Structural Scaffolds as Anti- Alzheimer Agents

Bhawana      Sati; Tyagi      Alka; Anurag      Chaudhary
doi:10.2174/1573406418666220815101124
Abstract

Background: Understanding the cognitive and behavioral aspects of Alzheimer's disease- related dementia is surely a sturdy task to deal with. In recent years, a broad search for novel anti-Alzheimer agents has been continuously conducted. The malfunctioning of various neurotransmitter systems and the accumulation of abnormal proteins in the brain are the two key characteristics of this disorder. This is supported by a growing amount of evidence. Some Pharmacophoric groups/combinations exhibit potential neuroprotective activity.
Methods: This study aims to compile the most recent and interesting target/target combinations/ pharmacophoric combinations to cure Alzheimer's disease. We concentrated our efforts to find the ability of certain pharmacophoric elements to interfere with various enzymatic and/or receptor systems or to work as neuroprotective agents. These pharmacophoric elements may be proved to be promising leads for future multi-target anti-Alzheimer drug discovery programs.
Results: Anticholinesterase drugs were mentioned as the best treatment thus far. Additionally, impairments in the serotonergic, GABAergic, noradrenergic, dopaminergic, and glutaminergic and a few other pathways have all been linked to memory, speech, behavioral and other alterations in Alzheimer's disease.
Conclusion: This includes the study of workable pharmacophoric groups/combinations, receptors/ enzymatic systems and related hypotheses to find the promising therapeutic lead compounds which could work as future anti-Alzheimer drugs. We discuss future work that would improve our understanding of this Disease.
Keywords: Alzheimer’s disease, Dementia, AD, AChE inhibitor, NMDA Receptor Antagonist, neuroprotective, Neurodegenerative disorder.
« Previous Next »
Graphical Abstract

[1]
Bondi, M.W.; Edmonds, E.C.; Salmon, D.P. Alzheimer’s disease: Past, present, and future. J. Int. Neuropsychol. Soc.,  2017, 23(9-10), 818-831.
 [http://dx.doi.org/10.1017/S135561771700100X] [PMID:  29198280]

[2]
Berchtold, N.C.; Cotman, C.W. Evolution in the conceptualization of dementia and Alzheimer’s disease: Greco-Roman period to the 1960s. Neurobiol. Aging,  1998, 19(3), 173-189.
 [http://dx.doi.org/10.1016/S0197-4580(98)00052-9] [PMID:  9661992]

[3]
Porsteinsson, A.P.; Isaacson, R.S.; Knox, S.; Sabbagh, M.N.; Rubino, I. Diagnosis of early Alzheimer’s disease: Clinical practice in 2021. J. Prev. Alzheimers Dis.,  2021, 8(3), 371-386.
 [PMID:  34101796]

[4]
Alzheimer, A.; Stelzmann, R.A.; Schnitzlein, H.N.; Murtagh, F.R. An english translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin. Anat.,  1995, 8(6), 429-431.
 [http://dx.doi.org/10.1002/ca.980080612] [PMID:  8713166]

[5]
Korolev, I.O. Alzheimer s disease A clinical and basic science review. Med. Student Res. J.,  2014, 04(September), 24-33.

[6]
Gilman, S. Oxford American Handbook of Neurology; Oxford University Press: Oxford, UK, 2010. 

[7]
Greene, J.D.W.; Hodges, J.R.; Baddeley, A.D. Autobiographical memory and executive function in early dementia of Alzheimer type. Neuropsychologia,  1995, 33(12), 1647-1670.
 [http://dx.doi.org/10.1016/0028-3932(95)00046-1] [PMID:  8745122]

[8]
Baddeley, A.D. The trouble with levels: A re-examination of Craik and Lockhart’s framework for memory research. Psychol. Rev.,  1978, 85(3), 139-152.
 [http://dx.doi.org/10.1037/0033-295X.85.3.139]

[9]
Khan, M.M.; Ahsan, F.; Ahmad, U.; Akhtar, J. Badruddeen; Mujahid, M. Alzheimer disease: A review. World J. Pharm. Pharm. Sci.,  2016, 5(June), 649-666.

[10]
Plassman, B.L.; Langa, K.M.; Fisher, G.G.; Heeringa, S.G.; Weir, D.R.; Ofstedal, M.B.; Burke, J.R.; Hurd, M.D.; Potter, G.G.; Rodgers, W.L.; Steffens, D.C.; Willis, R.J.; Wallace, R.B. Prevalence of dementia in the United States: The aging, demographics, and memory study. Neuroepidemiology,  2007, 29(1-2), 125-132.
 [http://dx.doi.org/10.1159/000109998] [PMID:  17975326]

[11]
Association, A. 2013 Alzheimer’s disease facts and figures. Alzheimers Dement.,  2013, 9(2), 208-245.
 [http://dx.doi.org/10.1016/j.jalz.2013.02.003] [PMID:  23507120]

[12]
Prince, M.; Bryce, R.; Albanese, E.; Wimo, A.; Ribeiro, W.; Ferri, C.P. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement.,  2013, 9(1), 63-75.e2.
 [http://dx.doi.org/10.1016/j.jalz.2012.11.007] [PMID:  23305823]

