharmacol. Sin., 2008, 29(7), 773-780. doi: 10.1111/j.1745-7254.2008.00819.x PMID: 18565274
  28. Rui, W.; Reddy, H. Role of glutamate and NMDA receptors in Alzheimer’s disease. J. Alzheimers Dis., 2017, 57, 1041-1048.
  29. Zhong, W.; Wu, A.; Berglund, K.; Gu, X.; Jiang, M.Q.; Talati, J.; Zhao, J.; Wei, L.; Yu, S.P. Pathogenesis of sporadic Alzheimer’s disease by deficiency of NMDA receptor subunit GluN3A. Alzheimers Dement., 2022, 18(2), 222-239. doi: 10.1002/alz.12398 PMID: 34151525
  30. Yang, G.J.; Liu, H.; Ma, D.L.; Leung, C.H. Rebalancing metal dyshomeostasis for Alzheimer’s disease therapy. J. Biol. Inorg. Chem., 2019, 24(8), 1159-1170. doi: 10.1007/s00775-019-01712-y PMID: 31486954
  31. Squitti, R.; Faller, P.; Hureau, C.; Granzotto, A.; White, A.R.; Kepp, K.P. Copper imbalance in Alzheimer’s disease and its link with the amyloid hypothesis: Towards a combined clinical, chemical, and genetic etiology. J. Alzheimers Dis., 2021, 83(1), 23-41. doi: 10.3233/JAD-201556 PMID: 34219710
  32. Bush, A.I.; Tanzi, R.E. Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics, 2008, 5(3), 421-432. doi: 10.1016/j.nurt.2008.05.001 PMID: 18625454
  33. Li, Y.; Jiao, Q.; Xu, H.; Du, X.; Shi, L.; Jia, F.; Jiang, H. Biometal dyshomeostasis and toxic metal accumulations in the development of Alzheimer’s disease. Front. Mol. Neurosci., 2017, 10, 339. doi: 10.3389/fnmol.2017.00339 PMID: 29114205
  34. Lovell, M.A.; Robertson, J.D.; Teesdale, W.J.; Campbell, J.L.; Markesbery, W.R. Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol. Sci., 1998, 158(1), 47-52. doi: 10.1016/S0022-510X(98)00092-6 PMID: 9667777
  35. Barão, S.; Moechars, D.; Lichtenthaler, S.F.; De Strooper, B. BACE1 physiological functions may limit its use as therapeutic target for Alzheimer’s disease. Trends Neurosci., 2016, 39(3), 158-169. doi: 10.1016/j.tins.2016.01.003 PMID: 26833257
  36. Vassar, R.; Kandalepas, P.C. The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer’s disease. Alzheimers Res. Ther., 2011, 3(3), 20. doi: 10.1186/alzrt82 PMID: 21639952
  37. Patel, S.; Bansoad, A.V.; Singh, R.; Khatik, G.L. BACE1: A key regulator in Alzheimer’s disease progression and current development of its inhibitors. Curr. Neuropharmacol., 2022, 20(6), 1174-1193. doi: 10.2174/1570159X19666211201094031 PMID: 34852746
  38. Zhang, Y.; Thompson, R.; Zhang, H.; Xu, H. APP processing in Alzheimer’s disease. Mol. Brain, 2011, 4(1), 3. doi: 10.1186/1756-6606-4-3 PMID: 21214928
  39. Fahrenholz, F. Alpha-secretase as a therapeutic target. Curr. Alzheimer Res., 2007, 4(4), 412-417. doi: 10.2174/156720507781788837 PMID: 17908044
  40. Basi, G.S.; Hemphill, S.; Brigham, E.F.; Liao, A.; Aubele, D.L.; Baker, J.; Barbour, R.; Bova, M.; Chen, X.H.; Dappen, M.S.; Eichenbaum, T.; Goldbach, E.; Hawkinson, J.; Lawler-Herbold, R.; Hu, K.; Hui, T.; Jagodzinski, J.J.; Keim, P.S.; Kholodenko, D.; Latimer, L.H.; Lee, M.; Marugg, J.; Mattson, M.N.; McCauley, S.; Miller, J.L.; Motter, R.; Mutter, L.; Neitzel, M.L.; Ni, H.; Nguyen, L.; Quinn, K.; Ruslim, L.; Semko, C.M.; Shapiro, P.; Smith, J.; Soriano, F.; Szoke, B.; Tanaka, K.; Tang, P.; Tucker, J.A.; Ye, X.M.; Yu, M.; Wu, J.; Xu, Y.; Garofalo, A.W.; Sauer, J.M.; Konradi, A.W.; Ness, D.; Shopp, G.; Pleiss, M.A.; Freedman, S.B.; Schenk, D. Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer’s disease. Alzheimers Res. Ther., 2010, 2(6), 36. doi: 10.1186/alzrt60 PMID: 21190552
  41. Schedin-Weiss, S.; Inoue, M.; Hromadkova, L.; Teranishi, Y.; Yamamoto, N.G.; Wiehager, B.; Bogdanovic, N.; Winblad, B.; Sandebring-Matton, A.; Frykman, S.; Tjernberg, L.O. Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels. Alzheimers Res. Ther., 2017, 9(1), 57. doi: 10.1186/s13195-017-0279-1 PMID: 28764767
  42. Kumar, B.; Dwivedi, A.R.; Sarkar, B.; Gupta, S.K.; Krishnamurthy, S.; Mantha, A.K.; Parkash, J.; Kumar, V. 4,6-Diphenylpyrimidine derivatives as dual inhibitors of monoamine oxidase and acetylcholinesterase for the treatment of Alzheimer’s disease. ACS Chem. Neurosci., 2019, 10(1), 252-265. doi: 10.1021/acschemneuro.8b00220 PMID: 30296051
  43. Yeung, A.W.K.; Georgieva, M.G.; Atanasov, A.G.; Tzvetkov, N.T. Monoamine oxidases (MAOs) as privileged molecular targets in neuroscience: Research literature analysis. Front. Mol. Neurosci., 2019, 12, 143. doi: 10.3389/fnmol.2019.00143 PMID: 31191248
  44. Fiore, M.; Forli, S.; Manetti, F. Targeting mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2): Medicinal chemistry efforts to lead small molecule inhibitors to clinical trials. J. Med. Chem., 2016, 59(8), 3609-3634. doi: 10.1021/acs.jmedchem.5b01457 PMID: 26502061
  45. Duraisamy, S.; Bajpai, M.; Bughani, U.; Dastidar, S.G.; Ray, A.; Chopra, P. MK2: a novel molecular target for anti-inflammatory therapy. Expert Opin. Ther. Targets, 2008, 12(8), 921-936. doi: 10.1517/14728222.12.8.921 PMID: 18620516
  46. Corrêa, S.A.L.; Eales, K.L. The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease. J. Signal Transduct., 2012, 2012, 1-12. doi: 10.1155/2012/649079 PMID: 22792454
  47. Liu, S.L.; Wang, C.; Jiang, T.; Tan, L.; Xing, A.; Yu, J.T. The role of Cdk5 in Alzheimer’s disease. Mol. Neurobiol., 2016, 53(7), 4328-4342. doi: 10.1007/s12035-015-9369-x PMID: 26227906
  48. Silva, T.; Reis, J.; Teixeira, J.; Borges, F. Alzheimer’s disease, enzyme targets and drug discovery struggles: From natural products to drug prototypes. Ageing Res. Rev., 2014, 15, 116-145. doi: 10.1016/j.arr.2014.03.008 PMID: 24726823
  49. Arfeen, M.; Bhagat, S.; Patel, R.; Prasad, S.; Roy, I.; Chakraborti, A.K.; Bharatam, P.V. Design, synthesis and biological evaluation of 5-benzylidene-2-iminothiazolidin-4-ones as selective GSK-3β inhibitors. Eur. J. Med. Chem., 2016, 121, 727-736. doi: 10.1016/j.ejmech.2016.04.075 PMID: 27423119
  50. Fan, S.J.; Huang, F.I.; Liou, J.P.; Yang, C.R. The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer’s disease model. Cell Death Dis., 2018, 9(6), 655. doi: 10.1038/s41419-018-0688-5 PMID: 29844403
  51. Vitolo, O.V.; Sant’Angelo, A.; Costanzo, V.; Battaglia, F.; Arancio, O.; Shelanski, M. Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci., 2002, 99(20), 13217-13221. doi: 10.1073/pnas.172504199 PMID: 12244210
  52. Cuadrado-tejedor, M.; Franco, R. Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem. Neurosci., 2012, 2012(3), 832-844.
  53. Wu, Y.; Li, Z.; Huang, Y.Y.; Wu, D.; Luo, H.B. Novel phosphodiesterase inhibitors for cognitive improvement in Alzheimer’s disease. J. Med. Chem., 2018, 61(13), 5467-5483. doi: 10.1021/acs.jmedchem.7b01370 PMID: 29363967
  54. Desvergne, B.; Wahli, W. Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr. Rev., 1999, 20(5), 649-688. PMID: 10529898
  55. Li, M.; Meng, Y.; Chu, B.; Shen, Y.; Xue, X.; Song, C.; Liu, X.; Ding, M.; Cao, X.; Wang, P.; Xu, S.; Bi, J.; Xie, Z. Orexin-A exacerbates Alzheimer’s disease by inducing mitochondrial impairment. Neurosci. Lett., 2020, 718, 134741. doi: 10.1016/j.neulet.2020.134741 PMID: 31927055
  56. Lim, G.P.; Yang, F.; Chu, T.; Chen, P.; Beech, W.; Teter, B.; Tran, T.; Ubeda, O.; Ashe, K.H.; Frautschy, S.A.; Cole, G.M. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J. Neurosci., 2000, 20, 5709-5714.
  57. Li, H.; Wu, J.; Zhu, L.; Sha, L.; Yang, S.; Wei, J.; Ji, L.; Tang, X.; Mao, K.; Cao, L.; Wei, N.; Xie, W.; Yang, Z. Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer’s disease: Possible mechanisms of IDE in T2D and AD. Biosci. Rep., 2018, 38(1), BSR20170862. doi: 10.1042/BSR20170862 PMID: 29222348
  58. Garcia-Alloza, M.; Hirst, W.D.; Chen, C.P.L-H.; Lasheras, B.; Francis, P.T.; Ramírez, M.J. Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer’s disease. Neuropsychopharmacology, 2004, 29(2), 410-416. doi: 10.1038/sj.npp.1300330 PMID: 14571255
  59. de Bruin, N.; Kruse, C. 5-HT6 receptor antagonists: Potential efficacy for the treatment of cognitive impairment in schizophrenia. Curr. Pharm. Des., 2015, 21(26), 3739-3759. doi: 10.2174/1381612821666150605112105 PMID: 26044973
  60. Dias, K.S.T.; de Paula, C.T.; dos Santos, T.; Souza, I.N.O.; Boni, M.S.; Guimarães, M.J.R.; da Silva, F.M.R.; Castro, N.G.; Neves, G.A.; Veloso, C.C.; Coelho, M.M.; de Melo, I.S.F.; Giusti, F.C.V.; Giusti-Paiva, A.; da Silva, M.L.; Dardenne, L.E.; Guedes, I.A.; Pruccoli, L.; Morroni, F.; Tarozzi, A.; Viegas, C. Jr Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2017, 130, 440-457. doi: 10.1016/j.ejmech.2017.02.043 PMID: 28282613
  61. Gervais, F.G.; Xu, D.; Robertson, G.S.; Vaillancourt, J.P.; Zhu, Y.; Huang, J.; LeBlanc, A.; Smith, D.; Rigby, M.; Shearman, M.S.; Clarke, E.E.; Zheng, H.; Van Der Ploeg, L.H.T.; Ruffolo, S.C.; Thornberry, N.A.; Xanthoudakis, S.; Zamboni, R.J.; Roy, S.; Nicholson, D.W. Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-β precursor protein and amyloidogenic A β peptide formation. Cell, 1999, 97(3), 395-406. doi: 10.1016/S0092-8674(00)80748-5 PMID: 10319819
  62. Kwak, S.; Weiss, J.H. Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr. Opin. Neurobiol., 2006, 16(3), 281-287. doi: 10.1016/j.conb.2006.05.004 PMID: 16698262
  63. Joshi, S.; Kapur, J. Mechanisms of status epilepticus: α -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor hypothesis. Epilepsia, 2018, 59(S2), 78-81. doi: 10.1111/epi.14482 PMID: 30159880
  64. Kanninen, K.; Malm, T.M.; Jyrkkänen, H.K.; Goldsteins, G.; Keksa-Goldsteine, V.; Tanila, H.; Yamamoto, M.; Ylä-Herttuala, S.; Levonen, A.L.; Koistinaho, J. Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol. Cell. Neurosci., 2008, 39(3), 302-313. doi: 10.1016/j.mcn.2008.07.010 PMID: 18706502
  65. Gameiro, I.; Michalska, P.; Tenti, G.; Cores, Á.; Buendia, I.; Rojo, A.I.; Georgakopoulos, N.D.; Hernández-Guijo, J.M.; Teresa Ramos, M.; Wells, G.; López, M.G.; Cuadrado, A.; Menéndez, J.C.; León, R. Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease. Sci. Rep., 2017, 7(1), 45701. doi: 10.1038/srep45701 PMID: 28361919
  66. Jonsson, T.; Stefansson, H.; Steinberg, S.; Jonsdottir, I.; Jonsson, P.V.; Snaedal, J.; Bjornsson, S.; Huttenlocher, J.; Levey, A.I.; Lah, J.J.; Rujescu, D.; Hampel, H.; Giegling, I.; Andreassen, O.A.; Engedal, K.; Ulstein, I.; Djurovic, S.; Ibrahim-Verbaas, C.; Hofman, A.; Ikram, M.A.; van Duijn, C.M.; Thorsteinsdottir, U.; Kong, A.; Stefansson, K. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med., 2013, 368(2), 107-116. doi: 10.1056/NEJMoa1211103 PMID: 23150908
  67. Lill, C.M.; Rengmark, A.; Pihlstrøm, L.; Fogh, I.; Shatunov, A.; Sleiman, P.M.; Wang, L.S.; Liu, T.; Lassen, C.F.; Meissner, E.; Alexopoulos, P.; Calvo, A.; Chio, A.; Dizdar, N.; Faltraco, F.; Forsgren, L.; Kirchheiner, J.; Kurz, A.; Larsen, J.P.; Liebsch, M.; Linder, J.; Morrison, K.E.; Nissbrandt, H.; Otto, M.; Pahnke, J.; Partch, A.; Restagno, G.; Rujescu, D.; Schnack, C.; Shaw, C.E.; Shaw, P.J.; Tumani, H.; Tysnes, O.B.; Valladares, O.; Silani, V.; Berg, L.H.; Rheenen, W.; Veldink, J.H.; Lindenberger, U.; Steinhagen-Thiessen, E.; Teipel, S.; Perneczky, R.; Hakonarson, H.; Hampel, H.; Arnim, C.A.F.; Olsen, J.H.; Van Deerlin, V.M.; Al-Chalabi, A.; Toft, M.; Ritz, B.; Bertram, L. The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimers Dement., 2015, 11(12), 1407-1416. doi: 10.1016/j.jalz.2014.12.009 PMID: 25936935
  68. Xu, K.; Dai, X.L.; Huang, H.C.; Jiang, Z.F. Targeting HDACs: A promising therapy for Alzheimer’s disease. Oxid. Med. Cell. Longev., 2011, 2011, 143269. doi: 10.1155/2011/143269
  69. Houtkooper, R.H.; Pirinen, E.; Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol., 2012, 13(4), 225-238. doi: 10.1038/nrm3293 PMID: 22395773
  70. Staderini, M.; Martín, M.A.; Bolognesi, M.L.; Menéndez, J.C. Imaging of β-amyloid plaques by near infrared fluorescent tracers: A new frontier for chemical neuroscience. Chem. Soc. Rev., 2015, 44(7), 1807-1819. doi: 10.1039/C4CS00337C PMID: 25622714
  71. Golde, T.E.; Bacskai, B.J. Bringing amyloid into focus. Nat. Biotechnol., 2005, 23(5), 552-554. doi: 10.1038/nbt0505-552 PMID: 15877070
  72. Cui, M. Past and recent progress of molecular imaging probes for β-amyloid plaques in the brain. Curr. Med. Chem., 2013, 21(1), 82-112. doi: 10.2174/09298673113209990216 PMID: 23992340
  73. Tong, H.; Lou, K.; Wang, W. Near-infrared fluorescent probes for imaging of amyloid plaques in Alzheimer׳s disease. Acta Pharm. Sin. B, 2015, 5(1), 25-33. doi: 10.1016/j.apsb.2014.12.006 PMID: 26579421
  74. Tsoi, K.K.F.; Chan, J.Y.C.; Chan, F.C.H.; Hirai, H.W.; Kwok, T.C.Y.; Wong, S.Y.S. Monotherapy is good enough for patients with mild‐to‐moderate Alzheimer’s disease: A network meta‐analysis of 76 randomized controlled trials. Clin. Pharmacol. Ther., 2019, 105(1), 121-130. doi: 10.1002/cpt.1104 PMID: 29717478
  75. scarpini, E.; Schelterns, P.; Feldman, H. Treatment of Alzheimer’s disease; current status and new perspectives. Lancet Neurol., 2003, 2(9), 539-547. doi: 10.1016/S1474-4422(03)00502-7 PMID: 12941576
  76. Olin, J.; Schneider, L. Galantamine for Alzheimer’s disease. Cochrane Database Syst. Rev., 2002, (3), CD001747. PMID: 12137632
  77. Knorz, A.L.; Quante, A. Alzheimer’s disease: Efficacy of mono- and combination therapy. A systematic review. J. Geriatr. Psychiatry Neurol., 2022, 35(4), 475-486. doi: 10.1177/08919887211044746 PMID: 34476990
  78. Álvarez, X.A.; Linares, C.; Masliah, E. Combination drug therapy for the treatment of Alzheimer’s disease. Eur. Neurol. Rev., 2012, 7, 23-25.
  79. Kabir, M.T.; Uddin, M.S.; Mamun, A.A.; Jeandet, P.; Aleya, L.; Mansouri, R.A.; Ashraf, G.M.; Mathew, B.; Bin-Jumah, M.N.; Abdel-Daim, M.M. Combination drug therapy for the management of Alzheimer’s disease. Int. J. Mol. Sci., 2020, 21(9), 3272. doi: 10.3390/ijms21093272 PMID: 32380758
  80. Deardorff, W.J.; Grossberg, G. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease. Drug Des. Devel. Ther., 2016, 10, 3267-3279. doi: 10.2147/DDDT.S86463 PMID: 27757016
  81. Feldman, H.H.; Schmitt, F.A.; Olin, J.T.; Olin, J.T. Activities of daily living in moderate-to-severe Alzheimer disease: An analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Dis. Assoc. Disord., 2006, 20(4), 263-268. doi: 10.1097/01.wad.0000213859.35355.59 PMID: 17132971
  82. Choi, S.H.; Park, K.W.; Na, D.L.; Han, H.J.; Kim, E.J.; Shim, Y.S.; Lee, J.H. Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer’s disease: A multicenter, randomized, open-label, parallel-group study. Curr. Med. Res. Opin., 2011, 27(7), 1375-1383. doi: 10.1185/03007995.2011.582484 PMID: 21561398
  83. Farlow, M.R.; Alva, G.; Meng, X.; Olin, J.T. A 25-week, open-label trial investigating rivastigmine transdermal patches with concomitant memantine in mild-to-moderate Alzheimer’s disease: A post hoc analysis. Curr. Med. Res. Opin., 2010, 26(2), 263-269. doi: 10.1185/03007990903434914 PMID: 19929593
  84. Mullard, A. Landmark Alzheimer’s drug approval confounds research community. Nature, 2021, 594(7863), 309-310. doi: 10.1038/d41586-021-01546-2 PMID: 34103732
  85. Mahase, E. Alzheimer’s disease: FDA approves lecanemab amid cost and safety concerns. BMJ, 2023, 380, 73. doi: 10.1136/bmj.p73 PMID: 36631154
  86. Cummings, J.; Lee, G.; Nahed, P.; Kambar, M.E.Z.N.; Zhong, K.; Fonseca, J.; Taghva, K. Alzheimer’s Disease Drug Development Pipeline: 2022 In: Alzheimer’s Dement; Cambridge University Press,, 2022; p. 8. doi: 10.1017/9781108975759
  87. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/(Accessed on: Dec 17, 2021).
  88. Zimmermann, G.R.; Lehár, J.; Keith, C.T. Multi-target therapeutics: When the whole is greater than the sum of the parts. Drug Discov. Today, 2007, 12(1-2), 34-42. doi: 10.1016/j.drudis.2006.11.008 PMID: 17198971
  89. Frantz, S. Playing dirty. Nature, 2005, 437(7061), 942-943. doi: 10.1038/437942a PMID: 16222266
  90. Morphy, R.; Kay, C.; Rankovic, Z.; Morphy, R. From magic bullets to designed multiple ligands. Drug Discov. Today, 2004, 9(15), 641-651. doi: 10.1016/S1359-6446(04)03163-0 PMID: 15279847
  91. Zhou, J.; Jiang, X.; He, S.; Jiang, H.; Feng, F.; Liu, W.; Qu, W.; Sun, H. Rational design of multitarget-directed ligands: Strategies and emerging paradigms. J. Med. Chem., 2019, 62(20), 8881-8914. doi: 10.1021/acs.jmedchem.9b00017 PMID: 31082225
  92. Morphy, R.; Rankovic, Z. Designing multiple ligands - medicinal chemistry strategies and challenges. Curr. Pharm. Des., 2009, 15(6), 587-600. doi: 10.2174/138161209787315594 PMID: 19199984
  93. Hopkins, A.; Mason, J.; Overington, J. Can we rationally design promiscuous drugs? Curr. Opin. Struct. Biol., 2006, 16(1), 127-136. doi: 10.1016/j.sbi.2006.01.013 PMID: 16442279
  94. Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem., 2005, 48(21), 6523-6543. doi: 10.1021/jm058225d PMID: 16220969
  95. Savelieff, M.G.; Nam, G.; Kang, J.; Lee, H.J.; Lee, M.; Lim, M.H. Development of multifunctional molecules as potential therapeutic candidates for Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in the last decade. Chem. Rev., 2019, 119(2), 1221-1322. doi: 10.1021/acs.chemrev.8b00138 PMID: 30095897
  96. Ismaili, L.; Refouvelet, B.; Benchekroun, M.; Brogi, S.; Brindisi, M.; Gemma, S.; Campiani, G.; Filipic, S.; Agbaba, D.; Esteban, G.; Unzeta, M.; Nikolic, K.; Butini, S.; Marco-Contelles, J. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer’s disease. Prog. Neurobiol., 2017, 151, 4-34. doi: 10.1016/j.pneurobio.2015.12.003 PMID: 26797191
  97. Sultana, R.; Ravagna, A.; Mohmmad-Abdul, H.; Calabrese, V.; Butterfield, D.A. Ferulic acid ethyl ester protects neurons against amyloid beta- peptide(1-42)-induced oxidative stress and neurotoxicity: Relationship to antioxidant activity. J. Neurochem., 2005, 92(4), 749-758. doi: 10.1111/j.1471-4159.2004.02899.x PMID: 15686476
  98. Xie, S.S.; Lan, J.S.; Wang, X.; Wang, Z.M.; Jiang, N.; Li, F.; Wu, J.J.; Wang, J.; Kong, L.Y. Design, synthesis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease. Bioorg. Med. Chem., 2016, 24(7), 1528-1539. doi: 10.1016/j.bmc.2016.02.023 PMID: 26917219
  99. Sharma, K. Cholinesterase inhibitors as Alzheimer’s therapeutics (Review). Mol. Med. Rep., 2019, 20(2), 1479-1487. PMID: 31257471
  100. Posadas, I.; López-Hernández, B.; Ceña, V. Nicotinic receptors in neurodegeneration. Curr. Neuropharmacol., 2013, 11(3), 298-314. doi: 10.2174/1570159X11311030005 PMID: 24179465
  101. Alam, S.; Lingenfelter, K.S.; Bender, A.M.; Lindsley, C.W. Classics in chemical neuroscience. Memantine. ACS Chem. Neurosci., 2017, 8(9), 1823-1829. doi: 10.1021/acschemneuro.7b00270 PMID: 28737885
  102. Takada-Takatori, Y.; Kume, T.; Sugimoto, M.; Katsuki, H.; Sugimoto, H.; Akaike, A. Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology, 2006, 51(3), 474-486. doi: 10.1016/j.neuropharm.2006.04.007 PMID: 16762377
  103. Simoni, E.; Daniele, S.; Bottegoni, G.; Pizzirani, D.; Trincavelli, M.L.; Goldoni, L.; Tarozzo, G.; Reggiani, A.; Martini, C.; Piomelli, D.; Melchiorre, C.; Rosini, M.; Cavalli, A. Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer’s disease. J. Med. Chem., 2012, 55(22), 9708-9721. doi: 10.1021/jm3009458 PMID: 23033965
  104. Onor, M.L.; Trevisiol, M.; Aguglia, E. Rivastigmine in the treatment of Alzheimer’s disease: An update. Clin. Interv. Aging, 2007, 2(1), 17-32. doi: 10.2147/ciia.2007.2.1.17 PMID: 18044073
  105. Matthews, D.C.; Ritter, A.; Thomas, R.G.; Andrews, R.D.; Lukic, A.S.; Revta, C.; Kinney, J.W.; Tousi, B.; Leverenz, J.B.; Fillit, H.; Zhong, K.; Feldman, H.H.; Cummings, J. Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer’s dementia. Alzheimers Dement., 2021, 7(1), e12106. doi: 10.1002/trc2.12106 PMID: 33614888
  106. Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner, D.; Goldenberg, W.; Miskolczi, I.; Molnar, S.; Rantal, F.; Tamas, T.; Toth, G.; Zagyva, A.; Zekany, A.; Lavian, G.; Gross, A.; Friedman, R.; Razin, M.; Huang, W.; Krais, B.; Chorev, M.; Youdim, M.B.; Weinstock, M.; Weinstock, M. Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer’s disease. J. Med. Chem., 2002, 45(24), 5260-5279. doi: 10.1021/jm020120c PMID: 12431053
  107. Weinreb, O.; Amit, T.; Bar-Am, O.; Youdim, M.B.H. Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Curr. Drug Targets, 2012, 13(4), 483-494. doi: 10.2174/138945012799499794 PMID: 22280345
  108. Zheng, H.; Youdim, M.B.H.; Fridkin, M. Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective-neurorestorative moieties for Alzheimer’s therapy. J. Med. Chem., 2009, 52(14), 4095-4098. doi: 10.1021/jm900504c PMID: 19485411
  109. Wilkinson, D.G. The pharmacology of donepezil: A new treatment for Alzheimer’s disease. Expert Opin. Pharmacother., 1999, 1(1), 121-135. doi: 10.1517/14656566.1.1.121 PMID: 11249555
  110. Relman, A.S. Tacrine as a treatment for Alzheimer’s dementia: editor’s note. An interim report from the FDA. A response from Summers et al. N. Engl. J. Med., 1991, 324(5), 349-352. doi: 10.1056/NEJM199101313240525 PMID: 1986300
  111. Potkin, S.G.; Anand, R.; Fleming, K.; Alva, G.; Keator, D.; Carreon, D.; Messina, J.; Wu, J.C.; Hartman, R.; Fallon, J.H. Brain metabolic and clinical effects of rivastigmine in Alzheimer’s disease. Int. J. Neuropsychopharmacol., 2001, 4(3), 223-230. doi: 10.1017/S1461145701002528 PMID: 11602028
  112. Piazzi, L.; Cavalli, A.; Colizzi, F.; Belluti, F.; Bartolini, M.; Mancini, F.; Recanatini, M.; Andrisano, V.; Rampa, A. Multi-target-directed coumarin derivatives : HAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorg. Med. Chem. Lett., 2008, 18, 423-426.
  113. Viña, D.; Matos, M.J.; Yáñez, M.; Santana, L.; Uriarte, E. 3-Substituted coumarins as dual inhibitors of AChE and MAO for the treatment of Alzheimer’s disease. MedChemComm, 2012, 3(2), 213-218. doi: 10.1039/C1MD00221J
  114. Li, S.Y.; Wang, X.B.; Xie, S.S.; Jiang, N.; Wang, K.D.G.; Yao, H.Q.; Sun, H.B.; Kong, L.Y. Multifunctional tacrine-flavonoid hybrids with cholinergic, β-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2013, 69, 632-646. doi: 10.1016/j.ejmech.2013.09.024 PMID: 24095756
  115. Weinreb, O.; Mandel, S.; Bar-Am, O.; Yogev-Falach, M.; Avramovich-Tirosh, Y.; Amit, T.; Youdim, M.B.H. Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer’s disease drugs. Neurotherapeutics, 2009, 6(1), 163-174. doi: 10.1016/j.nurt.2008.10.030 PMID: 19110207
  116. Nobili, A.; Latagliata, E.C.; Viscomi, M.T.; Cavallucci, V.; Cutuli, D.; Giacovazzo, G.; Krashia, P.; Rizzo, F.R.; Marino, R.; Federici, M.; De Bartolo, P.; Aversa, D.; Dell’Acqua, M.C.; Cordella, A.; Sancandi, M.; Keller, F.; Petrosini, L.; Puglisi-Allegra, S.; Mercuri, N.B.; Coccurello, R.; Berretta, N.; D’Amelio, M. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat. Commun., 2017, 8(1), 14727. doi: 10.1038/ncomms14727 PMID: 28367951
  117. 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-β-mediated Alzheimer’s disease-associated pathogenesis in vitro and in vivo. PLoS One, 2012, 7(2), e31921. doi: 10.1371/journal.pone.0031921 PMID: 22384101
  118. Ma, T.; Tan, M.S.; Yu, J.T.; Tan, L. Resveratrol as a therapeutic agent for Alzheimer’s disease. BioMed Res. Int., 2014, 2014, 1-13. doi: 10.1155/2014/350516 PMID: 25525597
  119. Ferrero, H.; Solas, M.; Francis, P.T.; Ramirez, M.J. Serotonin 5-HT6 receptor antagonists in Alzheimer’s disease: Therapeutic rationale and current development status. CNS Drugs, 2017, 31(1), 19-32. doi: 10.1007/s40263-016-0399-3 PMID: 27914038
  120. Wang, Z.; Hu, J.; Yang, X.; Feng, X.; Li, X.; Huang, L.; Chan, A.S.C. Design, synthesis, and evaluation of orally bioavailable quinoline-indole derivatives as innovative multitarget-directed ligands: Promotion of cell proliferation in the adult murine hippocampus for the treatment of Alzheimer’s disease. J. Med. Chem., 2018, 61(5), 1871-1894. doi: 10.1021/acs.jmedchem.7b01417 PMID: 29420891
  121. Chen, Y.; Bian, Y.; Sun, Y.; Kang, C.; Yu, S.; Fu, T.; Li, W.; Pei, Y.; Sun, H. Identification of 4-aminoquinoline core for the design of new cholinesterase inhibitors. PeerJ, 2016, 4, e2140. doi: 10.7717/peerj.2140 PMID: 27441112
  122. Jordan, J.B.; Whittington, D.A.; Bartberger, M.D.; Sickmier, E.A.; Chen, K.; Cheng, Y.; Judd, T. Fragment-linking approach using 19 F NMR spectroscopy to obtain highly potent and selective inhibitors of β-secretase. J. Med. Chem., 2016, 59(8), 3732-3749. doi: 10.1021/acs.jmedchem.5b01917 PMID: 26978477
  123. Hiremathad, A.; Keri, R.S.; Esteves, A.R.; Cardoso, S.M.; Chaves, S.; Santos, M.A. Novel tacrine-hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer’s disease. Eur. J. Med. Chem., 2018, 148, 255-267. doi: 10.1016/j.ejmech.2018.02.023 PMID: 29466775
  124. Bag, S.; Tulsan, R.; Sood, A.; Cho, H.; Redjeb, H.; Zhou, W.; LeVine, H., III; Török, B.; Török, M. Sulfonamides as multifunctional agents for Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2015, 25(3), 626-630. doi: 10.1016/j.bmcl.2014.12.006 PMID: 25537270
  125. Fang, Y.; Zhou, H.; Gu, Q.; Xu, J. Synthesis and evaluation of tetrahydroisoquinoline-benzimidazole hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2019, 167, 133-145. doi: 10.1016/j.ejmech.2019.02.008 PMID: 30771601
  126. Jenagaratnam, L.; McShane, R. Clioquinol for the treatment of Alzheimer’s disease. Cochrane Database Syst. Rev., 2006, (1), CD005380. PMID: 16437529
  127. Prati, F.; Cavalli, A.; Bolognesi, M. Navigating the chemical space of multitarget-directed ligands: From hybrids to fragments in Alzheimer’s disease. Molecules, 2016, 21(4), 466. doi: 10.3390/molecules21040466 PMID: 27070562
  128. Czarnecka, K.; Girek, M.; Maciejewska, K.; Skibiński, R.; Jończyk, J.; Bajda, M.; Kabziński, J.; Sołowiej, P.; Majsterek, I.; Szymański, P.; Girek, M.; Maciejewska, K.; Skibiński, R.; Jończyk, J.; Bajda, M.; Kabziński, J.; Sołowiej, P.; Majsterek, I. New cyclopentaquinoline hybrids with multifunctional capacities for the treatment of Alzheimer’s disease. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 158-170. doi: 10.1080/14756366.2017.1406485 PMID: 29210299
  129. Chalupova, K.; Korabecny, J.; Bartolini, M.; Monti, B.; Lamba, D.; Caliandro, R.; Pesaresi, A.; Brazzolotto, X.; Gastellier, A.J.; Nachon, F.; Pejchal, J.; Jarosova, M.; Hepnarova, V.; Jun, D.; Hrabinova, M.; Dolezal, R.; Zdarova Karasova, J.; Mzik, M.; Kristofikova, Z.; Misik, J.; Muckova, L.; Jost, P.; Soukup, O.; Benkova, M.; Setnicka, V.; Habartova, L.; Chvojkova, M.; Kleteckova, L.; Vales, K.; Mezeiova, E.; Uliassi, E.; Valis, M.; Nepovimova, E.; Bolognesi, M.L.; Kuca, K. Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer’s disease. Eur. J. Med. Chem., 2019, 168, 491-514. doi: 10.1016/j.ejmech.2019.02.021 PMID: 30851693
  130. Makhaeva, G.F.; Kovaleva, N.V.; Rudakova, E.V.; Boltneva, N.P.; Lushchekina, S.V.; Faingold, I.I.; Poletaeva, D.A.; Soldatova, Y.V.; Kotelnikova, R.A.; Serkov, I.V.; Ustinov, A.K.; Proshin, A.N. New multifunctional agents based on conjugates of hydroxytoluene for Alzheimer’s disease treatment. Molecules, 2020, 25, 5891. doi: 10.3390/molecules25245891 PMID: 33322783
  131. Nazari, M.; Rezaee, E.; Hariri, R.; Akbarzadeh, T.; Tabatabai, S.A. Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation. EXCLI J., 2021, 20, 907-921. PMID: 34121977
  132. Wen-Juan, H.; Xia, L.Z.; Jia-cheng, S.; Jia-li, C.; Zhi-qiang, S. Synthesis and evaluation of coumarin/1,2,4-oxadiazole hybrids as selective BChE inhibitors with neuroprotective activity. J. Asian Nat. Prod. Res., 2018, 6020, 1-14.
  133. Sun, Q.; Peng, D.Y.; Yang, S.G.; Zhu, X.L.; Yang, W.C.; Yang, G.F. Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase. Bioorg. Med. Chem., 2014, 22(17), 4784-4791. doi: 10.1016/j.bmc.2014.06.057 PMID: 25088549
  134. Digiacomo, M.; Chen, Z.; Wang, S.; Lapucci, A.; Macchia, M.; Yang, X.; Chu, J.; Han, Y.; Pi, R.; Rapposelli, S. Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD. Bioorg. Med. Chem. Lett., 2015, 25(4), 807-810. doi: 10.1016/j.bmcl.2014.12.084 PMID: 25597007
  135. Panek, D.; Więckowska, A.; Wichur, T.; Bajda, M.; Godyń, J.; Jończyk, J.; Mika, K.; Janockova, J.; Soukup, O.; Knez, D.; Korabecny, J.; Gobec, S.; Malawska, B. Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation. Eur. J. Med. Chem., 2017, 125, 676-695. doi: 10.1016/j.ejmech.2016.09.078 PMID: 27721153
  136. Gazova, Z.; Soukup, O.; Sepsova, V.; Siposova, K.; Drtinova, L.; Jost, P.; Spilovska, K.; Korabecny, J.; Nepovimova, E.; Fedunova, D.; Horak, M.; Kaniakova, M.; Wang, Z.J.; Hamouda, A.K.; Kuca, K. Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer’s disease treatment. Biochim. Biophys. Acta Mol. Basis Dis., 2017, 1863(2), 607-619. doi: 10.1016/j.bbadis.2016.11.020 PMID: 27865910
  137. Panek, D.; Więckowska, A.; Jończyk, J.; Godyń, J.; Bajda, M.; Wichur, T.; Pasieka, A.; Knez, D.; Pišlar, A.; Korabecny, J.; Soukup, O.; Sepsova, V.; Sabaté, R.; Kos, J.; Gobec, S.; Malawska, B. Design, synthesis, and biological evaluation of 1-Benzylamino-2-hydroxyalkyl derivatives as new potential disease-modifying multifunctional anti-alzheimer’s agents. ACS Chem. Neurosci., 2018, 9(5), 1074-1094. doi: 10.1021/acschemneuro.7b00461 PMID: 29345897
  138. Sakata, R.P.; Antoniolli, G.; Lancellotti, M.; Kawano, D.F.; Guimarães Barbosa, E.; Almeida, W.P. Synthesis and biological evaluation of 2′-Aminochalcone: A multi-target approach to find drug candidates to treat Alzheimer’s disease. Bioorg. Chem., 2020, 103, 104201. doi: 10.1016/j.bioorg.2020.104201 PMID: 32890999
  139. Wang, L.; Esteban, G.; Ojima, M.; Bautista-Aguilera, O.M.; Inokuchi, T.; Moraleda, I.; Iriepa, I.; Samadi, A.; Youdim, M.B.H.; Romero, A.; Soriano, E.; Herrero, R.; Fernández Fernández, A.P. Ricardo-Martínez-Murillo; Marco-Contelles, J.; Unzeta, M. 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., 2014, 80, 543-561. doi: 10.1016/j.ejmech.2014.04.078 PMID: 24813882
  140. Benek, O.; Soukup, O.; Pasdiorova, M.; Hroch, L.; Sepsova, V.; Jost, P.; Hrabinova, M.; Jun, D.; Kuca, K.; Zala, D.; Ramsay, R.R.; Marco-Contelles, J.; Musilek, K. Design, synthesis and in vitro evaluation of indolotacrine analogues as multitarget-directed ligands for the treatment of Alzheimer’s disease. ChemMedChem, 2016, 11(12), 1264-1269. doi: 10.1002/cmdc.201500383 PMID: 26427608
  141. Marco-Contelles, J.; Unzeta, M.; Bolea, I.; Esteban, G.; Ramsay, R.R.; Romero, A.; Martínez-Murillo, R.; Carreiras, M.C.; Ismaili, L. ASS234, as a new multi-target directed propargylamine for Alzheimer’s disease therapy. Front. Neurosci., 2016, 10, 294. doi: 10.3389/fnins.2016.00294 PMID: 27445665
  142. Plazas, E.; Hagenow, S.; Avila Murillo, M.; Stark, H.; Cuca, L.E. Isoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aβ1-42 aggregation. Bioorg. Chem., 2020, 98, 103722. doi: 10.1016/j.bioorg.2020.103722 PMID: 32155491
  143. Piemontese, L.; Tomás, D.; Hiremathad, A.; Capriati, V.; Candeias, E.; Cardoso, S.M.; Chaves, S.; Santos, M.A.; Tomás, D.; Hiremathad, A.; Capriati, V.; Cardoso, S.M.; Chaves, S.; Donepezil, M.A.S. Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 1212-1224. doi: 10.1080/14756366.2018.1491564 PMID: 30160188
  144. Wang, Z.; Cao, M.; Xiang, H.; Wang, W.; Feng, X.; Yang, X. WBQ5187, a multitarget directed agent, ameliorates cognitive impairment in a transgenic mouse model of Alzheimer’s disease and modulates cerebral β-amyloid, gliosis, cAMP levels, and neurodegeneration. ACS Chem. Neurosci., 2019, 10(12), 4787-4799. doi: 10.1021/acschemneuro.9b00409 PMID: 31697472
  145. Gandini, A.; Bartolini, M.; Tedesco, D.; Martinez-Gonzalez, L.; Roca, C.; Campillo, N.E.; Zaldivar-Diez, J.; Perez, C.; Zuccheri, G.; Miti, A.; Feoli, A.; Castellano, S.; Petralla, S.; Monti, B.; Rossi, M.; Moda, F.; Legname, G.; Martinez, A.; Bolognesi, M.L. Tau-centric multitarget approach for Alzheimer’s Disease: Development of first-in-class dual glycogen synthase kinase 3β and tau-aggregation inhibitors. J. Med. Chem., 2018, 61(17), 7640-7656. doi: 10.1021/acs.jmedchem.8b00610 PMID: 30078314
  146. Wang, M.; Liu, T.; Chen, S.; Wu, M.; Han, J.; Li, Z. Design and synthesis of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives as novel GSK-3β inhibitors and evaluation of their potential as multifunctional anti-Alzheimer agents. Eur. J. Med. Chem., 2021, 209, 112874. doi: 10.1016/j.ejmech.2020.112874 PMID: 33017743
  147. Poliseno, V.; Chaves, S.; Brunetti, L.; Loiodice, F.; Carrieri, A.; Laghezza, A.; Tortorella, P.; Magalhães, J.D.; Cardoso, S.M.; Santos, M.A.; Piemontese, L. Derivatives of tenuazonic acid as potential new multi-target anti-Alzheimer’s disease agents. Biomolecules, 2021, 11(1), 111. doi: 10.3390/biom11010111 PMID: 33467709
  148. Kou, X.; Song, L.; Wang, Y.; Yu, Q.; Ju, H.; Yang, A.; Shen, R. Design, synthesis and anti-Alzheimer’s disease activity study of xanthone derivatives based on multi-target strategy. Bioorg. Med. Chem. Lett., 2020, 30(4), 126927. doi: 10.1016/j.bmcl.2019.126927 PMID: 31901382
  149. He, F.; Chou, C.J.; Scheiner, M.; Poeta, E.; Chen, Y. Melatonin-and ferulic acid-based hdac6 selective inhibitors exhibit pronounced immunomodulatory effects in vitro and neuroprotective effects in a pharmacological Alzheimer’s disease mouse model. J. Med. Chem., 2021, 64, 3794-3812. doi: 10.1021/acs.jmedchem.0c01940 PMID: 33769811
  150. Guo, J.; Cheng, M.; Liu, P.; Cao, D.; Luo, J.; Wan, Y.; Fang, Y.; Jin, Y.; Xie, S.S.; Liu, J. A multi-target directed ligands strategy for the treatment of Alzheimer’s disease: Dimethyl fumarate plus Tranilast modified Dithiocarbate as AChE inhibitor and Nrf2 activator. Eur. J. Med. Chem., 2022, 242, 114630. doi: 10.1016/j.ejmech.2022.114630 PMID: 35987018
  151. Codony, S.; Pont, C.; Griñán-Ferré, C.; Di Pede-Mattatelli, A.; Calvó-Tusell, C.; Feixas, F.; Osuna, S.; Jarné-Ferrer, J.; Naldi, M.; Bartolini, M.; Loza, M.I.; Brea, J.; Pérez, B.; Bartra, C.; Sanfeliu, C.; Juárez-Jiménez, J.; Morisseau, C.; Hammock, B.D.; Pallàs, M.; Vázquez, S.; Muñoz-Torrero, D. Discovery and in vivo proof of concept of a highly potent dual inhibitor of soluble epoxide hydrolase and acetylcholinesterase for the treatment of Alzheimer’s disease. J. Med. Chem., 2022, 65(6), 4909-4925. doi: 10.1021/acs.jmedchem.1c02150 PMID: 35271276
  152. Singh, J.V.; Thakur, S.; Kumar, N.; Singh, H.; Mithu, V.S.; Singh, H.; Bhagat, K.; Gulati, H.K.; Sharma, A.; Singh, H.; Sharma, S.; Bedi, P.M.S. Donepezil-inspired multitargeting indanone derivatives as effective anti-Alzheimer’s agents. ACS Chem. Neurosci., 2022, 13(6), 733-750. doi: 10.1021/acschemneuro.1c00535 PMID: 35195392
  153. Leuci, R.; Brunetti, L.; Laghezza, A.; Piemontese, L.; Carrieri, A.; Pisani, L.; Tortorella, P.; Catto, M.; Loiodice, F.; Pisani, L.; Tortorella, P.; Catto, M.; Loiodice, F.; Carrieri, A. A new series of aryloxyacetic acids endowed with multi-target activity towards peroxisome proliferator-activated receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE). Molecules, 2022, 27(3), 958. doi: 10.3390/molecules27030958 PMID: 35164223
  154. Peschiulli, A.; Oehlrich, D.; Van Gool, M.; Austin, N.; Van Brandt, S.; Surkyn, M.; De Cleyn, M.; Vos, A.; Tresadern, G.; Rombouts, F.J.R.; Macdonald, G.J.; Moechars, D.; Trabanco, A.A.; Gijsen, H.J.M. A brain-penetrant and bioavailable pyrazolopiperazine BACE1 inhibitor elicits sustained reduction of amyloid β in vivo. ACS Med. Chem. Lett., 2022, 13(1), 76-83. doi: 10.1021/acsmedchemlett.1c00445 PMID: 35059126
  155. Azmy, E.M.; Nassar, I.F. New Indole Derivatives as Multitarget Anti-Alzheimer’s Agents : Synthesis; Biological Evaluation and Molecular Dynamics, 2023.
  156. Hassan, A.S.; Morsy, N.M.; Aboulthana, W.M.; Ragab, A. Exploring novel derivatives of isatin-based Schiff bases as multi-target agents: design, synthesis, in vitro biological evaluation, and in silico ADMET analysis with molecular modeling simulations. RSC Advances, 2023, 13(14), 9281-9303. doi: 10.1039/D3RA00297G PMID: 36950709
  157. Muğlu, H.; Sönmez, F.; Çavuş, M.S.; Kurt, B.Z.; Yakan, H. New Schiff bases based on isatin and (thio)/carbohydrazone: Preparation, experimental-theoretical spectroscopic characterization, and DFT approach to antioxidant characteristics. Res. Chem. Intermed., 2023, 49(4), 1463-1484. doi: 10.1007/s11164-022-04908-1
  158. Chen, H.; Mi, J.; Li, S.; Liu, Z.; Yang, J.; Chen, R.; Wang, Y.; Ban, Y.; Zhou, Y.; Dong, W.; Sang, Z. Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease. J. Enzyme Inhib. Med. Chem., 2023, 38(1), 2169682. doi: 10.1080/14756366.2023.2169682 PMID: 36688444
  159. Cong, S.; Shi, Y.; Yu, G.; Zhong, F.; Li, J.; Liu, J.; Ye, C.; Tan, Z.; Deng, Y. Discovery of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones as balanced multifunctional agents against Alzheimer’s disease. Eur. J. Med. Chem., 2023, 250, 115216. doi: 10.1016/j.ejmech.2023.115216 PMID: 36857812
  160. Yelamanda Rao, K.; Jeelan Basha, S.; Monika, K.; Sreelakshmi, M.; Sivakumar, I.; Mallikarjuna, G.; Yadav, R.M.; Kumar, S.; Subramanyam, R.; Damu, A.G. Synthesis and anti-Alzheimer potential of novel α-amino phosphonate derivatives and probing their molecular interaction mechanism with acetylcholinesterase. Eur. J. Med. Chem., 2023, 253, 115288. doi: 10.1016/j.ejmech.2023.115288 PMID: 37031527
  161. Madhav, H.; Abdel-Rahman, S.A.; Hashmi, M.A.; Rahman, M.A.; Rehan, M.; Pal, K.; Nayeem, S.M.; Gabr, M.T.; Hoda, N. Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer’s agents: In-silico design, synthesis, and characterization. Eur. J. Med. Chem., 2023, 254, 115354. doi: 10.1016/j.ejmech.2023.115354 PMID: 37043996
  162. Liu, P.; Cheng, M.; Guo, J.; Cao, D.; Luo, J.; Wan, Y.; Fang, Y.; Jin, Y.; Xie, S.S.; Liu, J. Dual functional antioxidant and butyrylcholinesterase inhibitors for the treatment of Alzheimer’s disease: Design, synthesis and evaluation of novel melatonin-alkylbenzylamine hybrids. Bioorg. Med. Chem., 2023, 78, 117146. doi: 10.1016/j.bmc.2022.117146 PMID: 36580744
  163. Pasieka, A.; Panek, D.; Zaręba, P.; Sługocka, E.; Gucwa, N.; Espargaró, A.; Latacz, G.; Khan, N.; Bucki, A.; Sabaté, R.; Więckowska, A.; Malawska, B. Novel drug-like fluorenyl derivatives as selective butyrylcholinesterase and β-amyloid inhibitors for the treatment of Alzheimer’s disease. Bioorg. Med. Chem., 2023, 88-89, 117333. doi: 10.1016/j.bmc.2023.117333 PMID: 37236021
  164. Qin, P.; Ran, Y.; Xie, F.; Liu, Y.; Wei, C.; Luan, X.; Wu, J. Design, synthesis, and biological evaluation of novel N-Benzyl piperidine derivatives as potent HDAC/AChE inhibitors for Alzheimer’s disease. Bioorg. Med. Chem., 2023, 80, 117178. doi: 10.1016/j.bmc.2023.117178 PMID: 36706609
  165. Liu, X.; Yu, C.; Yao, Y.; Lai, H.; Ye, X.; Xu, J.; Guo, J.; Xiao, X.; Lin, C.; Huang, Z.; Lin, J.; Yu, C.; Zha, D. Novel neuroprotective pyromeconic acid derivatives with concurrent anti-Aβ deposition, anti-inflammatory, and anti-oxidation properties for treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2023, 248, 115120. doi: 10.1016/j.ejmech.2023.115120 PMID: 36682173
  166. Makhaeva, G.F.; Kovaleva, N.V.; Rudakova, E.V.; Boltneva, N.P.; Grishchenko, M.V.; Lushchekina, S.V.; Astakhova, T.Y.; Serebryakova, O.G.; Timokhina, E.N.; Zhilina, E.F.; Shchegolkov, E.V.; Ulitko, M.V.; Radchenko, E.V.; Palyulin, V.A.; Burgart, Y.V.; Saloutin, V.I.; Bachurin, S.O.; Richardson, R.J. Conjugates of tacrine and salicylic acid derivatives as new promising multitarget agents for Alzheimer’s disease. Int. J. Mol. Sci., 2023, 24(3), 2285. doi: 10.3390/ijms24032285 PMID: 36768608
  167. Rogers, S.L.; Farlow, M.R.; Doody, R.S.; Mohs, R.; Friedhoff, L.T. Donepezil Study Group. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology, 1989, 50(1), 136-145.
  168. Linse, S.; Scheidt, T.; Bernfur, K.; Vendruscolo, M.; Dobson, C.M.; Cohen, S.I.A.; Sileikis, E.; Lundqvist, M.; Qian, F.; O’Malley, T.; Bussiere, T.; Weinreb, P.H.; Xu, C.K.; Meisl, G.; Devenish, S.R.A.; Knowles, T.P.J.; Hansson, O. Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies. Nat. Struct. Mol. Biol., 2020, 27(12), 1125-1133. doi: 10.1038/s41594-020-0505-6 PMID: 32989305
  169. Honig, L.S.; Vellas, B.; Woodward, M.; Boada, M.; Bullock, R.; Borrie, M.; Hager, K.; Andreasen, N.; Scarpini, E.; Liu-Seifert, H.; Case, M.; Dean, R.A.; Hake, A.; Sundell, K.; Poole Hoffmann, V.; Carlson, C.; Khanna, R.; Mintun, M.; DeMattos, R.; Selzler, K.J.; Siemers, E. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med., 2018, 378(4), 321-330. doi: 10.1056/NEJMoa1705971 PMID: 29365294
  170. Ostrowitzki, S.; Lasser, R.A.; Dorflinger, E.; Scheltens, P.; Barkhof, F.; Nikolcheva, T.; Ashford, E.; Retout, S.; Hofmann, C.; Delmar, P.; Klein, G.; Andjelkovic, M.; Dubois, B.; Boada, M.; Blennow, K.; Santarelli, L.; Fontoura, P. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res. Ther., 2017, 9(1), 95. doi: 10.1186/s13195-017-0318-y PMID: 29221491

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers