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Multi-Target Drug Candidates for Multifactorial Alzheimer’s Disease: AChE and NMDAR as Molecular Targets

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Abstract

Alzheimer’s disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer’s symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.

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Abbreviations

AD:

Alzheimer’s disease

MTDLs:

multi-target-directed ligands

AChE:

acetylcholinesterase

ACh:

acetylcholine

NMDAR:

N-methyl-d-aspartic acid receptor

Aβ:

amyloid beta

NFTs:

neurofibrillary tangles

References

  1. Sharma P, Sharma A, Fayaz F et al (2020) Biological signatures of Alzheimer’s disease. Curr Top Med Chem 20:770–781. https://doi.org/10.2174/1568026620666200228095553

    Article  CAS  PubMed  Google Scholar 

  2. Uddin MS, Kabir MT, Tewari D et al (2020) Revisiting the role of brain and peripheral Aβ in the pathogenesis of Alzheimer’s disease. J Neurol Sci 416:116974. https://doi.org/10.1016/j.jns.2020.116974

    Article  CAS  PubMed  Google Scholar 

  3. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608. https://doi.org/10.15252/emmm.201606210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Uddin MS, Al Mamun A, Kabir MT et al (2019) Nootropic and anti-Alzheimer’s actions of medicinal plants: molecular insight into therapeutic potential to alleviate Alzheimer’s neuropathology. Mol Neurobiol 56:4925–4944. https://doi.org/10.1007/s12035-018-1420-2

    Article  CAS  PubMed  Google Scholar 

  5. Mufson EJ, Counts SE, Perez SE, Ginsberg SD (2008) Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev Neurother 8:1703–1718. https://doi.org/10.1586/14737175.8.11.1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Uddin MS, Al Mamun A, Asaduzzaman M et al (2018) Spectrum of disease and prescription pattern for outpatients with neurological disorders: an empirical pilot study in Bangladesh. Ann Neurosci 25:25–37. https://doi.org/10.1159/000481812

    Article  PubMed  Google Scholar 

  7. Yan R, Vassar R (2014) Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 13:319–329. https://doi.org/10.1016/S1474-4422(13)70276-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Uddin MS, Al Mamun A, Rahman MA et al (2020) Emerging proof of protein misfolding and interactions in multifactorial Alzheimer’s disease. Curr Top Med Chem:20. https://doi.org/10.2174/1568026620666200601161703

  9. Festa G, Mallamace F, Sancesario GM et al (2019) Aggregation states of Aβ1-40, Aβ1-42 and Aβp3-42 amyloid beta peptides: a SANS study. Int J Mol Sci 20. https://doi.org/10.3390/ijms20174126

  10. Mamun A, Uddin M, Mathew B, Ashraf G (2020) Toxic tau: structural origins of tau aggregation in Alzheimer’s disease. Neural Regen Res 15:1417–1420. https://doi.org/10.4103/1673-5374.274329

    Article  PubMed  PubMed Central  Google Scholar 

  11. Iqbal K, Alonso A d C, Chen S et al (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta Mol basis Dis 1739:198–210. https://doi.org/10.1016/j.bbadis.2004.09.008

    Article  CAS  Google Scholar 

  12. Uddin MS, Mamun AA, Kabir MT et al (2018) Neurochemistry of neurochemicals: messengers of brain functions. J Intellect Disabil - Diagnosis Treat 5:137–151. https://doi.org/10.6000/2292-2598.2017.05.04.6

  13. Parihar MS, Brewer GJ (2010) Amyloid-β as a modulator of synaptic plasticity. J Alzheimers Dis 22:741–763. https://doi.org/10.3233/JAD-2010-101020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Uddin MS, Kabir MT, Niaz K, Jeandet P, Clément C, Mathew B, Rauf A, Rengasamy KRR et al (2020) Molecular insight into the therapeutic promise of flavonoids against Alzheimer’s disease. Molecules 25:1267. https://doi.org/10.3390/MOLECULES25061267

  15. Sheng M, Sabatini BL, Südhof TC (2012) Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol 4:10. https://doi.org/10.1101/cshperspect.a005777

    Article  CAS  Google Scholar 

  16. Maurer SV, Williams CL (2017) The cholinergic system modulates memory and hippocampal plasticity via its interactions with non-neuronal cells. Front Immunol 8:1489. https://doi.org/10.3389/fimmu.2017.01489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM (2016) Alzheimer’s disease: targeting the cholinergic system. Curr Neuropharmacol 14:101–115. https://doi.org/10.2174/1570159x13666150716165726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lahiri D, Rogers J, Greig N, Sambamurti K (2004) Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents. Curr Pharm Des 10:3111–3119. https://doi.org/10.2174/1381612043383331

    Article  CAS  PubMed  Google Scholar 

  19. Herholz K (2008) Acetylcholine esterase activity in mild cognitive impairment and Alzheimer’s disease. Eur J Nucl Med Mol Imaging 35:25–29. https://doi.org/10.1007/s00259-007-0699-4

    Article  CAS  Google Scholar 

  20. Uddin MS, Al Mamun A, Takeda S et al (2018) Analyzing the chance of developing dementia among geriatric people: a cross-sectional pilot study in Bangladesh. Psychogeriatrics. 19:87–94. https://doi.org/10.1111/psyg.12368

    Article  PubMed  Google Scholar 

  21. Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 57:1041–1048. https://doi.org/10.3233/JAD-160763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lipton S (2005) The molecular basis of Memantine action in Alzheimers disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res 2:155–165. https://doi.org/10.2174/1567205053585846

    Article  CAS  PubMed  Google Scholar 

  23. Choi DW (1992) Excitotoxic cell death. J Neurobiol 23:1261–1276. https://doi.org/10.1002/neu.480230915

    Article  CAS  PubMed  Google Scholar 

  24. Koh JY, Choi DW (1991) Selective blockade of non-NMDA receptors does not block rapidly triggered glutamate-induced neuronal death. Brain Res 548:318–321. https://doi.org/10.1016/0006-8993(91)91140-v

    Article  CAS  PubMed  Google Scholar 

  25. Tymianski M, Charlton MP, Carlen PL, Tator CH (1993) Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci 13:2085–2104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mizuno S, Iijima R, Ogishima S et al (2012) AlzPathway: a comprehensive map of signaling pathways of Alzheimer’s disease. BMC Syst Biol 6:52. https://doi.org/10.1186/1752-0509-6-52

    Article  PubMed  PubMed Central  Google Scholar 

  27. Uddin MS, Kabir MT, Tewari D et al (2020) Emerging therapeutic promise of ketogenic diet to attenuate neuropathological alterations in Alzheimer’s disease. Mol Neurobiol:1–17. https://doi.org/10.1007/s12035-020-02065-3

  28. Yiannopoulou KG, Papageorgiou SG (2013) Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord 6:19–33. https://doi.org/10.1177/1756285612461679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Umar T, Hoda N (2018) Alzheimer’s disease: a systemic review of substantial therapeutic targets and the leading multi-functional molecules. Curr Top Med Chem 17:3370–3389. https://doi.org/10.2174/1568026618666180112161024

    Article  CAS  Google Scholar 

  30. Oset-Gasque MJ, Marco-Contelles J (2018) Alzheimer’s disease, the “one-molecule, one-target” paradigm, and the multitarget directed ligand approach. ACS Chem Neurosci 9:401–403. https://doi.org/10.1021/acschemneuro.8b00069

    Article  CAS  PubMed  Google Scholar 

  31. Agis-Torres A, Sölhuber M, Fernandez M, Sanchez-Montero JM (2014) Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for Alzheimer’s disease. Curr Neuropharmacol 12:2–36. https://doi.org/10.2174/1570159X113116660047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang T, Liu XH, Guan J et al (2019) Advancement of multi-target drug discoveries and promising applications in the field of Alzheimer’s disease. Eur J Med Chem 169:200–223. https://doi.org/10.1016/j.ejmech.2019.02.076

    Article  CAS  PubMed  Google Scholar 

  33. Alcaro S, Bolognesi ML, García-Sosa AT, Rapposelli S (2019) Editorial: Multi-target-directed ligands (MTDL) as challenging research tools in drug discovery: from design to pharmacological evaluation. Front Chem 7:71. https://doi.org/10.3389/fchem.2019.00071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Muayqil T, Camicioli R (2012) Systematic review and meta-analysis of combination therapy with cholinesterase inhibitors and memantine in Alzheimer’s disease and other dementias. Dement Geriatr Cogn Dis Extra 2:546–572. https://doi.org/10.1159/000343479

    Article  PubMed  PubMed Central  Google Scholar 

  35. Matsunaga S, Kishi T, Iwata N (2015) Combination therapy with cholinesterase inhibitors and memantine for Alzheimer’s disease: a systematic review and meta-analysis. Int J Neuropsychopharmacol 18:1–11. https://doi.org/10.1093/ijnp/pyu115

  36. Namzaric (memantine hydrochloride extended-release/donepezil hydrochloride) Capsules

  37. Al Mamun A, Uddin MS, Kabir MT et al (2020) Exploring the promise of targeting ubiquitin–proteasome system to combat Alzheimer’s disease. Neurotox Res 38:8–17. https://doi.org/10.1007/s12640-020-00185-1

    Article  CAS  PubMed  Google Scholar 

  38. Uddin MS, Devesh T, Al Mamun A et al (2020) Circadian and sleep dysfunction in Alzheimer’s disease. Ageing Res Rev 60:101046. https://doi.org/10.1016/J.ARR.2020.101046

    Article  PubMed  Google Scholar 

  39. Bloom BS, de Pouvourville N, Straus WL (2003) Cost of illness of Alzheimer’s disease: how useful are current estimates? Gerontologist 43:158–164. https://doi.org/10.1093/geront/43.2.158

    Article  PubMed  Google Scholar 

  40. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189. https://doi.org/10.1101/cshperspect.a006189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ibrahim AM, Pottoo FH, Dahiya ES et al (2020) Neuron-glia interaction: molecular basis of Alzheimer’s disease and applications of neuroproteomics. Eur J Neurosci. https://doi.org/10.1111/ejn.14838

  42. Habtemariam S (2019) Natural products in Alzheimer’s disease therapy: would old therapeutic approaches fix the broken promise of modern medicines? Molecules 24:1519. https://doi.org/10.3390/molecules24081519

  43. Al Mamun A, Sahab Uddin M, Fahim Bin Bashar M et al (2020) Molecular insight into the therapeutic promise of targeting APOE4 for Alzheimer’s disease. Oxidative Med Cell Longev 2020:5086250–5086216. https://doi.org/10.1155/2020/5086250

    Article  CAS  Google Scholar 

  44. Uddin MS, Kabir MT, Rahman MS et al (2020) Revisiting the amyloid cascade hypothesis: from anti-Aβ therapeutics to auspicious new ways for Alzheimer’s disease. Int J Mol Sci 21:5858. https://doi.org/10.3390/ijms21165858

    Article  CAS  PubMed Central  Google Scholar 

  45. Uddin MS, Kabir MT, Tewari D, Mathew B, Aleya L (2019) Emerging signal regulating potential of small molecule biflavonoids to combat neuropathological insults of Alzheimer’s disease. Sci Total Environ 134836:134836. https://doi.org/10.1016/j.scitotenv.2019.134836

    Article  CAS  Google Scholar 

  46. Tanjir Islam M, Sahab Uddin M, Nahar Lucky K et al (2017) Autophagic dysfunction in type 2 diabetes mellitus: pathophysiology and therapeutic implications. J Diabeteas Metab 8:1–8. https://doi.org/10.4172/2155-6156.1000742

  47. Santos RX, Correia SC, Wang X et al (2010) Alzheimer’s disease: diverse aspects of mitochondrial malfunctioning. Int J Clin Exp Pathol 3:570–581

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bhaskar K, Maphis N, Xu G et al (2014) Microglial derived tumor necrosis factor-α drives Alzheimer’s disease-related neuronal cell cycle events. Neurobiol Dis 62:273–285. https://doi.org/10.1016/j.nbd.2013.10.007

    Article  CAS  PubMed  Google Scholar 

  49. Uddin MS, Kabir MT, Al Mamun A et al (2020) Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease. Int Immunopharmacol 84:106479. https://doi.org/10.1016/j.intimp.2020.106479

    Article  CAS  PubMed  Google Scholar 

  50. Praticò D (2008) Evidence of oxidative stress in Alzheimer’s disease brain and antioxidant therapy: lights and shadows. Ann N Y Acad Sci 1147:70–78. https://doi.org/10.1196/annals.1427.010

    Article  CAS  PubMed  Google Scholar 

  51. Uddin MS, Kabir MT (2019) Oxidative stress in Alzheimer’s disease: molecular hallmarks of underlying vulnerability. In: Biological, diagnostic and therapeutic advances in Alzheimer’s disease. Springer Singapore, Singapore, pp. 91–115

    Chapter  Google Scholar 

  52. Moreira PI, Nunomura A, Nakamura M et al (2008) Nucleic acid oxidation in Alzheimer disease. Free Radic Biol Med 44:1493–1505. https://doi.org/10.1016/j.freeradbiomed.2008.01.002

    Article  CAS  PubMed  Google Scholar 

  53. Uddin MS, Al Mamun A, Kabir MT et al (2020) Neuroprotective role of polyphenols against oxidative stress-mediated neurodegeneration. Eur J Pharmacol:173412. https://doi.org/10.1016/j.ejphar.2020.173412

  54. Fukuda M, Kanou F, Shimada N et al (2009) Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer’s disease. Biomed Res 30:227–233. https://doi.org/10.2220/biomedres.30.227

    Article  CAS  PubMed  Google Scholar 

  55. Sultana R, Mecocci P, Mangialasche F, Cecchetti R, Baglioni M, Butterfield DA (2011) Increased protein and lipid oxidative damage in mitochondria isolated from lymphocytes from patients with Alzheimer’s disease: insights into the role of oxidative stress in Alzheimer’s disease and initial investigations into a potential biomarker for this. J Alzheimers Dis 24:77–84. https://doi.org/10.3233/JAD-2011-101425

    Article  CAS  PubMed  Google Scholar 

  56. Uddin MS, Upaganlawar AB (2019) Oxidative stress and antioxidant defense: biomedical value in health and diseases. Nova Science Publishers, Hauppauge

  57. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B et al (2012) Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69:836–841. https://doi.org/10.1001/archneurol.2012.85

    Article  PubMed  PubMed Central  Google Scholar 

  58. Aliev G, Li Y, Palacios HH, Obrenovich ME (2011) Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases. Recent Pat Cardiovasc Drug Discov 6:222–241. https://doi.org/10.2174/157489011797376942

    Article  CAS  PubMed  Google Scholar 

  59. Hayashi T, Shishido N, Nakayama K et al (2007) Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-β peptide. Free Radic Biol Med 43:1552–1559. https://doi.org/10.1016/j.freeradbiomed.2007.08.013

    Article  CAS  PubMed  Google Scholar 

  60. Nakamura M, Shishido N, Nunomura A et al (2007) Three histidine residues of amyloid-β peptide control the redox activity of copper and iron. Biochemistry 46:12737–12743. https://doi.org/10.1021/bi701079z

    Article  CAS  PubMed  Google Scholar 

  61. Lee YJ, Jeong SY, Karbowski M et al (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, Opa1 in apoptosis. Mol Biol Cell 15:5001–5011. https://doi.org/10.1091/mbc.E04-04-0294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta Mol basis Dis 1772:494–502. https://doi.org/10.1016/j.bbadis.2006.10.014

    Article  CAS  Google Scholar 

  63. Lee HJ, Park MK, Seo YR (2018) Pathogenic mechanisms of heavy metal induced-Alzheimer’s disease. Toxicol Environ Heal Sci 10:1–10. https://doi.org/10.1007/s13530-018-0340-x

    Article  CAS  Google Scholar 

  64. Simunkova M, Alwasel SH, Alhazza IM et al (2019) Management of oxidative stress and other pathologies in Alzheimer’s disease. Arch Toxicol 93:2491–2513. https://doi.org/10.1007/s00204-019-02538-y

    Article  CAS  PubMed  Google Scholar 

  65. Guglielmotto M, Giliberto L, Tamagno E, Tabaton M (2010) Oxidative stress mediates the pathogenic effect of different Alzheimer’s disease risk factors. Front Aging Neurosci 2. https://doi.org/10.3389/neuro.24.003.2010

  66. Lee HP, Zhu X, Casadesus G et al (2010) Antioxidant approaches for the treatment of Alzheimers disease. Expert Rev Neurother 10:1201–1208. https://doi.org/10.1586/ern.10.74

    Article  PubMed  Google Scholar 

  67. Khalil M, Teunissen C, Langkammer C (2011) Iron and neurodegeneration in multiple sclerosis. Mult Scler Int 2011:1–6. https://doi.org/10.1155/2011/606807

    Article  CAS  Google Scholar 

  68. Uddin MS, Kabir MT, Jeandet P, Mathew B, Ashraf GM, Perveen A, Bin-Jumah MN, Mousa SA et al (2020) Novel anti-Alzheimer’s therapeutic molecules targeting amyloid precursor protein processing. Oxidative Med Cell Longev 2020:1–19. https://doi.org/10.1155/2020/7039138

    Article  CAS  Google Scholar 

  69. Liang J, Li J, Jia R et al (2018) Identification of the optimal cognitive drugs among alzheimer’s disease: a Bayesian meta-analytic review. Clin Interv Aging 13:2061–2073. https://doi.org/10.2147/CIA.S184968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kabir MT, Uddin MS, Al Mamun A et al (2020) Combination drug therapy for the management of Alzheimer’s disease. Int J Mol Sci 21:3272. https://doi.org/10.3390/IJMS21093272

    Article  CAS  PubMed Central  Google Scholar 

  71. Qizilbash N, Whitehead A, Higgins J, Wilcock G, Schneider L, Farlow M, Dementia Trialists' Collaboration (1998) Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. J Am Med Assoc 280:1777–1782

    Article  CAS  Google Scholar 

  72. Birks JS, Chong LY, Grimley Evans J (2015, 2015) Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev 9:CD001191. https://doi.org/10.1002/14651858.CD001191.pub4

  73. Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL (1999) Structure of acetylcholinesterase complexed with (−)-galanthamine at 2.3 Å resolution. FEBS Lett 463:321–326. https://doi.org/10.1016/S0014-5793(99)01637-3

    Article  CAS  PubMed  Google Scholar 

  74. Dajas-Bailador FA, Heimala K, Wonnacott S (2003) The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Mol Pharmacol 64:1217–1226. https://doi.org/10.1124/mol.64.5.1217

    Article  CAS  PubMed  Google Scholar 

  75. Akk G, Steinbach JH (2005) Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site. J Neurosci 25:1992–2001. https://doi.org/10.1523/JNEUROSCI.4985-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Birks J, Harvey RJ (2006) Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev 6:CD001190. https://doi.org/10.1002/14651858.CD001190.pub3

  77. Nochi S, Asakawa N, Sato T (1995) Kinetic study on the inhibition of acetylcholinesterase by 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-Yl)methylpiperidine hydrochloride (E2020). Biol Pharm Bull 18:1145–1147. https://doi.org/10.1248/bpb.18.1145

    Article  CAS  PubMed  Google Scholar 

  78. Doody RS, Thomas RG, Farlow M et al (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370:311–321. https://doi.org/10.1056/NEJMoa1312889

    Article  CAS  PubMed  Google Scholar 

  79. Lo D, Grossberg GT (2011) Use of memantine for the treatment of dementia. Expert Rev Neurother 11:1359–1370. https://doi.org/10.1586/ern.11.132

    Article  CAS  PubMed  Google Scholar 

  80. Figueiredo CP, Clarke JR, Ledo JH et al (2013) Memantine rescues transient cognitive impairment caused by high-molecular-weight Aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers. J Neurosci 33:9626–9634. https://doi.org/10.1523/JNEUROSCI.0482-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Willard LB, Hauss-Wegrzyniak B, Danysz W, Wenk GL (2000) The cytotoxicity of chronic neuroinflammation upon basal forebrain cholinergic neurons of rats can be attenuated by glutamatergic antagonism or cyclooxygenase-2 inhibition. Exp Brain Res 134:58–65. https://doi.org/10.1007/s002210000446

    Article  CAS  PubMed  Google Scholar 

  82. Song MS, Rauw G, Baker GB, Kar S (2008) Memantine protects rat cortical cultured neurons against β-amyloid-induced toxicity by attenuating tau phosphorylation. Eur J Neurosci 28:1989–2002. https://doi.org/10.1111/j.1460-9568.2008.06498.x

    Article  CAS  PubMed  Google Scholar 

  83. Hu M, Schurdak ME, Puttfarcken PS, el Kouhen R, Gopalakrishnan M, Li J (2007) High content screen microscopy analysis of Aβ1-42-induced neurite outgrowth reduction in rat primary cortical neurons: neuroprotective effects of α7 neuronal nicotinic acetylcholine receptor ligands. Brain Res 1151:227–235. https://doi.org/10.1016/j.brainres.2007.03.051

    Article  CAS  PubMed  Google Scholar 

  84. Esposito Z, Belli L, Toniolo S et al (2013) Amyloid β, glutamate, excitotoxicity in Alzheimer’s disease: are we on the right track? CNS Neurosci Ther 19:549–555. https://doi.org/10.1111/cns.12095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Parsons CG, Danysz W, Dekundy A, Pulte I (2013) Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer’s disease. Neurotox Res 24:358–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Greenamyre JT, Young AB (1989) Excitatory amino acids and Alzheimer’s disease. Neurobiol Aging 10:593–602

    Article  CAS  PubMed  Google Scholar 

  87. Wenk GL, Danysz W, Mobley SL (1994) Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat. Brain Res 655:7–11. https://doi.org/10.1016/0006-8993(94)91590-3

    Article  CAS  PubMed  Google Scholar 

  88. Allen TGJ, Abogadie FC, Brown DA (2006) Simultaneous release of glutamate and acetylcholine from single magnocellular “cholinergic” basal forebrain neurons. J Neurosci 26:1588–1595. https://doi.org/10.1523/JNEUROSCI.3979-05.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nyakas C, Granic I, Halmy LG et al (2011) The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behav Brain Res 221:594–603. https://doi.org/10.1016/j.bbr.2010.05.033

    Article  CAS  PubMed  Google Scholar 

  90. Rosini M, Simoni E, Bartolini M et al (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 

  91. Rosini M, Simoni E, Minarini A, Melchiorre C (2014) Multi-target design strategies in the context of Alzheimer’s disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. Neurochem Res 39:1914–1923

    Article  CAS  PubMed  Google Scholar 

  92. Geerts H (2006) Pharmacology of acetylcholinesterase inhibitors and N-methyl-D-aspartate receptors for combination therapy in the treatment of Alzheimer’s disease. J Clin Pharmacol 46:8S–16S. https://doi.org/10.1177/0091270006288734

    Article  CAS  PubMed  Google Scholar 

  93. Busquet P, Capurro V, Cavalli A et al (2012) Synergistic effects of galantamine and memantine in attenuating scopolamine-induced amnesia in mice. J Pharmacol Sci 120:305–309. https://doi.org/10.1254/jphs.12166SC

    Article  CAS  PubMed  Google Scholar 

  94. Simoni E, Daniele S, Bottegoni G et al (2012) Combining galantamine 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 

  95. Miller G (2010) The puzzling rise and fall of a dark-horse Alzheimer’s drug. Science 327:1309

    Article  CAS  PubMed  Google Scholar 

  96. Rosini M, Simoni E, Bartolini M et al (2013) The bivalent ligand approach as a tool for improving the in vitro anti-Alzheimer multitarget profile of dimebon. ChemMedChem 8:1276–1281. https://doi.org/10.1002/cmdc.201300263

    Article  CAS  PubMed  Google Scholar 

  97. Makhaeva GF, Lushchekina SV, Boltneva NP et al (2015) Conjugates of γ 3-carbolines and phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer disease. Sci Rep 5:1–11. https://doi.org/10.1038/srep13164

    Article  CAS  Google Scholar 

  98. Makhaeva GF, Grigoriev VV, Proshin AN et al (2017) Novel conjugates of tacrine with 1,2,4,-thiadiazole as highly effective cholinesterase inhibitors, blockers of NMDA receptors, and antioxidants. Dokl Biochem Biophys 477:405–409. https://doi.org/10.1134/S1607672917060163

    Article  CAS  PubMed  Google Scholar 

  99. Pérez-Areales FJ, Turcu AL, Barniol-Xicota M et al (2019) A novel class of multitarget anti-Alzheimer benzohomoadamantane–chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors. Eur J Med Chem 180:613–626. https://doi.org/10.1016/j.ejmech.2019.07.051

  100. Bachurin SO, Shevtsova EF, Makhaeva GF et al (2017) Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment. Sci Rep 7:1–15. https://doi.org/10.1038/srep45627

    Article  CAS  Google Scholar 

  101. de Candia M, Zaetta G, Denora N, Tricarico D, Majellaro M, Cellamare S, Altomare CD (2017) New azepino[4,3-b]indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity. Eur J Med Chem 125:288–298. https://doi.org/10.1016/j.ejmech.2016.09.037

    Article  CAS  PubMed  Google Scholar 

  102. Shao D, Zou C, Luo C, Tang X, Li Y (2004) Synthesis and evaluation of tacrine–E2020 hybrids as acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 14:4639–4642. https://doi.org/10.1016/J.BMCL.2004.07.005

    Article  CAS  PubMed  Google Scholar 

  103. Alonso D, Dorronsoro I, Rubio L et al (2005) Donepezil–tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorg Med Chem 13:6588–6597. https://doi.org/10.1016/J.BMC.2005.09.029

    Article  CAS  PubMed  Google Scholar 

  104. Camps P, Formosa X, Galdeano C et al (2010) Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates. Chem Biol Interact 187:411–415. https://doi.org/10.1016/J.CBI.2010.02.013

    Article  CAS  PubMed  Google Scholar 

  105. Camps P, Formosa X, Galdeano C et al (2008) Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation. J Med Chem 51:3588–3598. https://doi.org/10.1021/jm8001313

    Article  CAS  PubMed  Google Scholar 

  106. Galdeano C, Viayna E, Sola I et al (2012) Huprine–tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer’s and prion diseases. J Med Chem 55:661–669. https://doi.org/10.1021/jm200840c

    Article  CAS  PubMed  Google Scholar 

  107. Cen J, Guo H, Hong C et al (2018) Development of tacrine–bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity. Eur J Med Chem 144:128–136. https://doi.org/10.1016/j.ejmech.2017.12.005

    Article  CAS  PubMed  Google Scholar 

  108. Rosini M, Andrisano V, Bartolini M et al (2005) Rational approach to discover multipotent anti-Alzheimer drugs. J Med Chem 48:360–363. https://doi.org/10.1021/jm049112h

    Article  CAS  PubMed  Google Scholar 

  109. González JF, Alcántara AR, Doadrio AL, Sánchez-Montero JM (2019) Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches. Expert Opin Drug Discovery 14:879–891

    Article  Google Scholar 

  110. Bolognesi ML, Cavalli A, Bergamini C et al (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 

  111. Rosini M, Simoni E, Bartolini M et al (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 

  112. Agatonovic-Kustrin S, Kettle C, Morton DW (2018) A molecular approach in drug development for Alzheimer’s disease. Biomed Pharmacother 106:553–565

    Article  CAS  PubMed  Google Scholar 

  113. Scott JW, Cort WM, Harley H, Parrish DR, Saucy G (1974) 6-Hydroxychroman-2-carboxylic acids: novel antioxidants. J Am Oil Chem Soc 51:200–203. https://doi.org/10.1007/BF02632894

    Article  CAS  Google Scholar 

  114. Quintanilla RA, Muñoz FJ, Metcalfe MJ et al (2005) Trolox and 17β-estradiol protect against amyloid β-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway. J Biol Chem 280:11615–11625. https://doi.org/10.1074/jbc.M411936200

    Article  CAS  PubMed  Google Scholar 

  115. Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O, Reubroycharoen P, Tohda M, Boonyarat C (2014) Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 75:21–30. https://doi.org/10.1016/j.ejmech.2014.01.020

    Article  CAS  PubMed  Google Scholar 

  116. Xie SS, Lan JS, Wang XB et al (2015) Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer’s disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties. Eur J Med Chem 93:42–50. https://doi.org/10.1016/j.ejmech.2015.01.058

    Article  CAS  PubMed  Google Scholar 

  117. Schewe T (1995) Molecular actions of Ebselen-an antiinflammatory antioxidant. Gen Pharmacol 26:1153–1169. https://doi.org/10.1016/0306-3623(95)00003-J

    Article  CAS  PubMed  Google Scholar 

  118. Yamagata K, Ichinose S, Miyashita A, Tagami M (2008) Protective effects of ebselen, a seleno-organic antioxidant on neurodegeneration induced by hypoxia and reperfusion in stroke-prone spontaneously hypertensive rat. Neuroscience 153:428–435. https://doi.org/10.1016/j.neuroscience.2008.02.028

    Article  CAS  PubMed  Google Scholar 

  119. Haratake M, Yoshida S, Mandai M et al (2013) Elevated amyloid-β plaque deposition in dietary selenium-deficient Tg2576 transgenic mice. Metallomics 5:479–483. https://doi.org/10.1039/c3mt00035d

    Article  CAS  PubMed  Google Scholar 

  120. Mao F, Chen J, Zhou Q et al (2013) Novel tacrine-ebselen hybrids with improved cholinesterase inhibitory, hydrogen peroxide and peroxynitrite scavenging activity. Bioorg Med Chem Lett 23:6737–6742. https://doi.org/10.1016/j.bmcl.2013.10.034

    Article  CAS  PubMed  Google Scholar 

  121. Howlett DR, George AR, Owen DE et al (1999) Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer β-amyloid fibril formation. Biochem J 343:419–423. https://doi.org/10.1042/0264-6021:3430419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lysko PG, Lysko KA, Webb CL et al (1998) Neuroprotective activities of carvedilol and a hydroxylated derivative. Role of membrane biophysical interactions. Biochem Pharmacol 56:1645–1656. https://doi.org/10.1016/S0006-2952(98)00275-5

    Article  CAS  PubMed  Google Scholar 

  123. Pi R, Mao X, Chao X et al (2012) Tacrine-6-ferulic acid, a novel multifunctional dimer, inhibits amyloid-β-mediated Alzheimer’s disease-associated pathogenesis in vitro and in vivo. PLoS One 7. https://doi.org/10.1371/journal.pone.0031921

  124. Prachayasittikul V, Prachayasittikul S, Ruchirawat S, Prachayasittikul V (2013) 8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications. Drug Des Devel Ther 7:1157–1178. https://doi.org/10.2147/DDDT.S49763

  125. Farrell RE (2010) RNA methodologies. Elsevier Inc., Amsterdam

  126. Fernández-Bachiller MI, Pérez C, González-Muñoz GC et al (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 

  127. Piazzi L, Rampa A, Bisi A et al (2003) 3-(4-{[benzyl(methyl)amino]methyl}-phenyl)-6,7-dimethoxy-2H-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

  128. Rizzo S, Bartolini M, Ceccarini L, Piazzi L, Gobbi S, Cavalli A, Recanatini M, Andrisano V et al (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 

  129. Viayna E, Gómez T, Galdeano C et al (2010) Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates. ChemMedChem 5:1855–1870. https://doi.org/10.1002/cmdc.201000322

    Article  CAS  PubMed  Google Scholar 

  130. Bolea I, Juárez-Jiménez J, De Los RC et al (2011) Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease. J Med Chem 54:8251–8270. https://doi.org/10.1021/jm200853t

    Article  CAS  PubMed  Google Scholar 

  131. Esteban G, Allan J, Samadi A et al (2014) Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer’s disease. Biochim Biophys Acta, Proteins Proteomics 1844:1104–1110. https://doi.org/10.1016/j.bbapap.2014.03.006

    Article  CAS  Google Scholar 

  132. Bolea I, Gella A, Monjas L et al (2013) Multipotent, permeable drug ASS234 inhibits Aβ aggregation, possesses antioxidant properties and protects from Aβ-induced apoptosis in vitro. Curr Alzheimer Res 10:797–808. https://doi.org/10.2174/15672050113109990151

    Article  CAS  PubMed  Google Scholar 

  133. Stasiak A, Mussur M, Unzeta M et al (2014) Effects of novel monoamine oxidases and cholinesterases targeting compounds on brain neurotransmitters and behavior in rat model of vascular dementia. Curr Pharm Des 20:161–171. https://doi.org/10.2174/13816128113199990026

    Article  CAS  PubMed  Google Scholar 

  134. Del Pino J, Marco-Contelles J, López-Muñoz F et al (2018) Neuroinflammation signaling modulated by ASS234, a multitarget small molecule for Alzheimer’s disease therapy. ACS Chem Neurosci 9:2880–2885. https://doi.org/10.1021/acschemneuro.8b00203

    Article  CAS  PubMed  Google Scholar 

  135. Zheng H, Youdim MBH, Fridkin M (2009) Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective−neurorestorative moieties for Alzheimer’s therapy. J Med Chem 52:4095–4098. https://doi.org/10.1021/jm900504c

    Article  CAS  PubMed  Google Scholar 

  136. Amit T, Avramovich-Tirosh Y, Youdim MBH, Mandel S (2008) Targeting multiple Alzheimer’s disease etiologies with multimodal neuroprotective and neurorestorative iron chelators. FASEB J 22:1296–1305. https://doi.org/10.1096/fj.07-8627rev

    Article  CAS  PubMed  Google Scholar 

  137. Gal S, Zheng H, Fridkin M, Youdim MBH (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem 95:79–88. https://doi.org/10.1111/j.1471-4159.2005.03341.x

    Article  CAS  PubMed  Google Scholar 

  138. Zheng H, Gal S, Weiner LM et al (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. J Neurochem 95:68–78. https://doi.org/10.1111/j.1471-4159.2005.03340.x

    Article  CAS  PubMed  Google Scholar 

  139. Sheng R, Lin X, Li J et al (2005) Design, synthesis, and evaluation of 2-phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem Lett 15:3834–3837. https://doi.org/10.1016/J.BMCL.2005.05.132

    Article  CAS  PubMed  Google Scholar 

  140. Bullock R, Touchon J, Bergman H, Gambina G, He Y, Rapatz G, Nagel J, Lane R (2005) Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer’s disease over a 2-year period. Curr Med Res Opin 21:1317–1327. https://doi.org/10.1185/030079905X56565

    Article  CAS  PubMed  Google Scholar 

  141. Lecoutey C, Hedou D, Freret T, Giannoni P, Gaven F, Since M, Bouet V, Ballandonne C et al (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 

  142. Faye C, Hen R, Guiard BP, Denny CA, Gardier AM, Mendez-David I, David DJ (2020) Rapid anxiolytic effects of RS67333, a serotonin type 4 receptor agonist, and diazepam, a benzodiazepine, are mediated by projections from the prefrontal cortex to the dorsal raphe nucleus. Biol Psychiatry 87:514–525. https://doi.org/10.1016/j.biopsych.2019.08.009

    Article  CAS  PubMed  Google Scholar 

  143. Giannoni P, Gaven F, De Bundel D et al (2013) Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer’s disease. Front Aging Neurosci 5:96. https://doi.org/10.3389/fnagi.2013.00096

  144. Rochais C, Lecoutey C, Gaven F et al (2015) Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) 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 

  145. Keri RS, Budagumpi S, Pai RK, Balakrishna RG (2014) Chromones as a privileged scaffold in drug discovery: a review. Eur J Med Chem 78:340–374. https://doi.org/10.1016/j.ejmech.2014.03.047

    Article  CAS  PubMed  Google Scholar 

  146. Hossain MF, Uddin MS, Uddin GMS et al (2019) Melatonin in Alzheimer’s disease: a latent endogenous regulator of neurogenesis to mitigate Alzheimer’s neuropathology. Mol Neurobiol 56:8255–8276

    Article  CAS  PubMed  Google Scholar 

  147. Edmondson DE, Mattevi A, Binda C et al (2012) Structure and mechanism of monoamine oxidase. Curr Med Chem 11:1983–1993. https://doi.org/10.2174/0929867043364784

    Article  Google Scholar 

  148. Tipton KF, Boyce S, O’Sullivan J et al (2012) Monoamine oxidases: certainties and uncertainties. Curr Med Chem 11:1965–1982. https://doi.org/10.2174/0929867043364810

    Article  Google Scholar 

  149. Pachón-Angona I, Refouvelet B, Andrýs R et al (2019) Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer’s disease therapy. J Enzyme Inhib Med Chem 34:479–489. https://doi.org/10.1080/14756366.2018.1545766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Weinreb O, Amit T, Bar-Am O, Youdim MBH (2010) Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol 92:330–344

    Article  CAS  PubMed  Google Scholar 

  151. Weinreb O, Amit T, Riederer P et al (2011) Neuroprotective profile of the multitarget drug rasagiline in Parkinson’s disease. Int Rev Neurobiol 100:127–149. https://doi.org/10.1016/B978-0-12-386467-3.00007-8

    Article  CAS  PubMed  Google Scholar 

  152. Zheng H, Amit T, Bar-Am O et al (2012) From anti-Parkinson’s drug rasagiline to novel multitarget iron chelators with acetylcholinesterase and monoamine oxidase inhibitory and neuroprotective properties for Alzheimer’s disease. J Alzheimers Dis 30:1–16

    Article  PubMed  Google Scholar 

  153. Weinreb O, Amit T, Bar-Am O, Youdim MBH (2016) Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β-amyloid in ageing and Alzheimer’s disease. Br J Pharmacol 173:2080–2094. https://doi.org/10.1111/bph.13318

    Article  CAS  PubMed  Google Scholar 

  154. Uddin MS, Kabir MT, Rahman MM et al (2020) TV 3326 for Alzheimer’s dementia: a novel multimodal ChE and MAO inhibitors to mitigate Alzheimer’s-like neuropathology. J Pharm Pharmacol 72:1001–1012. https://doi.org/10.1111/jphp.13244

    Article  CAS  PubMed  Google Scholar 

  155. Bar-Am O, Weinreb O, Amit T, Youdim MBH (2009) The novel cholinesterase-monoamine oxidase inhibitor and antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells and aged rats. J Mol Neurosci 37:135–145. https://doi.org/10.1007/s12031-008-9139-6

    Article  CAS  PubMed  Google Scholar 

  156. Weinreb O, Bar-Am O, Amit T et al (2008) The neuroprotective effect of ladostigil against hydrogen peroxide-mediated cytotoxicity. Chem Biol Interact 175:318–326. https://doi.org/10.1016/j.cbi.2008.05.038

    Article  CAS  PubMed  Google Scholar 

  157. Uddin MS, Kabir MT, Rahman MH et al (2020) Exploring the multifunctional neuroprotective promise of rasagiline derivatives for multi-dysfunctional Alzheimer’s disease. Curr Pharm Des 26. https://doi.org/10.2174/1381612826666200406075044

  158. Weinreb O, Amit T, Bar-Am O, Youdim MBH (2007) Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. In: Annals of the New York Academy of Sciences. Blackwell Publishing Inc., pp. 155–168

  159. Schneider LS, Geffen Y, Rabinowitz J et al (2019) Low-dose ladostigil for mild cognitive impairment: a phase 2 placebo-controlled clinical trial. Neurology 93:e1474–e1484. https://doi.org/10.1212/WNL.0000000000008239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 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. https://doi.org/10.1016/j.nurt.2008.10.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Capurro V, Busquet P, Lopes JP et al (2013) Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer’s disease. PLoS One 8. https://doi.org/10.1371/journal.pone.0056870

  162. Zheng H, Fridkin M, Youdim M (2014) From single target to multitarget/network therapeutics in Alzheimer’s therapy. Pharmaceuticals 7:113–135. https://doi.org/10.3390/ph7020113

  163. Reggiani AM, Simoni E, Caporaso R et al (2016) In vivo characterization of ARN14140, a memantine/galantamine-based multi-target compound for Alzheimer’s disease. Sci Rep 6:1–11. https://doi.org/10.1038/srep33172

    Article  CAS  Google Scholar 

  164. Peters O, Fuentes M, Joachim LK et al (2015) Combined treatment with memantine and galantamine-CR compared with galantamine-CR only in antidementia drug naïve patients with mild-to-moderate Alzheimer’s disease. Alzheimers Dement Transl Res Clin Interv 1:198–204. https://doi.org/10.1016/j.trci.2015.10.001

    Article  Google Scholar 

  165. Peters O, Lorenz D, Fesche A et al (2012) A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI. J Nutr Health Aging 16:544–548. https://doi.org/10.1007/s12603-012-0062-8

    Article  CAS  PubMed  Google Scholar 

  166. Matsuzono K, Hishikawa N, Ohta Y et al (2015) Combination therapy of cholinesterase inhibitor (donepezil or galantamine) plus memantine in the Okayama memantine study. J Alzheimers Dis 45:771–780. https://doi.org/10.3233/JAD-143084

    Article  CAS  PubMed  Google Scholar 

  167. Singhal M, Merino V, Rosini M et al (2019) Controlled iontophoretic delivery in vitro and in vivo of ARN14140 – a multitarget compound for Alzheimer’s disease. Mol Pharm 16:3460–3468. https://doi.org/10.1021/acs.molpharmaceut.9b00252

    Article  CAS  PubMed  Google Scholar 

  168. Choi YB, Tenneti L, Le DA et al (2000) Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nat Neurosci 3:15–21. https://doi.org/10.1038/71090

    Article  CAS  PubMed  Google Scholar 

  169. Takahashi H, Xia P, Cui J et al (2015) Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease. Sci Rep 5:14781. https://doi.org/10.1038/srep14781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Talantova M, Sanz-Blasco S, Zhang X et al (2013) Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 110. https://doi.org/10.1073/pnas.1306832110

  171. Kaniakova M, Nepovimova E, Kleteckova L et al (2019) Combination of memantine and 6-chlorotacrine as novel multi-target compound against Alzheimer’s disease. Curr Alzheimer Res 16:821–833. https://doi.org/10.2174/1567205016666190228122218

  172. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712. https://doi.org/10.1038/nrd3505

    Article  CAS  PubMed  Google Scholar 

  173. Nguyen L, Lucke-Wold BP, Mookerjee SA et al (2015) Role of sigma-1 receptors in neurodegenerative diseases. J Pharmacol Sci 127:17–29. https://doi.org/10.1016/j.jphs.2014.12.005

    Article  CAS  PubMed  Google Scholar 

  174. Lahmy V, Meunier J, Malmström S et al (2013) Blockade of tau hyperphosphorylation and aβ 1-42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ 1 receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 38:1706–1723. https://doi.org/10.1038/npp.2013.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Besnard J, Ruda GF, Setola V et al (2012) Automated design of ligands to polypharmacological profiles. Nature 492:215–220. https://doi.org/10.1038/nature11691

    Article  CAS  PubMed  Google Scholar 

  176. Al-Ali H, Lee DH, Danzi MC et al (2015) Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth. ACS Chem Biol 10:1939–1951. https://doi.org/10.1021/acschembio.5b00289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kumar R, Harilal S, Gupta SV et al (2019) Exploring the new horizons of drug repurposing: a vital tool for turning hard work into smart work. Eur J Med Chem 182:111602. https://doi.org/10.1016/j.ejmech.2019.111602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Kabir MT, Uddin MS, Begum MM et al (2019) Cholinesterase inhibitors for Alzheimer’s disease: multitargeting strategy based on anti-Alzheimer’s drugs repositioning. Curr Pharm Des 25:3519–3535. https://doi.org/10.2174/1381612825666191008103141

  179. Kabir MT, Sufian MA, Uddin MS et al (2019) NMDA receptor antagonists: repositioning of memantine as a multitargeting agent for Alzheimer’s therapy. Curr Pharm Des 25:3506–3518. https://doi.org/10.2174/1381612825666191011102444

    Article  CAS  PubMed  Google Scholar 

  180. Xie SS, Wang XB, Li JY et al (2013) Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease. Eur J Med Chem 64:540–553. https://doi.org/10.1016/j.ejmech.2013.03.051

    Article  CAS  PubMed  Google Scholar 

  181. Ali MA, Yar MS, Hasan MZ et al (2009) Design, synthesis and evaluation of novel 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4-substituted phenyl methanone analogues. Bioorg Med Chem Lett 19:5075–5077. https://doi.org/10.1016/j.bmcl.2009.07.042

    Article  CAS  PubMed  Google Scholar 

  182. Khoobi M, Alipour M, Moradi A et al (2013) Design, synthesis, docking study and biological evaluation of some novel tetrahydrochromeno [3′,4′:5,6]pyrano[2,3-b]quinolin-6(7H)-one derivatives against acetyl- and butyrylcholinesterase. Eur J Med Chem 68:291–300. https://doi.org/10.1016/j.ejmech.2013.07.045

    Article  CAS  PubMed  Google Scholar 

  183. Catto M, Pisani L, Leonetti F et al (2013) Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase. Bioorg Med Chem 21:146–152. https://doi.org/10.1016/j.bmc.2012.10.045

    Article  CAS  PubMed  Google Scholar 

  184. Jin P, Kim JA, Choi DY, Lee YJ, Jung HS, Hong JT (2013) Anti-inflammatory and anti-amyloidogenic effects of a small molecule, 2,4-bis(p-hydroxyphenyl)-2-butenal in Tg2576 Alzheimer’s disease mice model. J Neuroinflammation 10. https://doi.org/10.1186/1742-2094-10-2

  185. Harilal S, Jose J et al (2020) Revisiting the blood–brain barrier: a hard nut to crack in the transportation of drug molecules. Brain Res Bull. https://doi.org/10.1016/j.brainresbull.2020.03.018

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Acknowledgments

This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-Track Research Funding Program. This work was supported by King Saud University, Deanship of Scientific Research, College of Science Research Center.

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Authors and Affiliations

  1. Department of Pharmacy, Southeast University, Dhaka, Bangladesh

    Md. Sahab Uddin & Abdullah Al Mamun

  2. Pharmakon Neuroscience Research Network, Dhaka, Bangladesh

    Md. Sahab Uddin & Abdullah Al Mamun

  3. Department of Pharmacy, Brac University, Dhaka, Bangladesh

    Md. Tanvir Kabir

  4. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

  5. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

  6. Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11474, Saudi Arabia

    May N. Bin-Jumah

  7. Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia

    Mohamed M. Abdel-Daim

  8. Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt

    Mohamed M. Abdel-Daim

Authors
  1. Md. Sahab Uddin
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  2. Abdullah Al Mamun
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  3. Md. Tanvir Kabir
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  4. Ghulam Md Ashraf
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  5. May N. Bin-Jumah
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  6. Mohamed M. Abdel-Daim
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Contributions

M.S.U. conceived the original idea and designed the outlines of the study. M.S.U., A.A.M., and M.T.K. wrote the draft of the manuscript. M.S.U. prepared the figures for the manuscript. G.M.A., M.N.B.-J., and M.M.A.-D. performed the literature review and aided in revising the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Md. Sahab Uddin.

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Uddin, M.S., Al Mamun, A., Kabir, M.T. et al. Multi-Target Drug Candidates for Multifactorial Alzheimer’s Disease: AChE and NMDAR as Molecular Targets. Mol Neurobiol 58, 281–303 (2021). https://doi.org/10.1007/s12035-020-02116-9

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