[13]
Ott, A.; Breteler, M.M.; van Harskamp, F.; Claus, J.J.; van der Cammen, T.J.; Grobbee, D.E.; Hofman, A. Prevalence of Alzheimer’s disease and vascular dementia: Association with education. The Rotterdam study. BMJ,  1995, 310(6985), 970-973.
 [http://dx.doi.org/10.1136/bmj.310.6985.970] [PMID:  7728032]

[14]
Selkoe, D.J. Alzheimer’s disease is a synaptic failure. Science,  2002, 298(5594), 789-791.
 [http://dx.doi.org/10.1126/science.1074069] [PMID:  12399581]

[15]
Bachurin, S.O.; Makhaeva, G.F.; Shevtsova, E.F.; Aksinenko, A.Y.; Grigoriev, V.V.; Shevtsov, P.N.; Goreva, T.V.; Epishina, T.A.; Kovaleva, N.V.; Pushkareva, E.A.; Boltneva, N.P.; Lushchekina, S.V.; Gabrelyan, A.V.; Zamoyski, V.L.; Dubova, L.G.; Rudakova, E.V.; Fisenko, V.P.; Bovina, E.V.; Richardson, R.J. Conjugation of aminoadamantane and γ-carboline pharmacophores gives rise to unexpected properties of multifunctional ligands. Molecules,  2021, 26(5527), 1-26.
 [http://dx.doi.org/10.3390/molecules26185527] [PMID:  34576998]

[16]
Long, J.M.; Holtzman, D.M. Alzheimer disease: An update on pathobiology and treatment strategies. Cell,  2019, 179(2), 312-339.
 [http://dx.doi.org/10.1016/j.cell.2019.09.001] [PMID:  31564456]

[17]
Rocca, W.A.; Petersen, R.C.; Knopman, D.S.; Hebert, L.E.; Evans, D.A.; Hall, K.S.; Gao, S.; Unverzagt, F.W.; Langa, K.M.; Larson, E.B.; White, L.R. Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States. Alzheimers Dement.,  2011, 7(1), 80-93.
 [http://dx.doi.org/10.1016/j.jalz.2010.11.002] [PMID:  21255746]

[18]
Calabrò, M.; Rinaldi, C.; Santoro, G.; Crisafulli, C. The biological pathways of Alzheimer disease: A review. AIMS Neurosci.,  2020, 8(1), 86-132.
 [http://dx.doi.org/10.3934/Neuroscience.2021005] [PMID:  33490374]

[19]
Brown, T. Design thinking. Harv. Bus. Rev.,  2008, 86(6), 84-92, 141.
 [PMID:  18605031]

[20]
Albertini, C.; Salerno, A.; de Sena Murteira Pinheiro, P.; Bolognesi, M.L. From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology. Med. Res. Rev.,  2021, 41(5), 2606-2633.
 [http://dx.doi.org/10.1002/med.21699] [PMID:  32557696]

[21]
Bautista-Aguilera, O.M.; Esteban, G.; Bolea, I.; Nikolic, K.; Agbaba, D.; Moraleda, I.; Iriepa, I.; Samadi, A.; Soriano, E.; Unzeta, M.; Marco-Contelles, J. Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease. Eur. J. Med. Chem.,  2014, 75, 82-95.
 [http://dx.doi.org/10.1016/j.ejmech.2013.12.028] [PMID:  24530494]

[22]
Luo, W.; Li, Y-P.; He, Y.; Huang, S-L.; Tan, J-H.; Ou, T-M.; Li, D.; Gu, L-Q.; Huang, Z-S. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as dual inhibitors for cholinesterases and amyloid beta aggregation. Bioorg. Med. Chem.,  2011, 19(2), 763-770.
 [http://dx.doi.org/10.1016/j.bmc.2010.12.022] [PMID:  21211982]

[23]
Bartus, R.T. On neurodegenerative diseases, models, and treatment strategies: Lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp. Neurol.,  2000, 163(2), 495-529.
 [http://dx.doi.org/10.1006/exnr.2000.7397] [PMID:  10833325]

[24]
Reid, G.A.; Chilukuri, N.; Darvesh, S. Butyrylcholinesterase and the cholinergic system. Neuroscience,  2013, 234, 53-68.
 [http://dx.doi.org/10.1016/j.neuroscience.2012.12.054] [PMID:  23305761]

[25]
Sims, N.R.; Bowen, D.M.; Allen, S.J.; Smith, C.C.T.; Neary, D.; Thomas, D.J.; Davison, A.N. Presynaptic cholinergic dysfunction in patients with dementia. J. Neurochem.,  1983, 40(2), 503-509.
 [http://dx.doi.org/10.1111/j.1471-4159.1983.tb11311.x] [PMID:  6822833]

[26]
Xie, S.S.; Wang, X.B.; Li, J.Y.; Yang, L.; Kong, L.Y. Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease. Eur. J. Med. Chem.,  2013, 64, 540-553.
 [http://dx.doi.org/10.1016/j.ejmech.2013.03.051] [PMID:  23685572]

[27]
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. Peer J. 2016, 4e-2140(7), 1-15.

[28]
Ogura, H.; Kosasa, T.; Kuriya, Y.; Yamanishi, Y. Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro. Methods Find. Exp. Clin. Pharmacol.,  2000, 22(8), 609-613.
 [http://dx.doi.org/10.1358/mf.2000.22.8.701373] [PMID:  11256231]

[29]
Weinstock, M. Selectivity of cholinesterase inhibition: Clinical implications for the treatment of Alzheimer’s disease. CNS Drugs,  1999, 12(4), 307-323.
 [http://dx.doi.org/10.2165/00023210-199912040-00005]

[30]
Rajeshwari, R.; Chand, K.; Candeias, E.; Cardoso, S.M.; Chaves, S.; Santos, M.A. New multitarget hybrids bearing tacrine and phenylbenzothiazole motifs as potential drug candidates for Alzheimer’s disease. Molecules,  2019, 24(3), 1-15.
 [http://dx.doi.org/10.3390/molecules24030587] [PMID:  30736397]

[31]
Bar-On, P.; Millard, C.B.; Harel, M.; Dvir, H.; Enz, A.; Sussman, J.L.; Silman, I. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry,  2002, 41(11), 3555-3564.
 [http://dx.doi.org/10.1021/bi020016x] [PMID:  11888271]

[32]
Greig, N.H.; De Micheli, E.; Holloway, H.W.; Yu, Q.S.; Utsuki, T.; Perry, T.A.; Brossi, A.; Ingram, D.K.; Deutsch, J.; Lahiri, D.K.; Soncrant, T.T. The experimental Alzheimer drug phenserine: Preclinical pharmacokinetics and pharmacodynamics. Acta Neurol. Scand. Suppl.,  2000, 176, 74-84.
 [http://dx.doi.org/10.1034/j.1600-0404.2000.00311.x] [PMID:  11261809]

[33]
Adams, J. Drug Evaluation. Aust. Prescr.,  1996, 19(1), 1087-1097.

[34]
Simeon-Rudolf, V.; Kovarik, Z. Radić Z.; Reiner, E. Reversible inhibition of acetylcholinesterase and butyrylcholinesterase by 4,4-bipyridine and by a coumarin derivative. Chem. Biol. Interact.,  1999, 119-120, 119-128.
 [http://dx.doi.org/10.1016/S0009-2797(99)00020-4] [PMID:  10421445]

[35]
Radić Z.; Duran, R.; Vellom, D.C.; Li, Y.; Cervenansky, C.; Taylor, P. Site of fasciculin interaction with acetylcholinesterase. J. Biol. Chem.,  1994, 269(15), 11233-11239.
 [http://dx.doi.org/10.1016/S0021-9258(19)78115-0] [PMID:  8157652]

[36]
Piazzi, L.; Rampa, A.; Bisi, A.; Gobbi, S.; Belluti, F.; Cavalli, A.; Bartolini, M.; Andrisano, V.; Valenti, P.; Recanatini, M. 3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation: A dual function lead for Alzheimers disease therapy. J. Med. Chem.,  2003, 46(12), 2279-2282.
 [http://dx.doi.org/10.1021/jm0340602] [PMID:  12773032]

[37]
Piazzi, L.; Cavalli, A.; Belluti, F.; Bisi, A.; Gobbi, S.; Rizzo, S.; Bartolini, M.; Andrisano, V.; Recanatini, M.; Rampa, A. Brief Articles. J. Med. Chem.,  2007, 50(17), 4250-4254.
 [http://dx.doi.org/10.1021/jm070100g] [PMID:  17655212]

[38]
Rizzo, S.; Bartolini, M.; Ceccarini, L.; Piazzi, L.; Gobbi, S.; Cavalli, A.; Recanatini, M.; Andrisano, V.; Rampa, A. Targeting Alzheimer’s disease: Novel indanone hybrids bearing a pharmacophoric fragment of AP2238. Bioorg. Med. Chem.,  2010, 18(5), 1749-1760.
 [http://dx.doi.org/10.1016/j.bmc.2010.01.071] [PMID:  20171894]

[39]
Camps, P.; Formosa, X.; Galdeano, C.; Gómez, T.; Muñoz-Torrero, D.; Scarpellini, M.; Viayna, E.; Badia, A.; Clos, M.V.; Camins, A.; Pallàs, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Estelrich, J.; Lizondo, M.; Bidon-Chanal, A.; Luque, F.J. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation. J. Med. Chem.,  2008, 51(12), 3588-3598.
 [http://dx.doi.org/10.1021/jm8001313] [PMID:  18517184]

[40]
Rydberg, E.H.; Brumshtein, B.; Greenblatt, H.M.; Wong, D.M.; Shaya, D.; Williams, L.D.; Carlier, P.R.; Pang, Y.P.; Silman, I.; Sussman, J.L. Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge. J. Med. Chem.,  2006, 49(18), 5491-5500.
 [http://dx.doi.org/10.1021/jm060164b] [PMID:  16942022]

[41]
Bosak, A.; Opsenica, D.M.; Šinko, G.; Zlatar, M.; Kovarik, Z. Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase. Chem. Biol. Interact.,  2019, 308(March), 101-109.
 [http://dx.doi.org/10.1016/j.cbi.2019.05.024] [PMID:  31100281]

[42]
Harel, M.; Sonoda, L.K.; Silman, I.; Sussman, J.L.; Rosenberry, T.L. Crystal structure of thioflavin T bound to the peripheral site of Torpedo californica acetylcholinesterase reveals how thioflavin T acts as a sensitive fluorescent reporter of ligand binding to the acylation site. J. Am. Chem. Soc.,  2008, 130(25), 7856-7861.
 [http://dx.doi.org/10.1021/ja7109822] [PMID:  18512913]

[43]
Alipour, M.; Khoobi, M.; Moradi, A.; Nadri, H.; Homayouni Moghadam, F.; Emami, S.; Hasanpour, Z.; Foroumadi, A.; Shafiee, A. Synthesis and anti-cholinesterase activity of new 7-hydroxycoumarin derivatives. Eur. J. Med. Chem.,  2014, 82, 536-544.
 [http://dx.doi.org/10.1016/j.ejmech.2014.05.056] [PMID:  24941128]

[44]
Khoobi, M.; Alipour, M.; Moradi, A.; Sakhteman, A.; Nadri, H.; Razavi, S.F.; Ghandi, M.; Foroumadi, A.; Shafiee, A. 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.,  2013, 68, 291-300.
 [http://dx.doi.org/10.1016/j.ejmech.2013.07.045] [PMID:  23988412]

[45]
Razavi, S.F.; Khoobi, M.; Nadri, H.; Sakhteman, A.; Moradi, A.; Emami, S.; Foroumadi, A.; Shafiee, A. Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors. Eur. J. Med. Chem.,  2013, 64, 252-259.
 [http://dx.doi.org/10.1016/j.ejmech.2013.03.021] [PMID:  23644208]

[46]
Bagheri, S.M.; Khoobi, M.; Nadri, H.; Moradi, A.; Emami, S.; Jalili-Baleh, L.; Jafarpour, F.; Homayouni Moghadam, F.; Foroumadi, A.; Shafiee, A. Synthesis and anticholinergic activity of 4-hydroxycoumarin derivatives containing substituted benzyl-1,2,3-triazole moiety. Chem. Biol. Drug Des.,  2015, 86(5), 1215-1220.
 [http://dx.doi.org/10.1111/cbdd.12588] [PMID:  26010139]

[47]
Cacabelos, R.; Takeda, M.; Winblad, B. The glutamatergic system and neurodegeneration in dementia: Preventive strategies in Alzheimers disease. Int. J. Geriatr. Psychiatry,  1999, 14(1), 3-47.
 [http://dx.doi.org/10.1002/(SICI)1099-1166(199901)14:1<3:AID-GPS897>3.0.CO;2-7] [PMID:  10029935]

[48]
Sokolov, V.B.; Aksinenko, A.Y.; Epishina, T.A.; Goreva, T.V.; Grigoriev, V.V.; Gabrel, A.V.; Bachurin, S.O. Synthesis and biological activity of N substituted tetrahydro γ-carbolins bearing bis ( dimethylamino ) phenothiazine moiety. Russ. Chemical. Bull., International Edition, , 2015; 64, pp. (3)718-722.

[49]
Zheng, H.; Fridkin, M.; Youdim, M. From single target to multitarget/network therapeutics in Alzheimer’s therapy. Pharmaceuticals (Basel),  2014, 7(2), 113-135.
 [http://dx.doi.org/10.3390/ph7020113] [PMID:  24463342]

[50]
Sokolov, V.B.; Aksinenko, A.Y.; Nikolaeva, N.S.; Grigor’ev, V.V.; Kinzirsky, A.S.; Bachurin, S.O. Modification of biologically active amides and amines with fluoro-containing heterocycles 11. tetrahydrocarbazoles modified with 2-(5-fluoropyridin-3-yl)ethyl fragment. Russ. Chem. Bull.,  2014, 63(5), 1137-1141.
 [http://dx.doi.org/10.1007/s11172-014-0561-3]

[51]
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.
 [http://dx.doi.org/10.1021/jm7009364] [PMID:  18181565]

[52]
Francis, P.T.; Parsons, C.G.; Jones, R.W. Rationale for combining glutamatergic and cholinergic approaches in the symptomatic treatment of Alzheimer’s disease. Expert Rev. Neurother.,  2012, 12(11), 1351-1365.
 [http://dx.doi.org/10.1586/ern.12.124] [PMID:  23234396]

[53]
Bolognesi, M.L. Polypharmacology in a single drug: Multitarget drugs. Curr. Med. Chem.,  2013, 20(13), 1639-1645.
 [http://dx.doi.org/10.2174/0929867311320130004] [PMID:  23410164]

[54]
Sokolov, V.B.; Aksinenko, A.Y.; Goreva, T.V.; Epishina, T.A.; Grigor’ev, V.V.; Gabrel’yan, A.V.; Vinogradova, D.V.; Neganova, M.E.; Shevtsova, E.F.; Bachurin, S.O. Molecular design of multitarget neuroprotectors 3. Synthesis and bioactivity of tetrahydrocarbazole-aminoadamantane conjugates. Russ. Chem. Bull.,  2016, 65(5), 1354-1359.
 [http://dx.doi.org/10.1007/s11172-016-1461-5]

[55]
Maramai, S.; Benchekroun, M.; Gabr, M.T.; Yahiaoui, S. Multitarget therapeutic strategies for Alzheimer’s disease: Review on emerging target combinations. BioMed Res. Int.,  2020, 20205120230
 [http://dx.doi.org/10.1155/2020/5120230] [PMID:  32714977]

[56]
Gabr, M.T.; Abdel-Raziq, M.S. Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors. Bioorg. Med. Chem. Lett.,  2018, 28(17), 2910-2913.
 [http://dx.doi.org/10.1016/j.bmcl.2018.07.019] [PMID:  30017317]

[57]
Pérez-Areales, F.J.; Turcu, A.L.; Barniol-Xicota, M.; Pont, C.; Pivetta, D.; Espargaró, A.; Bartolini, M.; De Simone, A.; Andrisano, V.; Pérez, B.; Sabate, R.; Sureda, F.X.; Vázquez, S.; Muñoz-Torrero, D. A novel class of multitarget anti-Alzheimer benzohomoadamantane chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors. Eur. J. Med. Chem.,  2019, 180, 613-626.
 [http://dx.doi.org/10.1016/j.ejmech.2019.07.051] [PMID:  31351393]

[58]
Emilsson, L.; Saetre, P.; Jazin, E. Alzheimer’s disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signaling. Neurobiol. Dis.,  2006, 21(3), 618-625.
 [http://dx.doi.org/10.1016/j.nbd.2005.09.004] [PMID:  16257224]

[59]
Diaz, J.C.; Simakova, O.; Jacobson, K.A.; Arispe, N.; Pollard, H.B. Small molecule blockers of the Alzheimer abeta calcium channel potently protect neurons from abeta cytotoxicity. Proc. Natl. Acad. Sci. USA,  2009, 106(9), 3348-3353.
 [http://dx.doi.org/10.1073/pnas.0813355106] [PMID:  19204293]

[60]
Chioua, M.; Buzzi, E.; Moraleda, I.; Iriepa, I.; Maj, M.; Wnorowski, A.; Giovannini, C.; Tramarin, A.; Portali, F.; Ismaili, L.; López-Alvarado, P.; Bolognesi, M.L. Jóźwiak, K.; Menéndez, J.C.; Marco-Contelles, J.; Bartolini, M. Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer’s disease. Eur. J. Med. Chem.,  2018, 155, 839-846.
 [http://dx.doi.org/10.1016/j.ejmech.2018.06.044] [PMID:  29958119]

[61]
Mitchell, E.S.; Neumaier, J.F. 5-HT6 receptors: A novel target for cognitive enhancement. Pharmacol. Ther.,  2005, 108(3), 320-333.
 [http://dx.doi.org/10.1016/j.pharmthera.2005.05.001] [PMID:  16005519]

[62]
Ivachtchenko, A.V.; Lavrovsky, Y.; Ivanenkov, Y.A. AVN-211, novel and highly selective 5-HT6 receptor small molecule antagonist, for the treatment of Alzheimer’s disease. Mol. Pharm.,  2016, 13(3), 945-963.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.5b00830] [PMID:  26886442]

[63]
Ivachtchenko, A.V.; Golovina, E.S.; Kadieva, M.G.; Kysil, V.M.; Mitkin, O.D.; Tkachenko, S.E.; Okun, I. Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists. Bioorg. Med. Chem.,  2011, 19(4), 1482-1491.
 [http://dx.doi.org/10.1016/j.bmc.2010.12.055] [PMID:  21277782]

[64]
Ivachtchenko, A.V.; Lavrovsky, Y.; Okun, I. AVN-101: A multi-target drug candidate for the treatment of CNS disorders. J. Alzheimers Dis.,  2016, 53(2), 583-620.
 [http://dx.doi.org/10.3233/JAD-151146] [PMID:  27232215]

[65]
Alsaedi, A.M.R.; Farghaly, T.A.; Shaaban, M.R. Synthesis and antimicrobial evaluation of novel pyrazolopyrimidines incorporated with mono- and diphenylsulfonyl groups. Molecules,  2019, 24(21), 1-21.
 [http://dx.doi.org/10.3390/molecules24214009] [PMID:  31694325]

[66]
Blandina, P.; Giorgetti, M.; Bartolini, L.; Cecchi, M.; Timmerman, H.; Leurs, R.; Pepeu, G.; Giovannini, M.G. Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. Br. J. Pharmacol.,  1996, 119(8), 1656-1664.
 [http://dx.doi.org/10.1111/j.1476-5381.1996.tb16086.x] [PMID:  8982515]

[67]
Bembenek, S.D.; Keith, J.M.; Letavic, M.A.; Apodaca, R.; Barbier, A.J.; Dvorak, L.; Aluisio, L.; Miller, K.L.; Lovenberg, T.W.; Carruthers, N.I. Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling. Bioorg. Med. Chem.,  2008, 16(6), 2968-2973.
 [http://dx.doi.org/10.1016/j.bmc.2007.12.048] [PMID:  18249544]

[68]
Bolognesi, M.L.; Cavalli, A.; Valgimigli, L.; Bartolini, M.; Rosini, M.; Andrisano, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed drug design strategy: From a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer’s disease. J. Med. Chem.,  2007, 50(26), 6446-6449.
 [http://dx.doi.org/10.1021/jm701225u] [PMID:  18047264]

[69]
Huang, W.; Tang, L.; Shi, Y.; Huang, S.; Xu, L.; Sheng, R.; Wu, P.; Li, J.; Zhou, N.; Hu, Y. Searching for the Multi-Target-Directed Ligands against Alzheimer’s disease: Discovery of quinoxaline-based hybrid compounds with AChE, HR and BACE 1 inhibitory activities. Bioorg. Med. Chem.,  2011, 19(23), 7158-7167.
 [http://dx.doi.org/10.1016/j.bmc.2011.09.061] [PMID:  22019465]

[70]
Okamura, N.; Suemoto, T.; Furumoto, S.; Suzuki, M.; Shimadzu, H.; Akatsu, H.; Yamamoto, T.; Fujiwara, H.; Nemoto, M.; Maruyama, M.; Arai, H.; Yanai, K.; Sawada, T.; Kudo, Y. Quinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in Alzheimer’s disease. J. Neurosci.,  2005, 25(47), 10857-10862.
 [http://dx.doi.org/10.1523/JNEUROSCI.1738-05.2005] [PMID:  16306398]

[71]
Nash, A.; Gijsen, H.J.M.; Hrupka, B.J.; Teng, K.S.L.; Lichtenthaler, S.F.; Takeshima, H.; Gunnersen, J.M.; Munro, K.M. BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory. Sci. Rep.,  2021, 11(1), 15084.
 [http://dx.doi.org/10.1038/s41598-021-94369-0] [PMID:  34302009]

[72]
Imbimbo, B.P.; Watling, M. Investigational BACE inhibitors for the treatment of Alzheimer’s disease. Expert Opin. Investig. Drugs,  2019, 28(11), 967-975.
 [http://dx.doi.org/10.1080/13543784.2019.1683160] [PMID:  31661331]

[73]
Yang, L.; Lindholm, K.; Yan, R.; Citron, M.; Xia, W.; Yang, X.; Beach, T.; Sue, L.; Wong, P.; Price, D.; Li, R.; Shen, Y. Elevated  -secretase expression and enzymatic activity measuring t-cell – mediated cytotoxicity using antibody to activated caspase 3. Nat. Med.,  2003, 9(1), 3-4.
 [http://dx.doi.org/10.1038/nm0103-3] [PMID:  12514700]

[74]
Munro, K.M.; Nash, A.; Pigoni, M.; Lichtenthaler, S.F.; Gunnersen, J.M. Functions of the Alzheimer’s disease protease BACE1 at the synapse in the central nervous system. J. Mol. Neurosci.,  2016, 60(3), 305-315.
 [http://dx.doi.org/10.1007/s12031-016-0800-1] [PMID:  27456313]

[75]
Saturnino, C.; Iacopetta, D.; Sinicropi, M.S.; Rosano, C.; Caruso, A.; Caporale, A.; Marra, N.; Marengo, B.; Pronzato, M.A.; Parisi, O.I.; Longo, P.; Ricciarelli, R. N-alkyl carbazole derivatives as new tools for Alzheimer’s disease: Preliminary studies. Molecules,  2014, 19(7), 9307-9317.
 [http://dx.doi.org/10.3390/molecules19079307] [PMID:  24991761]

[76]
Maia, M.A.; Sousa, E. BACE-1 and -secretase as therapeutic targets for Alzheimer’s disease. Pharmaceuticals (Basel),  2019, 12(1), 1-31.
 [http://dx.doi.org/10.3390/ph12010041] [PMID:  30893882]

[77]
Doody, R.S.; Raman, R.; Farlow, M.; Iwatsubo, T.; Vellas, B.; Joffe, S.; Kieburtz, K.; He, F.; Sun, X.; Thomas, R.G.; Aisen, P.S.; Siemers, E.; Sethuraman, G.; Mohs, R. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med.,  2013, 369(4), 341-350.
 [http://dx.doi.org/10.1056/NEJMoa1210951] [PMID:  23883379]

[78]
Coric, V.; van Dyck, C.H.; Salloway, S.; Andreasen, N.; Brody, M.; Richter, R.W.; Soininen, H.; Thein, S.; Shiovitz, T.; Pilcher, G.; Colby, S.; Rollin, L.; Dockens, R.; Pachai, C.; Portelius, E.; Andreasson, U.; Blennow, K.; Soares, H.; Albright, C.; Feldman, H.H.; Berman, R.M. Safety and tolerability of the -secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol.,  2012, 69(11), 1430-1440.
 [http://dx.doi.org/10.1001/archneurol.2012.2194] [PMID:  22892585]

[79]
Bollen, E.; Prickaerts, J. Phosphodiesterases in neurodegenerative disorders. IUBMB Life,  2012, 64(12), 965-970.
 [http://dx.doi.org/10.1002/iub.1104] [PMID:  23129425]

[80]
Beavo, J.A. Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms. Physiol. Rev.,  1995, 75(4), 725-748.
 [http://dx.doi.org/10.1152/physrev.1995.75.4.725] [PMID:  7480160]

[81]
Uthayathas, S.; Karuppagounder, S.S.; Thrash, B.M.; Parameshwaran, K.; Suppiramaniam, V.; Dhanasekaran, M. Versatile effects of sildenafil: Recent pharmacological applications. Pharmacol. Rep.,  2007, 59(2), 150-163.
 [PMID:  17556793]

[82]
Liu, L.; Xu, H.; Ding, S.; Wang, D.; Song, G.; Huang, X. Phosphodiesterase 5 inhibitors as novel agents for the treatment of Alzheimer’s disease. Brain Res. Bull.,  2019, 153, 223-231.
 [http://dx.doi.org/10.1016/j.brainresbull.2019.09.001] [PMID:  31493542]

[83]
Fiorito, J.; Saeed, F.; Zhang, H.; Staniszewski, A.; Feng, Y.; Francis, Y.I.; Rao, S.; Thakkar, D.M.; Deng, S.X.; Landry, D.W.; Arancio, O. Synthesis of quinoline derivatives: Discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer’s disease. Eur. J. Med. Chem.,  2013, 60, 285-294.
 [http://dx.doi.org/10.1016/j.ejmech.2012.12.009] [PMID:  23313637]

[84]
Nguyen, M.; Huang, M.; Liu, Y.; Meunier, B.; Robert, A. Is iron associated with amyloid involved in the oxidative stress of Alzheimer’s disease? C. R. Chim.,  2017, 20(11–12), 987-989.
 [http://dx.doi.org/10.1016/j.crci.2017.07.009]

[85]
Zhang, W.; Huang, M.; Bijani, C.; Liu, Y.; Robert, A.; Meunier, B. Synthesis and characterization of copper-specific tetradendate ligands as potential treatment for Alzheimer’s disease. Chem. Rep.,  2018, 21(5), 475-483.
 [http://dx.doi.org/10.1016/j.crci.2018.01.005]

[86]
Ye, J.; Zhai, H.Z. Oxidative stress and Alzheimer disease. Zhongguo Linchuang Kangfu,  2005, 9(33), 117-119.

[87]
Wyss-Coray, T.; Masliah, E.; Mallory, M.; McConlogue, L.; Johnson-Wood, K.; Lin, C.; Mucke, L. Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer’s disease. Nature,  1997, 389(6651), 603-606.
 [http://dx.doi.org/10.1038/39321] [PMID:  9335500]

[88]
Harman, D. Alzheimer’s disease: A hypothesis on pathogenesis. J. Am. Aging Assoc.,  2000, 23(3), 147-161.
 [PMID:  23604855]

[89]
Yan, S.D.; Chen, X.; Schmidt, A.M.; Brett, J.; Godman, G.; Zou, Y.S.; Scott, C.W.; Caputo, C.; Frappier, T.; Smith, M.A.; Perry, G.; Yen, S.H.; Stern, D. Glycated tau protein in Alzheimer disease: A mechanism for induction of oxidant stress. Proc. Natl. Acad. Sci. USA,  1994, 91(16), 7787-7791.
 [http://dx.doi.org/10.1073/pnas.91.16.7787] [PMID:  8052661]

[90]
Smith, M.A.; Richey Harris, P.L.; Sayre, L.M.; Beckman, J.S.; Perry, G. Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J. Neurosci.,  1997, 17(8), 2653-2657.
 [http://dx.doi.org/10.1523/JNEUROSCI.17-08-02653.1997] [PMID:  9092586]

[91]
Smith, M.A.; Taneda, S.; Richey, P.L.; Miyata, S.; Yant, S.; Sternt, D.; Sayre, L.M.; Monnier, V.M.; Perry, G. Advanced maillard reaction end products are associated with Alzheimer disease Pathology. Proc. Natl. Acad. Sci. USA,  1995, 92(5), 1794-1794.
 [http://dx.doi.org/10.1073/pnas.92.5.1794e] [PMID:  8202552]

[92]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science,  2002, 297(5580), 353-356.
 [http://dx.doi.org/10.1126/science.1072994] [PMID:  12130773]

[93]
Gasparini, L.; Ongini, E.; Wenk, G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease: Old and new mechanisms of action. J. Neurochem.,  2004, 91(3), 521-536.
 [http://dx.doi.org/10.1111/j.1471-4159.2004.02743.x] [PMID:  15485484]

[94]
Amr, A.E. Synthesis of some heterocyclic compounds as potential antimicrobial agents using 2,6-diacetylpyridine as synthon, n. Indian J. Heterocycl. Chem.,  2000, 10, 49-56.

[95]
Abdalla, M.M.; Al-Omar, M.A.; Al-Salahi, R.A.; Amr, A.G.E.; Sabrye, N.M. A new investigation for some steroidal derivatives as anti-Alzheimer agents. Int. J. Biol. Macromol.,  2012, 51(1-2), 56-63.
 [http://dx.doi.org/10.1016/j.ijbiomac.2012.04.012] [PMID:  22542854]

[96]
Tipton, K.F. Enzymology of monoamine oxidase. Cell Biochem. Funct.,  1986, 4(2), 79-87.
 [http://dx.doi.org/10.1002/cbf.290040202] [PMID:  3518979]

[97]
Youdim, M.B.H.; Edmondson, D.; Tipton, K.F. The therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci.,  2006, 7(4), 295-309.
 [http://dx.doi.org/10.1038/nrn1883] [PMID:  16552415]

[98]
Kennedy, B.P.; Ziegler, M.G.; Alford, M.; Hansen, L.A.; Thal, L.J.; Masliah, E. Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer’s disease. J. Neural Transm. (Vienna),  2003, 110(7), 789-801.
 [http://dx.doi.org/10.1007/s00702-003-0828-6] [PMID:  12811639]

[99]
Narayan, P.; Ehsani, S.; Lindquist, S. Erratum: Combating neurodegenerative disease with chemical probes and model systems. Nat. Chem. Biol.,  2015, 11(2), 172.
 [http://dx.doi.org/10.1038/nchembio0215-172c]

[100]
Youdim, M.B.H.; Bakhle, Y.S. Monoamine oxidase: Isoforms and inhibitors in Parkinson’s disease and depressive illness. Br. J. Pharmacol.,  2006, 147(S1)(Suppl. 1), S287-S296.
 [http://dx.doi.org/10.1038/sj.bjp.0706464] [PMID:  16402116]

[101]
Trippier, P.C.; Jansen Labby, K.; Hawker, D.D.; Mataka, J.J.; Silverman, R.B. Target- and mechanism-based therapeutics for neurodegenerative diseases: Strength in numbers. J. Med. Chem.,  2013, 56(8), 3121-3147.
 [http://dx.doi.org/10.1021/jm3015926] [PMID:  23458846]

[102]
Hare, M.L. Tyramine oxidase: A new enzyme system in liver. Biochem. J.,  1928, 22(4), 968-979.
 [http://dx.doi.org/10.1042/bj0220968] [PMID:  16744124]

[103]
Manzoor, S.; Hoda, N. A comprehensive review of monoamine oxidase inhibitors as anti-Alzheimer’s disease agents: A review. Eur. J. Med. Chem.,  2020, 206112787
 [http://dx.doi.org/10.1016/j.ejmech.2020.112787] [PMID:  32942081]

[104]
Rauhamaki, P.A.; Postila, S.; Niinivehmas, S.; Kortet, E.; Schildt, M.P.; Manivannan, E.M. Ahinko, P.; Koskimies, N.; Nyberg, P. H.; E.Multamaki, M.; Pasanen, R.O.; Juvonen, H.; Raunio, J. H.; Pentikainen, O. T Structure-activity relationship analysis of 3- Phenylcoumarin-based monoamine oxidase B inhibitors. Front Chem.,  2018, 6(March), 1-18.

[105]
Yang, J.; Zhang, P.; Hu, Y.; Liu, T.; Sun, J.; Wang, X. Synthesis and biological evaluation of 3-arylcoumarins as potential anti-Alzheimer’s disease agents. J. Enzyme Inhib. Med. Chem.,  2019, 34(1), 651-656.
 [http://dx.doi.org/10.1080/14756366.2019.1574297] [PMID:  30746966]

[106]
Zhang, C.; Yang, K.; Yu, S.; Su, J.; Yuan, S.; Han, J.; Chen, Y.; Gu, J.; Zhou, T.; Bai, R.; Xie, Y. Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer’s disease. Eur. J. Med. Chem.,  2019, 180, 367-382.
 [http://dx.doi.org/10.1016/j.ejmech.2019.07.031] [PMID:  31325784]

[107]
Munda, P. State of the art: Alzheimer’s disease. Mt. Sinai Sch. Med.,  2015, 2, 28-32.

[108]
Stewart, W.F.; Kawas, C.; Corrada, M.; Metter, E.J. Risk of Alzheimer’s disease and duration of NSAID use. Neurology,  1997, 48(3), 626-632.
 [http://dx.doi.org/10.1212/WNL.48.3.626] [PMID:  9065537]

[109]
Henderson, V.W.; Paganini-Hill, A.; Miller, B.L.; Elble, R.J.; Reyes, P.F.; Shoupe, D.; McCleary, C.A.; Klein, R.A.; Hake, A.M.; Farlow, M.R. Estrogen for Alzheimer’s disease in women: Randomized, double-blind, placebo-controlled trial. Neurology,  2000, 54(2), 295-301.
 [http://dx.doi.org/10.1212/WNL.54.2.295] [PMID:  10668686]

[110]
Schmidt, R.; Fazekas, F.; Reinhart, B.; Kapeller, P.; Fazekas, G.; Offenbacher, H.; Eber, B.; Schumacher, M.; Freidl, W. Estrogen replacement therapy in older women: A neuropsychological and brain MRI study. J. Am. Geriatr. Soc.,  1996, 44(11), 1307-1313.
Rights & Permissions Print Cite
Article Metrics
44
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1573406418666220815101124	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638
Medicinal Chemistry

Structural Scaffolds as Anti- Alzheimer Agents

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles
