Progress in Target Drug Molecules for Alzheimer's Disease

Jiayang       Xie; Ruirui       Liang; Yajiang       Wang; Junyi       Huang; Xin       Cao; Bing       Niu
Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disease that 4 widespread in the elderly. The etiology of AD is complicated, and its pathogenesis is still unclear. Although there are many researches on anti-AD drugs, they are limited to reverse relief symptoms and cannot treat diseases. Therefore, the development of high-efficiency anti-AD drugs with no side effects has become an urgent need. Based on the published literature, this paper summarizes the main targets of AD and their drugs, and focuses on the research and development progress of these drugs in recent years.
Keywords: Amyloid beta (Aβ), Acetylcholinesterase (AChE), Amyloid-beta binding alcohol dehydrogenase (ABAD), Butyrylcholinesterase (BChE), B-site APP cleaving enzyme 1 (BACE1), Cyclin-dependent kinase-5 (CDK-5), Glycogen synthase kinase-3β (GSK-3β), Monoamine oxidase (MAO), Tau protein.
« Previous Next »
Graphical Abstract

[1] 
Jack, C.R., Jr; Knopman, D.S.; Jagust, W.J.; Shaw, L.M.; Aisen, P.S.; Weiner, M.W.; Petersen, R.C.; Trojanowski, J.Q. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol.,  2010, 9(1), 119-128.
[http://dx.doi.org/10.1016/S1474-4422(09)70299-6] [PMID:  20083042] 
[2] 
Hardy, J.A.; Higgins, G.A. Alzheimer’s disease: the amyloid cascade hypothesis. Science,  1992, 256(5054), 184-185.
[http://dx.doi.org/10.1126/science.1566067] [PMID:  1566067] 
[3] 
Mohamed, T.; Shakeri, A.; Rao, P.P. Amyloid cascade in Alzheimer’s disease: Recent advances in medicinal chemistry. Eur. J. Med. Chem.,  2016, 113, 258-272.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.049] [PMID:  26945113] 
[4] 
Scheff, S.W.; Price, D.A.; Schmitt, F.A.; DeKosky, S.T.; Mufson, E.J. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology,  2007, 68(18), 1501-1508.
[http://dx.doi.org/10.1212/01.wnl.0000260698.46517.8f] [PMID:  17470753] 
[5] 
Rosenberg, P.B.; Nowrangi, M.A.; Lyketsos, C.G. Neuropsychiatric symptoms in Alzheimer’s disease: What might be associated brain circuits? Mol. Aspects Med.,  2015, 43-44, 25-37.
[http://dx.doi.org/10.1016/j.mam.2015.05.005] [PMID:  26049034] 
[6] 
Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature,  2006, 443(7113), 787-795.
[http://dx.doi.org/10.1038/nature05292] [PMID:  17051205] 
[7] 
Arvanitakis, Z.; Wilson, R.S.; Bienias, J.L.; Evans, D.A.; Bennett, D.A. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch. Neurol.,  2004, 61(5), 661-666.
[http://dx.doi.org/10.1001/archneur.61.5.661] [PMID:  15148141] 
[8] 
Glynn-Servedio, B.E.; Ranola, T.S. AChE inhibitors and NMDA receptor antagonists in advanced Alzheimer’s Disease. Consult Pharm.,  2017, 32(9), 511-518.
[http://dx.doi.org/10.4140/TCP.n.2017.511] [PMID:  28855009] 
[9] 
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] 
[10] 
Nepovimova, E.; Korabecny, J.; Dolezal, R.; Babkova, K.; Ondrejicek, A.; Jun, D.; Sepsova, V.; Horova, A.; Hrabinova, M.; Soukup, O.; Bukum, N.; Jost, P.; Muckova, L.; Kassa, J.; Malinak, D.; Andrs, M.; Kuca, K. Tacrine-trolox hybrids: A novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity. J. Med. Chem.,  2015, 58(22), 8985-9003.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01325] [PMID:  26503905] 
[11] 
Ambure, P.; Bhat, J.; Puzyn, T.; Roy, K. Identifying natural compounds as multi-target-directed ligands against Alzheimer’s disease: an in silico approach. J. Biomol. Struct. Dyn.,  2019, 37(5), 1282-1306.
[http://dx.doi.org/10.1080/07391102.2018.1456975] [PMID:  29578387] 
[12] 
Carreiras, M.C.; Mendes, E.; Perry, M.J.; Francisco, A.P.; Marco-Contelles, J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr. Top. Med. Chem.,  2013, 13(15), 1745-1770.
[http://dx.doi.org/10.2174/15680266113139990135] [PMID:  23931435] 
[13] 
Unzeta, M.; Esteban, G.; Bolea, I.; Fogel, W.A.; Ramsay, R.R.; Youdim, M.B.; Tipton, K.F. Marco-contelles, j. multi-target directed donepezil-like ligands for alzheimer’s disease. Front. Neurosci.,  2016, 10, 205.
[http://dx.doi.org/10.3389/fnins.2016.00205] [PMID:  27252617] 
[14] 
Dias, K.S.; Viegas, C. Jr Multi-Target Directed Drugs: A modern approach for design of new drugs for the treatment of alzheimer’s disease. Curr. Neuropharmacol.,  2014, 12(3), 239-255.
[http://dx.doi.org/10.2174/1570159X1203140511153200] [PMID:  24851088] 
[15] 
Agis-Torres, A.; Sölhuber, M.; Fernandez, M.; Sanchez-Montero, J.M. Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for alzheimer’s disease. Curr. Neuropharmacol.,  2014, 12(1), 2-36.
[http://dx.doi.org/10.2174/1570159X113116660047] [PMID:  24533013] 
[16] 
Jones, M.R.; Mathieu, E.; Dyrager, C.; Faissner, S.; Vaillancourt, Z.; Korshavn, K.J.; Lim, M.H.; Ramamoorthy, A.; Wee Yong, V.; Tsutsui, S.; Stys, P.K.; Storr, T. Multi-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer’s disease. Chem. Sci. (Camb.),  2017, 8(8), 5636-5643.
[http://dx.doi.org/10.1039/C7SC01269A] [PMID:  28989601] 
[17] 
Fronza, M.G.; Baldinotti, R.; Martins, M.C.; Goldani, B.; Dalberto, B.T.; Kremer, F.S.; Begnini, K.; Pinto, L.D.S.; Lenardão, E.J.; Seixas, F.K.; Collares, T.; Alves, D.; Savegnago, L. Rational design, cognition and neuropathology evaluation of QTC-4-MeOBnE in a streptozotocin-induced mouse model of sporadic Alzheimer’s disease. Sci. Rep.,  2019, 9(1), 7276.
[http://dx.doi.org/10.1038/s41598-019-43532-9] [PMID:  31086208] 
[18] 
Guzior, N.; Wieckowska, A.; Panek, D.; Malawska, B. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer’s disease. Curr. Med. Chem.,  2015, 22(3), 373-404.
[http://dx.doi.org/10.2174/0929867321666141106122628] [PMID:  25386820] 
[19] 
Jalili-Baleh, L.; Babaei, E.; Abdpour, S.; Nasir Abbas Bukhari, S.; Foroumadi, A.; Ramazani, A.; Sharifzadeh, M.; Abdollahi, M.; Khoobi, M. A review on flavonoid-based scaffolds as multi-target-directed ligands (MTDLs) for Alzheimer’s disease. Eur. J. Med. Chem.,  2018, 152, 570-589.
[http://dx.doi.org/10.1016/j.ejmech.2018.05.004] [PMID:  29763806] 
[20] 
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] 
[21] 
Marešová, P.; Mohelská, H.; Dolejš, J.; Kuča, K. Socio-economic aspects of Alzheimer’s disease. Curr. Alzheimer Res.,  2015, 12(9), 903-911.
[http://dx.doi.org/10.2174/156720501209151019111448] [PMID:  26510983] 
[22] 
Cimler, R.; Maresova, P.; Kuhnova, J.; Kuca, K. Predictions of Alzheimer’s disease treatment and care costs in European countries. PLoS One,  2019, 14(1)e0210958
[http://dx.doi.org/10.1371/journal.pone.0210958] [PMID:  30682120] 
[23] 
Sharma, P.; Tripathi, A.; Tripathi, P.N.; Singh, S.S.; Singh, S.P.; Shrivastava, S.K. Novel molecular hybrids of n-benzylpiperidine and 1,3,4-oxadiazole as multitargeted therapeutics to treat alzheimer’s disease. ACS Chem. Neurosci.,  2019, 10(10), 4361-4384.
[http://dx.doi.org/10.1021/acschemneuro.9b00430] [PMID:  31491074] 
[24] 
Blokland, A. Acetylcholine: a neurotransmitter for learning and memory? Brain Res. Brain Res. Rev.,  1995, 21(3), 285-300.
[http://dx.doi.org/10.1016/0165-0173(95)00016-X] [PMID:  8806017] 
[25] 
Lane, R.M.; Potkin, S.G.; Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol.,  2006, 9(1), 101-124.
[http://dx.doi.org/10.1017/S1461145705005833] [PMID:  16083515] 
[26] 
Thompson, P.A.; Wright, D.E.; Counsell, C.E.; Zajicek, J. Statistical analysis, trial design and duration in Alzheimer’s disease clinical trials: a review. Int. Psychogeriatr.,  2012, 24(5), 689-697.
[http://dx.doi.org/10.1017/S1041610211001116] [PMID:  21910950] 
[27] 
Perry, E.K. The cholinergic hypothesis--ten years on. Br. Med. Bull.,  1986, 42(1), 63-69.
[http://dx.doi.org/10.1093/oxfordjournals.bmb.a072100] [PMID:  3513895] 
[28] 
Yankner, B.A. Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron,  1996, 16(5), 921-932.
[http://dx.doi.org/10.1016/S0896-6273(00)80115-4] [PMID:  8630250] 
[29] 
Terry, A.V., Jr; Buccafusco, J.J. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther.,  2003, 306(3), 821-827.
[http://dx.doi.org/10.1124/jpet.102.041616] [PMID:  12805474] 
[30] 
Drachman, D.A.; Leavitt, J. Human memory and the cholinergic system. A relationship to aging? Arch. Neurol.,  1974, 30(2), 113-121.
[http://dx.doi.org/10.1001/archneur.1974.00490320001001] [PMID:  4359364] 
[31] 
Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Farlow, M.R.; Giacobini, E.; Grossberg, G.T.; Khachaturian, A.S.; Vergallo, A.; Cavedo, E.; Snyder, P.J.; Khachaturian, Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain,  2018, 141(7), 1917-1933.
[http://dx.doi.org/10.1093/brain/awy132] [PMID:  29850777] 
[32] 
Winslow, B.T.; Onysko, M.K.; Stob, C.M.; Hazlewood, K.A. Treatment of alzheimer disease. Am. Fam. Physician,  2011, 83(12), 1403-1412.
[PMID:  21671540] 
[33] 
Holzgrabe, U.; Kapková, P.; Alptüzün, V.; Scheiber, J.; Kugelmann, E. Targeting acetylcholinesterase to treat neurodegeneration. Expert Opin. Ther. Targets,  2007, 11(2), 161-179.
[http://dx.doi.org/10.1517/14728222.11.2.161] [PMID:  17227232] 
[34] 
Darvesh, S. Butyrylcholinesterase as a diagnostic and therapeutic target for alzheimer’s disease. Curr. Alzheimer Res.,  2016, 13(10), 1173-1177.
[http://dx.doi.org/10.2174/1567205013666160404120542] [PMID:  27040140] 
[35] 
Goldkind, L.; Laine, L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol. Drug Saf.,  2006, 15(4), 213-220.
[http://dx.doi.org/10.1002/pds.1207] [PMID:  16456879] 
[36] 
Soukup, O.; Jun, D.; Zdarova-Karasova, J.; Patocka, J.; Musilek, K.; Korabecny, J.; Krusek, J.; Kaniakova, M.; Sepsova, V.; Mandikova, J.; Trejtnar, F.; Pohanka, M.; Drtinova, L.; Pavlik, M.; Tobin, G.; Kuca, K. A resurrection of 7-MEOTA: a comparison with tacrine. Curr. Alzheimer Res.,  2013, 10(8), 893-906.
[http://dx.doi.org/10.2174/1567205011310080011] [PMID:  24093535] 
[37] 
Khoobi, M.; Ghanoni, F.; Nadri, H.; Moradi, A.; Pirali Hamedani, M.; Homayouni Moghadam, F.; Emami, S.; Vosooghi, M.; Zadmard, R.; Foroumadi, A.; Shafiee, A. New tetracyclic tacrine analogs containing pyrano[2,3-c]pyrazole: efficient synthesis, biological assessment and docking simulation study. Eur. J. Med. Chem.,  2015, 89, 296-303.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.049] [PMID:  25462245] 
[38] 
da Costa, J.S.; Lopes, J.P.; Russowsky, D.; Petzhold, C.L.; Borges, A.C.; Ceschi, M.A.; Konrath, E.; Batassini, C.; Lunardi, P.S.; Gonçalves, C.A. Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors. Eur. J. Med. Chem.,  2013, 62, 556-563.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.029] [PMID:  23422935] 
[39] 
Rodríguez-Franco, M.I.; Fernández-Bachiller, M.I.; Pérez, C.; Hernández-Ledesma, B.; Bartolomé, B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem.,  2006, 49(2), 459-462.
[http://dx.doi.org/10.1021/jm050746d] [PMID:  16420031] 
[40] 
García-Font, N.; Hayour, H.; Belfaitah, A.; Pedraz, J.; Moraleda, I.; Iriepa, I.; Bouraiou, A.; Chioua, M.; Marco-Contelles, J.; Oset-Gasque, M.J. Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer’s disease. Eur. J. Med. Chem.,  2016, 118, 178-192.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.023] [PMID:  27128182] 
[41] 
Hariri, R. Novel Tacrine-Based Pyrano[3 ',4 ':5,6]pyrano[2,3-b]quinolinones: Synthesis and cholinesterase inhibitory activity. Arch. Pharm. (Weinheim),  2016, 349(12), 915-924.
[http://dx.doi.org/10.1002/ardp.201600123] [PMID:  27910192] 
[42] 
Jann, M.W. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy,  2000, 20(1), 1-12.
[http://dx.doi.org/10.1592/phco.20.1.1.34664] [PMID:  10641971] 
[43] 
Ferris, C.F.; Kulkarni, P.; Yee, J.R.; Nedelman, M.; de Jong, I.E.M. The serotonin receptor 6 antagonist idalopirdine and acetylcholinesterase inhibitor donepezil have synergistic effects on brain activity-A functional MRI study in the awake Rat. Front. Pharmacol.,  2017, 8, 279.
[http://dx.doi.org/10.3389/fphar.2017.00279] [PMID:  28659792] 
[44] 
Heinrich, M. Galanthamine from Galanthus and other Amaryllidaceae–chemistry and biology based on traditional use.The Alkaloids: Chemistry and Biology; Elsevier, 2010, pp. 157-165.
[45] 
Castillo, W.O.; Aristizabal-Pachon, A.F. Galantamine protects against beta amyloid peptide-induced DNA damage in a model for Alzheimer’s disease. Neural Regen. Res.,  2017, 12(6), 916-917.
[http://dx.doi.org/10.4103/1673-5374.208572] [PMID:  28761423] 
[46] 
Stavrakov, G.; Philipova, I.; Zheleva-Dimitrova, D.; Valkova, I.; Salamanova, E.; Konstantinov, S.; Doytchinova, I. Docking-based design and synthesis of galantamine-camphane hybrids as inhibitors of acetylcholinesterase. Chem. Biol. Drug Des.,  2017, 90(5), 709-718.
[http://dx.doi.org/10.1111/cbdd.12991] [PMID:  28374576] 
[47] 
Mei, Z.; Zheng, P.; Tan, X.; Wang, Y.; Situ, B. Huperzine A alleviates neuroinflammation, oxidative stress and improves cognitive function after repetitive traumatic brain injury. Metab. Brain Dis.,  2017, 32(6), 1861-1869.
[http://dx.doi.org/10.1007/s11011-017-0075-4] [PMID:  28748496] 
[48] 
García, M.V.; Poser, G.L.V.; Apel, M.; Tlatilpa, R.C.; Mendoza-Ruiz, A.; Villarreal, M.L.; Henriques, A.T.; Taketa, A.C. Anticholinesterase activity and identification of huperzine A in three mexican lycopods: huperzia cuernavacensis, huperzia dichotoma and huperzia linifolia (Lycopodiaceae). Pak. J. Pharm. Sci.,  2017, 30(1)(Suppl.), 235-239.
[PMID:  28625948] 
[49] 
Zhang, H.; Guo, Y.; Meng, L.; Sun, H.; Yang, Y.; Gao, Y.; Sun, J. Rapid screening and characterization of acetylcholinesterase inhibitors from Yinhuang oral liquid using ultrafiltration-liquid chromatography-electrospray ionization tandem mass spectrometry. Pharmacogn. Mag.,  2018, 14(54), 248-252.
[http://dx.doi.org/10.4103/pm.pm_166_17] [PMID:  29720840] 
[50] 
Afshari, A.R.; Sadeghnia, H.R.; Mollazadeh, H. A Review on potential mechanisms of terminalia chebula in alzheimer’s disease. Adv. Pharmacol. Sci., 2016.2016, 8964849. 
[http://dx.doi.org/10.1155/2016/8964849] [PMID:  26941792] 
[51] 
Hajimehdipoor, H. Evaluating the antioxidant and acetylcholinesterase inhibitory activities of some plants from Kohgiluyeh va Boyerahmad province, Iran. RJP,  2016, 3(4), 1-7.
[52] 
Zhao, H.; Zhou, S.; Zhang, M.; Feng, J.; Wang, S.; Wang, D.; Geng, Y.; Wang, X. An in vitro AChE inhibition assay combined with UF-HPLC-ESI-Q-TOF/MS approach for screening and characterizing of AChE inhibitors from roots of Coptis chinensis Franch. J. Pharm. Biomed. Anal.,  2016, 120, 235-240.
[http://dx.doi.org/10.1016/j.jpba.2015.12.025] [PMID:  26760241] 
[53] 
Niu, B.; Zhang, M.; Du, P.; Jiang, L.; Qin, R.; Su, Q.; Chen, F.; Du, D.; Shu, Y.; Chou, K.C. Small molecular floribundiquinone B derived from medicinal plants inhibits acetylcholinesterase activity. Oncotarget,  2017, 8(34), 57149-57162.
[http://dx.doi.org/10.18632/oncotarget.19169] [PMID:  28915661] 
[54] 
Yang, Y.; Liang, X.; Jin, P.; Li, N.; Zhang, Q.; Yan, W.; Zhang, H.; Sun, J. Screening and determination for potential acetylcholinesterase inhibitory constituents from ginseng stem-leaf saponins using ultrafiltration (UF)-LC-ESI-MS2. Phytochem. Anal.,  2019, 30(1), 26-33.
[http://dx.doi.org/10.1002/pca.2787] [PMID:  30159954] 
[55] 
Kamarozaman, A.S. New dihydrostilbenes from Macaranga heynei IM Johnson, biological activities and structure-activity relationship. Phytochem. Lett.,  2019, 30, 174-180.
[http://dx.doi.org/10.1016/j.phytol.2019.02.002] 
[56] 
Chen, H.W.; He, X.H.; Yuan, R.; Wei, B.J.; Chen, Z.; Dong, J.X.; Wang, J. Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo. Fitoterapia,  2016, 110, 142-149.
[http://dx.doi.org/10.1016/j.fitote.2016.03.011] [PMID:  26976216] 
[57] 
Hiremathad, A. Tacrine-allyl/propargylcysteine-benzothiazole tri-hybrids as potential anti-Alzheimer’s drug candidates. RSC Advances,  2016, 6(58), 53519-53532.
[http://dx.doi.org/10.1039/C6RA03455A] 
[58] 
Barbosa, F.A.R.; Canto, R.F.S.; Saba, S.; Rafique, J.; Braga, A.L. Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer’s disease. Bioorg. Med. Chem.,  2016, 24(22), 5762-5770.
[http://dx.doi.org/10.1016/j.bmc.2016.09.031] [PMID:  27681239] 
[59] 
Dos Santos, T.C.; Gomes, T.M.; Pinto, B.A.S.; Camara, A.L.; Paes, A.M.A. Naturally occurring acetylcholinesterase inhibitors and their potential use for alzheimer’s disease therapy. Front. Pharmacol.,  2018, 9, 1192.
[http://dx.doi.org/10.3389/fphar.2018.01192] [PMID:  30405413] 
[60] 
Touj, N. Synthesis, spectroscopic properties and biological activity of new Cu(I) N-Heterocyclic carbene complexes. J. Mol. Struct.,  2019, 1181, 209-219.
[http://dx.doi.org/10.1016/j.molstruc.2018.12.093] 
[61] 
Buendia, I.; Parada, E.; Navarro, E.; León, R.; Negredo, P.; Egea, J.; López, M.G. Subthreshold concentrations of melatonin and galantamine improves pathological AD-hallmarks in hippocampal organotypic cultures. Mol. Neurobiol.,  2016, 53(5), 3338-3348.
[http://dx.doi.org/10.1007/s12035-015-9272-5] [PMID:  26081146] 
[62] 
Herrik, K.F.; Mørk, A.; Richard, N.; Bundgaard, C.; Bastlund, J.F.; de Jong, I.E.M. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus. Neuropharmacology,  2016, 107, 351-363.
[http://dx.doi.org/10.1016/j.neuropharm.2016.03.043] [PMID:  27039041] 
[63] 
Zhang, J.; Zhang, L.; Sun, X.; Yang, Y.; Kong, L.; Lu, C.; Lv, G.; Wang, T.; Wang, H.; Fu, F. Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation. J. Pharmacol. Exp. Ther.,  2016, 359(2), 374-382.
[http://dx.doi.org/10.1124/jpet.116.233841] [PMID:  27535978] 
[64] 
Gareri, P.; Castagna, A.; Cotroneo, A.M.; Putignano, D.; Conforti, R.; Santamaria, F.; Marino, S.; Putignano, S. The citicholinage study: citicoline plus cholinesterase inhibitors in aged patients affected with alzheimer’s disease study. J. Alzheimers Dis.,  2017, 56(2), 557-565.
[http://dx.doi.org/10.3233/JAD-160808] [PMID:  28035929] 
[65] 
Nicolet, Y.; Lockridge, O.; Masson, P.; Fontecilla-Camps, J.C.; Nachon, F. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J. Biol. Chem.,  2003, 278(42), 41141-41147.
[http://dx.doi.org/10.1074/jbc.M210241200] [PMID:  12869558] 
[66] 
Jing, L.; Wu, G.; Kang, D.; Zhou, Z.; Song, Y.; Liu, X.; Zhan, P. Contemporary medicinal-chemistry strategies for the discovery of selective butyrylcholinesterase inhibitors. Drug Discov. Today,  2019, 24(2), 629-635.
[http://dx.doi.org/10.1016/j.drudis.2018.11.012] [PMID:  30503804] 
[67] 
Carolan, C.G.; Dillon, G.P.; Gaynor, J.M.; Reidy, S.; Ryder, S.A.; Khan, D.; Marquez, J.F.; Gilmer, J.F. Isosorbide-2-carbamate esters: potent and selective butyrylcholinesterase inhibitors. J. Med. Chem.,  2008, 51(20), 6400-6409.
[http://dx.doi.org/10.1021/jm800564y] [PMID:  18817366] 
[68] 
Jones, M.; Wang, J.; Harmon, S.; Kling, B.; Heilmann, J.; Gilmer, J.F. Novel selective butyrylcholinesterase inhibitors incorporating antioxidant functionalities as potential bimodal therapeutics for Alzheimer’s disease. Molecules,  2016, 21(4), 440.
[http://dx.doi.org/10.3390/molecules21040440] [PMID:  27534722] 
[69] 
Sawatzky, E.; Wehle, S.; Kling, B.; Wendrich, J.; Bringmann, G.; Sotriffer, C.A.; Heilmann, J.; Decker, M. Discovery of highly selective and nanomolar carbamate-based butyrylcholinesterase inhibitors by rational investigation into their inhibition mode. J. Med. Chem.,  2016, 59(5), 2067-2082.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01674] [PMID:  26886849] 
[70] 
Greig, N.H.; Utsuki, T.; Ingram, D.K.; Wang, Y.; Pepeu, G.; Scali, C.; Yu, Q.S.; Mamczarz, J.; Holloway, H.W.; Giordano, T.; Chen, D.; Furukawa, K.; Sambamurti, K.; Brossi, A.; Lahiri, D.K. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc. Natl. Acad. Sci. USA,  2005, 102(47), 17213-17218.
[http://dx.doi.org/10.1073/pnas.0508575102] [PMID:  16275899] 
[71] 
Watkins, P.B.; Zimmerman, H.J.; Knapp, M.J.; Gracon, S.I.; Lewis, K.W. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA,  1994, 271(13), 992-998.
[http://dx.doi.org/10.1001/jama.1994.03510370044030] [PMID:  8139084] 
[72] 
Cheng, Z-Q.; Zhu, K.K.; Zhang, J.; Song, J.L.; Muehlmann, L.A.; Jiang, C.S.; Liu, C.L.; Zhang, H. Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors. Bioorg. Chem.,  2019, 83, 277-288.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.057] [PMID:  30391700] 
[73] 
Wu, G.; Gao, Y.; Kang, D.; Huang, B.; Huo, Z.; Liu, H.; Poongavanam, V.; Zhan, P.; Liu, X. Design, synthesis and biological evaluation of tacrine-1,2,3-triazole derivatives as potent cholinesterase inhibitors. MedChemComm,  2017, 9(1), 149-159.
[http://dx.doi.org/10.1039/C7MD00457E] [PMID:  30108908] 
[74] 
Cheng, Z-Q.; Song, J.L.; Zhu, K.; Zhang, J.; Jiang, C.S.; Zhang, H. Total synthesis of pulmonarin B and design of brominated phenylacetic acid/tacrine hybrids: marine pharmacophore inspired discovery of new ChE and Aβ aggregation Inhibitors. Mar. Drugs,  2018, 16(9), 293.
[http://dx.doi.org/10.3390/md16090293] [PMID:  30134630] 
[75] 
Lee, S.; Youn, K.; Lim, G.; Lee, J.; Jun, M. In silico docking and in vitro approaches towards bace1 and cholinesterases inhibitory effect of citrus flavanones. Molecules,  2018, 23(7), 1509.
[http://dx.doi.org/10.3390/molecules23071509] [PMID:  29932100] 
[76] 
Choi, Y-H. (‒)-Pteroside N and pterosinone, new BACE1 and cholinesterase inhibitors from Pteridium aquilinum. Phytochem. Lett.,  2018, 27, 63-68.
[http://dx.doi.org/10.1016/j.phytol.2018.06.021] 
[77] 
Koirala, P.; Seong, S.H.; Jung, H.A.; Choi, J.S. Comparative evaluation of the antioxidant and anti-alzheimer’s disease potential of coumestrol and puerarol isolated from pueraria lobata using molecular modeling studies. Molecules,  2018, 23(4), 785.
[http://dx.doi.org/10.3390/molecules23040785] [PMID:  29597336] 
[78] 
Ali Reza, A.S.M.; Hossain, M.S.; Akhter, S.; Rahman, M.R.; Nasrin, M.S.; Uddin, M.J.; Sadik, G.; Khurshid Alam, A.H.M. In vitro antioxidant and cholinesterase inhibitory activities of Elatostema papillosum leaves and correlation with their phytochemical profiles: a study relevant to the treatment of Alzheimer’s disease. BMC Complement. Altern. Med.,  2018, 18(1), 123.
[http://dx.doi.org/10.1186/s12906-018-2182-0] [PMID:  29622019] 
[79] 
Li, Q. Cholinesterase, β-amyloid aggregation inhibitory and antioxidant capacities of Chinese medicinal plants. Ind. Crops Prod.,  2017, 108, 512-519.
[http://dx.doi.org/10.1016/j.indcrop.2017.07.001] 
[80] 
Orhan, I.E.; Senol, F.S.; Shekfeh, S.; Skalicka-Wozniak, K.; Banoglu, E. Pteryxin - A promising butyrylcholinesterase-inhibiting coumarin derivative from Mutellina purpurea. Food Chem. Toxicol.,  2017, 109(Pt 2), 970-974.
[http://dx.doi.org/10.1016/j.fct.2017.03.016] [PMID:  28286309] 
[81] 
Lee, Y.K.; Bang, H.J.; Oh, J.B.; Whang, W.K. Bioassay-guided isolated compounds from Morinda officinalis inhibit Alzheimer’s disease pathologies. Molecules,  2017, 22(10), 1638.
[http://dx.doi.org/10.3390/molecules22101638] [PMID:  28961196] 
[82] 
Chethana, K.R.; Senol, F.S.; Orhan, I.E.; Anilakumar, K.R.; Keri, R.S. Cassia tora Linn.: A boon to Alzheimer’s disease for its anti-amyloidogenic and cholinergic activities. Phytomedicine,  2017, 33, 43-52.
[http://dx.doi.org/10.1016/j.phymed.2017.06.002] [PMID:  28887919] 
[83] 
Budryn, G.; Grzelczyk, J.; Jaśkiewicz, A.; Żyżelewicz, D.; Pérez-Sánchez, H.; Cerón-Carrasco, J.P. Evaluation of butyrylcholinesterase inhibitory activity by chlorogenic acids and coffee extracts assed in ITC and docking simulation models. Food Res. Int.,  2018, 109, 268-277.
[http://dx.doi.org/10.1016/j.foodres.2018.04.041] [PMID:  29803450] 
[84] 
Jiang, Y.; Gao, H. Pharmacophore-based drug design for the identification of novel butyrylcholinesterase inhibitors against Alzheimer’s disease. Phytomedicine,  2019, 54, 278-290.
[http://dx.doi.org/10.1016/j.phymed.2018.09.199] [PMID:  30668379] 
[85] 
Makhaeva, G.F.; Boltneva, N.P.; Lushchekina, S.V.; Rudakova, E.V.; Serebryakova, O.G.; Kulikova, L.N.; Beloglazkin, A.A.; Borisov, R.S.; Richardson, R.J. Synthesis, molecular docking, and biological activity of 2-vinyl chromones: Toward selective butyrylcholinesterase inhibitors for potential Alzheimer’s disease therapeutics. Bioorg. Med. Chem.,  2018, 26(16), 4716-4725.
[http://dx.doi.org/10.1016/j.bmc.2018.08.010] [PMID:  30104121] 
[86] 
Kumar, R.S.; Almansour, A.I.; Arumugam, N.; Al-Thamili, D.M.; Basiri, A.; Kotresha, D.; Manohar, T.S.; Venketesh, S.; Asad, M.; Asiri, A.M. Highly functionalized 2-amino-4H-pyrans as potent cholinesterase inhibitors. Bioorg. Chem.,  2018, 81, 134-143.
[http://dx.doi.org/10.1016/j.bioorg.2018.08.009] [PMID:  30121001] 
[87] 
Kumar, A.; Pintus, F.; Di Petrillo, A.; Medda, R.; Caria, P.; Matos, M.J.; Viña, D.; Pieroni, E.; Delogu, F.; Era, B.; Delogu, G.L.; Fais, A. Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer’s disease. Sci. Rep.,  2018, 8(1), 4424.
[http://dx.doi.org/10.1038/s41598-018-22747-2] [PMID:  29535344] 
[88] 
Iqbal, K.; Liu, F.; Gong, C.X.; Grundke-Iqbal, I. Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res.,  2010, 7(8), 656-664.
[http://dx.doi.org/10.2174/156720510793611592] [PMID:  20678074] 
[89] 
Khatoon, S.; Grundke-Iqbal, I.; Iqbal, K. Guanosine triphosphate binding to β-subunit of tubulin in Alzheimer’s disease brain: role of microtubule-associated protein τ. J. Neurochem.,  1995, 64(2), 777-787.
[http://dx.doi.org/10.1046/j.1471-4159.1995.64020777.x] [PMID:  7830071] 
[90] 
Noble, W.; Olm, V.; Takata, K.; Casey, E.; Mary, O.; Meyerson, J.; Gaynor, K.; LaFrancois, J.; Wang, L.; Kondo, T.; Davies, P.; Burns, M. Veeranna; Nixon, R.; Dickson, D.; Matsuoka, Y.; Ahlijanian, M.; Lau, L.F.; Duff, K. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron,  2003, 38(4), 555-565.
[http://dx.doi.org/10.1016/S0896-6273(03)00259-9] [PMID:  12765608] 
[91] 
Hernández, F.; Gómez de Barreda, E.; Fuster-Matanzo, A.; Lucas, J.J.; Avila, J. GSK3: a possible link between beta amyloid peptide and tau protein. Exp. Neurol.,  2010, 223(2), 322-325.
[http://dx.doi.org/10.1016/j.expneurol.2009.09.011] [PMID:  19782073] 
[92] 
Flaherty, D.B.; Soria, J.P.; Tomasiewicz, H.G.; Wood, J.G. Phosphorylation of human tau protein by microtubule-associated kinases: GSK3beta and cdk5 are key participants. J. Neurosci. Res.,  2000, 62(3), 463-472.
[http://dx.doi.org/10.1002/1097-4547(20001101)62:3<463:AID-JNR16>3.0.CO;2-7] [PMID:  11054815] 
[93] 
Grill, J.D.; Cummings, J.L. Novel targets for Alzheimer’s disease treatment. Expert Rev. Neurother.,  2010, 10(5), 711.
[http://dx.doi.org/10.1586/ern.10.29] [PMID:  20420492] 
[94] 
Kontsekova, E.; Zilka, N.; Kovacech, B.; Novak, P.; Novak, M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res. Ther.,  2014, 6(4), 44.
[http://dx.doi.org/10.1186/alzrt278] [PMID:  25478017] 
[95] 
Chai, X.; Wu, S.; Murray, T.K.; Kinley, R.; Cella, C.V.; Sims, H.; Buckner, N.; Hanmer, J.; Davies, P.; O’Neill, M.J.; Hutton, M.L.; Citron, M. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J. Biol. Chem.,  2011, 286(39), 34457-34467.
[http://dx.doi.org/10.1074/jbc.M111.229633] [PMID:  21841002] 
[96] 
Pedersen, J.T.; Sigurdsson, E.M. Tau immunotherapy for Alzheimer’s disease. Trends Mol. Med.,  2015, 21(6), 394-402.
[http://dx.doi.org/10.1016/j.molmed.2015.03.003] [PMID:  25846560] 
[97] 
Boutajangout, A.; Ingadottir, J.; Davies, P.; Sigurdsson, E.M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem.,  2011, 118(4), 658-667.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07337.x] [PMID:  21644996] 
[98] 
Yanamandra, K.; Jiang, H.; Mahan, T.E.; Maloney, S.E.; Wozniak, D.F.; Diamond, M.I.; Holtzman, D.M. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann. Clin. Transl. Neurol.,  2015, 2(3), 278-288.
[http://dx.doi.org/10.1002/acn3.176] [PMID:  25815354] 
[99] 
Yanamandra, K.; Kfoury, N.; Jiang, H.; Mahan, T.E.; Ma, S.; Maloney, S.E.; Wozniak, D.F.; Diamond, M.I.; Holtzman, D.M. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron,  2013, 80(2), 402-414.
[http://dx.doi.org/10.1016/j.neuron.2013.07.046] [PMID:  24075978] 
[100] 
d’Abramo, C.; Acker, C.M.; Jimenez, H.T.; Davies, P. Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. PLoS One,  2013, 8(4)e62402
[http://dx.doi.org/10.1371/journal.pone.0062402] [PMID:  23638068] 
[101] 
Agadjanyan, M.G.; Zagorski, K.; Petrushina, I.; Davtyan, H.; Kazarian, K.; Antonenko, M.; Davis, J.; Bon, C.; Blurton-Jones, M.; Cribbs, D.H.; Ghochikyan, A. Humanized monoclonal antibody armanezumab specific to N-terminus of pathological tau: characterization and therapeutic potency. Mol. Neurodegener.,  2017, 12(1), 33.
[http://dx.doi.org/10.1186/s13024-017-0172-1] [PMID:  28472993] 
[102] 
Dai, C.L.; Chen, X.; Kazim, S.F.; Liu, F.; Gong, C.X.; Grundke-Iqbal, I.; Iqbal, K. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J. Neural Transm. (Vienna),  2015, 122(4), 607-617.
[http://dx.doi.org/10.1007/s00702-014-1315-y] [PMID:  25233799] 
[103] 
Walls, K.C.; Ager, R.R.; Vasilevko, V.; Cheng, D.; Medeiros, R.; LaFerla, F.M. p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice. Neurosci. Lett.,  2014, 575, 96-100.
[http://dx.doi.org/10.1016/j.neulet.2014.05.047] [PMID:  24887583] 
[104] 
Ittner, A.; Bertz, J.; Suh, L.S.; Stevens, C.H.; Götz, J.; Ittner, L.M. Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. J. Neurochem.,  2015, 132(1), 135-145.
[http://dx.doi.org/10.1111/jnc.12821] [PMID:  25041093] 
[105] 
Kontsekova, E.; Zilka, N.; Kovacech, B.; Skrabana, R.; Novak, M. Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res. Ther.,  2014, 6(4), 45.
[http://dx.doi.org/10.1186/alzrt277] [PMID:  25478018] 
[106] 
Sankaranarayanan, S.; Barten, D.M.; Vana, L.; Devidze, N.; Yang, L.; Cadelina, G.; Hoque, N.; DeCarr, L.; Keenan, S.; Lin, A.; Cao, Y.; Snyder, B.; Zhang, B.; Nitla, M.; Hirschfeld, G.; Barrezueta, N.; Polson, C.; Wes, P.; Rangan, V.S.; Cacace, A.; Albright, C.F.; Meredith, J., Jr; Trojanowski, J.Q.; Lee, V.M.; Brunden, K.R.; Ahlijanian, M. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS One,  2015, 10(5)e0125614
[http://dx.doi.org/10.1371/journal.pone.0125614] [PMID:  25933020] 
[107] 
Theunis, C.; Adolfsson, O.; Crespo-Biel, N.; Piorkowska, K.; Pihlgren, M.; Hickman, D.T.; Gafner, V.; Borghgraef, P.; Devijver, H.; Pfeifer, A.; Van Leuven, F.; Muhs, A. Novel Phospho-tau monoclonal antibody generated using a liposomal vaccine, with enhanced recognition of a conformational Tauopathy epitope. J. Alzheimers Dis.,  2017, 56(2), 585-599.
[http://dx.doi.org/10.3233/JAD-160695] [PMID:  28035925] 
[108] 
Bright, J.; Hussain, S.; Dang, V.; Wright, S.; Cooper, B.; Byun, T.; Ramos, C.; Singh, A.; Parry, G.; Stagliano, N.; Griswold-Prenner, I. Human secreted tau increases amyloid-beta production. Neurobiol. Aging,  2015, 36(2), 693-709.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.007] [PMID:  25442111] 
[109] 
Congdon, E.E.; Sigurdsson, E.M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol.,  2018, 14(7), 399-415.
[http://dx.doi.org/10.1038/s41582-018-0013-z] [PMID:  29895964] 
[110] 
Jadhav, S.; Avila, J.; Schöll, M.; Kovacs, G.G.; Kövari, E.; Skrabana, R.; Evans, L.D.; Kontsekova, E.; Malawska, B.; de Silva, R.; Buee, L.; Zilka, N. A walk through tau therapeutic strategies. Acta Neuropathol. Commun.,  2019, 7(1), 22.
[http://dx.doi.org/10.1186/s40478-019-0664-z] [PMID:  30767766] 
[111] 
Gu, H. Advances in the development of antibody-based immunotherapy against prion disease. Antib. Technol. J.,,  2014, 45
[http://dx.doi.org/10.2147/ANTI.S53336] 
[112] 
Serrano-Pozo, A.; William, C.M.; Ferrer, I.; Uro-Coste, E.; Delisle, M.B.; Maurage, C.A.; Hock, C.; Nitsch, R.M.; Masliah, E.; Growdon, J.H.; Frosch, M.P.; Hyman, B.T. Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology. Brain,  2010, 133(Pt 5), 1312-1327.
[http://dx.doi.org/10.1093/brain/awq056] [PMID:  20360050] 
[113] 
Winblad, B.; Graf, A.; Riviere, M.E.; Andreasen, N.; Ryan, J.M. Active immunotherapy options for Alzheimer’s disease. Alzheimers Res. Ther.,  2014, 6(1), 7.
[http://dx.doi.org/10.1186/alzrt237] [PMID:  24476230] 
[114] 
Novak, P.; Schmidt, R.; Kontsekova, E.; Zilka, N.; Kovacech, B.; Skrabana, R.; Vince-Kazmerova, Z.; Katina, S.; Fialova, L.; Prcina, M.; Parrak, V.; Dal-Bianco, P.; Brunner, M.; Staffen, W.; Rainer, M.; Ondrus, M.; Ropele, S.; Smisek, M.; Sivak, R.; Winblad, B.; Novak, M. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol.,  2017, 16(2), 123-134.
[http://dx.doi.org/10.1016/S1474-4422(16)30331-3] [PMID:  27955995] 
[115] 
Avila, J.; Wandosell, F.; Hernández, F. Role of glycogen synthase kinase-3 in Alzheimer’s disease pathogenesis and glycogen synthase kinase-3 inhibitors. Expert Rev. Neurother.,  2010, 10(5), 703-710.
[http://dx.doi.org/10.1586/ern.10.40] [PMID:  20420491] 
[116] 
Cai, Z.; Zhao, Y.; Zhao, B. Roles of glycogen synthase kinase 3 in Alzheimer’s disease. Curr. Alzheimer Res.,  2012, 9(7), 864-879.
[http://dx.doi.org/10.2174/156720512802455386] [PMID:  22272620] 
[117] 
Bhat, R.; Xue, Y.; Berg, S.; Hellberg, S.; Ormö, M.; Nilsson, Y.; Radesäter, A.C.; Jerning, E.; Markgren, P.O.; Borgegård, T.; Nylöf, M.; Giménez-Cassina, A.; Hernández, F.; Lucas, J.J.; Díaz-Nido, J.; Avila, J. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J. Biol. Chem.,  2003, 278(46), 45937-45945.
[http://dx.doi.org/10.1074/jbc.M306268200] [PMID:  12928438] 
[118] 
del Ser, T.; Steinwachs, K.C.; Gertz, H.J.; Andrés, M.V.; Gómez-Carrillo, B.; Medina, M.; Vericat, J.A.; Redondo, P.; Fleet, D.; León, T. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J. Alzheimers Dis.,  2013, 33(1), 205-215.
[http://dx.doi.org/10.3233/JAD-2012-120805] [PMID:  22936007] 
[119] 
Liang, Z.; Li, Q.X. Discovery of selective, substrate-competitive, and passive membrane permeable glycogen synthase kinase-3β Inhibitors: synthesis, biological evaluation, and molecular modeling of new C-glycosylflavones. ACS Chem. Neurosci.,  2018, 9(5), 1166-1183.
[http://dx.doi.org/10.1021/acschemneuro.8b00010] [PMID:  29381861] 
[120] 
Kim, K.; Cha, J.S.; Kim, J.S.; Ahn, J.; Ha, N.C.; Cho, H.S. Crystal structure of GSK3β in complex with the flavonoid, morin. Biochem. Biophys. Res. Commun.,  2018, 504(2), 519-524.
[http://dx.doi.org/10.1016/j.bbrc.2018.08.182] [PMID:  30197003] 
[121] 
Sciú, M.L.; Sebastián-Pérez, V.; Martinez-Gonzalez, L.; Benitez, R.; Perez, D.I.; Pérez, C.; Campillo, N.E.; Martinez, A.; Moyano, E.L. Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3. J. Enzyme Inhib. Med. Chem.,  2019, 34(1), 87-96.
[http://dx.doi.org/10.1080/14756366.2018.1530223] [PMID:  30362380] 
[122] 
Koehler, D.; Shah, Z.A.; Williams, F.E. The GSK3β inhibitor, TDZD-8, rescues cognition in a zebrafish model of okadaic acid-induced Alzheimer’s disease. Neurochem. Int.,  2019, 122, 31-37.
[http://dx.doi.org/10.1016/j.neuint.2018.10.022] [PMID:  30392874] 
[123] 
Huang, H.J.; Chen, S.L.; Huang, H.Y.; Sun, Y.C.; Lee, G.C.; Lee-Chen, G.J.; Hsieh-Li, H.M.; Su, M.T. Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice. Psychopharmacology (Berl.),  2019, 236(2), 763-773.
[http://dx.doi.org/10.1007/s00213-018-5108-0] [PMID:  30426182] 
[124] 
Hu, X-L.; Guo, C.; Hou, J.Q.; Feng, J.H.; Zhang, X.Q.; Xiong, F.; Ye, W.C.; Wang, H. Stereoisomers of schisandrin B are potent ATP competitive GSK-3β inhibitors with neuroprotective effects against alzheimer’s disease: stereochemistry and biological activity. ACS Chem. Neurosci.,  2019, 10(2), 996-1007.
[http://dx.doi.org/10.1021/acschemneuro.8b00252] [PMID:  29944335] 
[125] 
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.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00610] [PMID:  30078314] 
[126] 
Hu, J.; Yang, Y.; Wang, M.; Yao, Y.; Chang, Y.; He, Q.; Ma, R.; Li, G. Complement C3a receptor antagonist attenuates tau hyperphosphorylation via glycogen synthase kinase 3β signaling pathways. Eur. J. Pharmacol.,  2019, 850, 135-140.
[http://dx.doi.org/10.1016/j.ejphar.2019.02.020] [PMID:  30771350] 
[127] 
Mishiba, T.; Tanaka, M.; Mita, N.; He, X.; Sasamoto, K.; Itohara, S.; Ohshima, T. Cdk5/p35 functions as a crucial regulator of spatial learning and memory. Mol. Brain,  2014, 7, 82.
[http://dx.doi.org/10.1186/s13041-014-0082-x] [PMID:  25404232] 
[128] 
Dhavan, R.; Tsai, L.H. A decade of CDK5. Nat. Rev. Mol. Cell Biol.,  2001, 2(10), 749-759.
[http://dx.doi.org/10.1038/35096019] [PMID:  11584302] 
[129] 
Hassen, G.W. Calpain Inhibition: A potential therapeutic target for neurodegenerative and neuromuscular disorders. Front. CNS Drug Discov.,  2017, 3, 33-71.
[http://dx.doi.org/10.2174/9781681084435117030004] 
[130] 
Tsai, L-H.; Lee, M-S.; Cruz, J. Cdk5, a therapeutic target for alzheimer’s disease? biochimica et biophysica acta (BBA)-. Proteins and Proteomics,  2004, 1697(1-2), 137-142.
[http://dx.doi.org/10.1016/j.bbapap.2003.11.019] 
[131] 
Shupp, A.; Casimiro, M.C.; Pestell, R.G. Biological functions of cdk5 and potential cdk5 targeted clinical treatments. Oncotarget,  2017, 8(10), 17373-17382.
[http://dx.doi.org/10.18632/oncotarget.14538] [PMID:  28077789] 
[132] 
Martin, L.; Latypova, X.; Wilson, C.M.; Magnaudeix, A.; Perrin, M.L.; Yardin, C.; Terro, F. Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res. Rev.,  2013, 12(1), 289-309.
[http://dx.doi.org/10.1016/j.arr.2012.06.003] [PMID:  22742992] 
[133] 
He, Y.; Pan, S.; Xu, M.; He, R.; Huang, W.; Song, P.; Huang, J.; Zhang, H.T.; Hu, Y. Adeno-associated virus 9-mediated Cdk5 inhibitory peptide reverses pathologic changes and behavioral deficits in the Alzheimer’s disease mouse model. FASEB J.,  2017, 31(8), 3383-3392.
[http://dx.doi.org/10.1096/fj.201700064R] [PMID:  28420695] 
[134] 
Shukla, V.; Seo, J.; Binukumar, B.K.; Amin, N.D.; Reddy, P.; Grant, P.; Kuntz, S.; Kesavapany, S.; Steiner, J.; Mishra, S.K.; Tsai, L.H.; Pant, H.C. TFP5, a peptide inhibitor of aberrant and hyperactive cdk5/p25, attenuates pathological phenotypes and restores synaptic function in ck-p25Tg Mice. J. Alzheimers Dis.,  2017, 56(1), 335-349.
[http://dx.doi.org/10.3233/JAD-160916] [PMID:  28085018] 
[135] 
Coman, H.; Nemes, B. New therapeutic targets in alzheimer’s disease. Int. J. Gerontol.,  2017, 11(1), 2-6.
[http://dx.doi.org/10.1016/j.ijge.2016.07.003] 
[136] 
Yu, Y.; Zhang, L.; Li, X.; Run, X.; Liang, Z.; Li, Y.; Liu, Y.; Lee, M.H.; Grundke-Iqbal, I.; Iqbal, K.; Vocadlo, D.J.; Liu, F.; Gong, C.X. Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation. PLoS One,  2012, 7(4)e35277
[http://dx.doi.org/10.1371/journal.pone.0035277] [PMID:  22536363] 
[137] 
Pevet, I.; Brulé, C.; Tizot, A.; Gohier, A.; Cruzalegui, F.; Boutin, J.A.; Goldstein, S. Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors. Bioorg. Med. Chem.,  2011, 19(8), 2517-2528.
[http://dx.doi.org/10.1016/j.bmc.2011.03.021] [PMID:  21459579] 
[138] 
Giacomini, C.; Koo, C.Y.; Yankova, N.; Tavares, I.A.; Wray, S.; Noble, W.; Hanger, D.P.; Morris, J.D.H. A new TAO kinase inhibitor reduces tau phosphorylation at sites associated with neurodegeneration in human tauopathies. Acta Neuropathol. Commun.,  2018, 6(1), 37.
[http://dx.doi.org/10.1186/s40478-018-0539-8] [PMID:  29730992] 
[139] 
Wischik, C.M.; Edwards, P.C.; Lai, R.Y.; Roth, M.; Harrington, C.R. Selective inhibition of alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl. Acad. Sci. USA,  1996, 93(20), 11213-11218.
[http://dx.doi.org/10.1073/pnas.93.20.11213] [PMID:  8855335] 
[140] 
Wang, F.; Chen, D.; Wu, P.; Klein, C.; Jin, C. Formaldehyde, epigenetics, and alzheimer’s disease. Chem. Res. Toxicol.,  2019, 32(5), 820-830.
[PMID:  30964647] 
[141] 
Crowe, A.; Huang, W.; Ballatore, C.; Johnson, R.L.; Hogan, A.M.; Huang, R.; Wichterman, J.; McCoy, J.; Huryn, D.; Auld, D.S.; Smith, A.B., III; Inglese, J.; Trojanowski, J.Q.; Austin, C.P.; Brunden, K.R.; Lee, V.M. Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry,  2009, 48(32), 7732-7745.
[http://dx.doi.org/10.1021/bi9006435] [PMID:  19580328] 
[142] 
Frenkel-Pinter, M.; Tal, S.; Scherzer-Attali, R.; Abu-Hussien, M.; Alyagor, I.; Eisenbaum, T.; Gazit, E.; Segal, D. Cl-NQTrp alleviates tauopathy symptoms in a model organism through the inhibition of tau aggregation-engendered toxicity. Neurodegener. Dis.,  2017, 17(2-3), 73-82.
[http://dx.doi.org/10.1159/000448518] [PMID:  27760426] 
[143] 
Silva, T.; Mohamed, T.; Shakeri, A.; Rao, P.P.N.; Soares da Silva, P.; Remião, F.; Borges, F. Repurposing nitrocatechols: 5-Nitro-α-cyanocarboxamide derivatives of caffeic acid and caffeic acid phenethyl ester effectively inhibit aggregation of tau-derived hexapeptide AcPHF6. Eur. J. Med. Chem.,  2019, 167, 146-152.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.006] [PMID:  30771602] 
[144] 
Melnyk, P.; Vingtdeux, V.; Burlet, S.; Eddarkaoui, S.; Grosjean, M.E.; Larchanché, P.E.; Hochart, G.; Sergheraert, C.; Estrella, C.; Barrier, M.; Poix, V.; Plancq, P.; Lannoo, C.; Hamdane, M.; Delacourte, A.; Verwaerde, P.; Buée, L.; Sergeant, N. Chloroquine and chloroquinoline derivatives as models for the design of modulators of amyloid Peptide precursor metabolism. ACS Chem. Neurosci.,  2015, 6(4), 559-569.
[http://dx.doi.org/10.1021/cn5003013] [PMID:  25611616] 
[145] 
Burlet, S. Sulphate salts of N-(3-(4-(3-(diisobutylamino) propyl) piperazin-1-yl) propyl)-1H-benzo [d] imidazol-2-amine, preparation thereof and use of the same. E.P. 2938597A1 2017.
[146] 
Okuda, M.; Hijikuro, I.; Fujita, Y.; Wu, X.; Nakayama, S.; Sakata, Y.; Noguchi, Y.; Ogo, M.; Akasofu, S.; Ito, Y.; Soeda, Y.; Tsuchiya, N.; Tanaka, N.; Takahashi, T.; Sugimoto, H. PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo. PLoS One,  2015, 10(2)e0117511
[http://dx.doi.org/10.1371/journal.pone.0117511] [PMID:  25659102] 
[147] 
Lv, P.; Xia, C.L.; Wang, N.; Liu, Z.Q.; Huang, Z.S.; Huang, S.L. Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation. Bioorg. Med. Chem.,  2018, 26(16), 4693-4705.
[http://dx.doi.org/10.1016/j.bmc.2018.08.007] [PMID:  30107970] 
[148] 
Madav, Y.; Wairkar, S.; Prabhakar, B. Recent therapeutic strategies targeting beta amyloid and tauopathies in Alzheimer’s disease. Brain Res. Bull.,  2019, 146, 171-184.
[http://dx.doi.org/10.1016/j.brainresbull.2019.01.004] [PMID:  30634016] 
[149] 
Matsuoka, Y.; Jouroukhin, Y.; Gray, A.J.; Ma, L.; Hirata-Fukae, C.; Li, H.F.; Feng, L.; Lecanu, L.; Walker, B.R.; Planel, E.; Arancio, O.; Gozes, I.; Aisen, P.S. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer’s disease. J. Pharmacol. Exp. Ther.,  2008, 325(1), 146-153.
[http://dx.doi.org/10.1124/jpet.107.130526] [PMID:  18199809] 
[150] 
Barten, D.M.; Fanara, P.; Andorfer, C.; Hoque, N.; Wong, P.Y.; Husted, K.H.; Cadelina, G.W.; Decarr, L.B.; Yang, L.; Liu, V.; Fessler, C.; Protassio, J.; Riff, T.; Turner, H.; Janus, C.G.; Sankaranarayanan, S.; Polson, C.; Meredith, J.E.; Gray, G.; Hanna, A.; Olson, R.E.; Kim, S.H.; Vite, G.D.; Lee, F.Y.; Albright, C.F. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J. Neurosci.,  2012, 32(21), 7137-7145.
[http://dx.doi.org/10.1523/JNEUROSCI.0188-12.2012] [PMID:  22623658] 
[151] 
Zheng, H.; Koo, E.H. Biology and pathophysiology of the amyloid precursor protein. Mol. Neurodegener.,  2011, 6(1), 27.
[http://dx.doi.org/10.1186/1750-1326-6-27] [PMID:  21527012] 
[152] 
Michael, S. Wolfe, D.M.B., Daniel R. Montagna, Matthew Seghers, Dennis J. Selkoe, The amyloid-b generating tri-peptide cleavage mechanism of gamma-secretase: implications for alzheimer’s disease. Alzheimers Dement.,  2016, 12(7), P1041.
[http://dx.doi.org/10.1016/j.jalz.2016.06.2161] 
[153] 
Lin, X.; Koelsch, G.; Wu, S.; Downs, D.; Dashti, A.; Tang, J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc. Natl. Acad. Sci. USA,  2000, 97(4), 1456-1460.
[http://dx.doi.org/10.1073/pnas.97.4.1456] [PMID:  10677483] 
[154] 
Pasternak, S.H.; Callahan, J.W.; Mahuran, D.J. The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer’s disease: reexamining the spatial paradox from a lysosomal perspective. J. Alzheimers Dis.,  2004, 6(1), 53-65.
[http://dx.doi.org/10.3233/JAD-2004-6107] [PMID:  15004328] 
[155] 
Sannerud, R.; Esselens, C.; Ejsmont, P.; Mattera, R.; Rochin, L.; Tharkeshwar, A.K.; De Baets, G.; De Wever, V.; Habets, R.; Baert, V.; Vermeire, W.; Michiels, C.; Groot, A.J.; Wouters, R.; Dillen, K.; Vints, K.; Baatsen, P.; Munck, S.; Derua, R.; Waelkens, E.; Basi, G.S.; Mercken, M.; Vooijs, M.; Bollen, M.; Schymkowitz, J.; Rousseau, F.; Bonifacino, J.S.; Van Niel, G.; De Strooper, B.; Annaert, W. Restricted location of PSEN2/γ-secretase determines substrate specificity and generates an intracellular Aβ pool. Cell,  2016, 166(1), 193-208.
[http://dx.doi.org/10.1016/j.cell.2016.05.020] [PMID:  27293189] 
[156] 
Oppong, S.Y.; Hooper, N.M. Characterization of a secretase activity which releases angiotensin-converting enzyme from the membrane. Biochem. J.,  1993, 292(Pt 2), 597-603.
[http://dx.doi.org/10.1042/bj2920597] [PMID:  8389141] 
[157] 
Morgan, C.; Colombres, M.; Nuñez, M.T.; Inestrosa, N.C. Structure and function of amyloid in alzheimer’s disease. Prog. Neurobiol.,  2004, 74(6), 323-349.
[http://dx.doi.org/10.1016/j.pneurobio.2004.10.004] [PMID:  15649580] 
[158] 
Sharma, P.; Srivastava, P.; Seth, A.; Tripathi, P.N.; Banerjee, A.G.; Shrivastava, S.K. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog. Neurobiol.,  2019, 174, 53-89.
[http://dx.doi.org/10.1016/j.pneurobio.2018.12.006] [PMID:  30599179] 
[159] 
Finneran, D.J.; Nash, K.R. Neuroinflammation and fractalkine signaling in alzheimer’s disease. J. Neuroinflammation,  2019, 16(1), 30.
[http://dx.doi.org/10.1186/s12974-019-1412-9] [PMID:  30744705] 
[160] 
Sommer, B. Alzheimer’s disease and the amyloid cascade hypothesis: ten years on. Curr. Opin. Pharmacol.,  2002, 2(1), 87-92.
[http://dx.doi.org/10.1016/S1471-4892(01)00126-6] [PMID:  11786314] 
[161] 
Streit, W.J.; Mrak, R.E.; Griffin, W.S. Microglia and neuroinflammation: a pathological perspective. J. Neuroinflammation,  2004, 1(1), 14.
[http://dx.doi.org/10.1186/1742-2094-1-14] [PMID:  15285801] 
[162] 
Sierra-Fonseca, J.A.; Gosselink, K.L. Tauopathy and neurodegeneration: A role for stress. Neurobiol. Stress,  2018, 9, 105-112.
[http://dx.doi.org/10.1016/j.ynstr.2018.08.009] [PMID:  30450376] 
[163] 
Das, U.; Wang, L.; Ganguly, A.; Saikia, J.M.; Wagner, S.L.; Koo, E.H.; Roy, S. Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nat. Neurosci.,  2016, 19(1), 55-64.
[http://dx.doi.org/10.1038/nn.4188] [PMID:  26642089] 
[164] 
Vassar, R.; Bennett, B.D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E.A.; Denis, P.; Teplow, D.B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M.A.; Biere, A.L.; Curran, E.; Burgess, T.; Louis, J.C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science,  1999, 286(5440), 735-741.
[http://dx.doi.org/10.1126/science.286.5440.735] [PMID:  10531052] 
[165] 
Yan, R.; Vassar, R. Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol.,  2014, 13(3), 319-329.
[http://dx.doi.org/10.1016/S1474-4422(13)70276-X] [PMID:  24556009] 
[166] 
Sinha, S.; Anderson, J.P.; Barbour, R.; Basi, G.S.; Caccavello, R.; Davis, D.; Doan, M.; Dovey, H.F.; Frigon, N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.; Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, G.; Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S.M.; Wang, S.; Walker, D.; Zhao, J.; McConlogue, L.; John, V. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature,  1999, 402(6761), 537-540.
[http://dx.doi.org/10.1038/990114] [PMID:  10591214] 
[167] 
Hong, L.; Turner, R.T., III; Koelsch, G.; Shin, D.; Ghosh, A.K.; Tang, J. Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3. Biochemistry,  2002, 41(36), 10963-10967.
[http://dx.doi.org/10.1021/bi026232n] [PMID:  12206667] 
[168] 
Shuto, D.; Kasai, S.; Kimura, T.; Liu, P.; Hidaka, K.; Hamada, T.; Shibakawa, S.; Hayashi, Y.; Hattori, C.; Szabo, B.; Ishiura, S.; Kiso, Y. KMI-008, a novel beta-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: design and synthesis of substrate-based octapeptides. Bioorg. Med. Chem. Lett.,  2003, 13(24), 4273-4276.
[http://dx.doi.org/10.1016/j.bmcl.2003.09.053] [PMID:  14643307] 
[169] 
Zuo, Z.; Luo, X.; Zhu, W.; Shen, J.; Shen, X.; Jiang, H.; Chen, K. Molecular docking and 3D-QSAR studies on the binding mechanism of statine-based peptidomimetics with beta-secretase. Bioorg. Med. Chem.,  2005, 13(6), 2121-2131.
[http://dx.doi.org/10.1016/j.bmc.2005.01.002] [PMID:  15727865] 
[170] 
Menting, K.W.; Claassen, J.A.H.R. β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front. Aging Neurosci.,  2014, 6, 165.
[http://dx.doi.org/10.3389/fnagi.2014.00165] [PMID:  25100992] 
[171] 
Ben Halima, S.; Mishra, S.; Raja, K.M.P.; Willem, M.; Baici, A.; Simons, K.; Brüstle, O.; Koch, P.; Haass, C.; Caflisch, A.; Rajendran, L. Specific inhibition of β-secretase processing of the alzheimer disease amyloid precursor protein. Cell Rep.,  2016, 14(9), 2127-2141.
[http://dx.doi.org/10.1016/j.celrep.2016.01.076] [PMID:  26923602] 
[172] 
Hitt, B.; Riordan, S.M.; Kukreja, L.; Eimer, W.A.; Rajapaksha, T.W.; Vassar, R. β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J. Biol. Chem.,  2012, 287(46), 38408-38425.
[http://dx.doi.org/10.1074/jbc.M112.415505] [PMID:  22988240] 
[173] 
Coimbra, J.R.M.; Marques, D.F.F.; Baptista, S.J.; Pereira, C.M.F.; Moreira, P.I.; Dinis, T.C.P.; Santos, A.E.; Salvador, J.A.R. Highlights in BACE1 inhibitors for alzheimer’s disease treatment. Front Chem.,  2018, 6, 178.
[http://dx.doi.org/10.3389/fchem.2018.00178] [PMID:  29881722] 
[174] 
Oehlrich, D.; Prokopcova, H.; Gijsen, H.J.M. The evolution of amidine-based brain penetrant BACE1 inhibitors. Bioorg. Med. Chem. Lett.,  2014, 24(9), 2033-2045.
[http://dx.doi.org/10.1016/j.bmcl.2014.03.025] [PMID:  24704031] 
[175] 
Yan, R. Stepping closer to treating alzheimer’s disease patients with BACE1 inhibitor drugs. Transl. Neurodegener.,  2016, 5, 13.
[http://dx.doi.org/10.1186/s40035-016-0061-5] [PMID:  27418961] 
[176] 
Mullard, A. BACE inhibitor bust in Alzheimer trial. Nat. Rev. Drug Discov.,  2017, 16(3), 155.
[PMID:  28248932] 
[177] 
Merck, S. merck announces discontinuation of APECS study evaluating verubecestat (MK-8931) for the treatment of people with prodromal alzheimer's disease. 2018.
[178] 
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.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01917] [PMID:  26978477] 
[179] 
Egbertson, M.; McGaughey, G.B.; Pitzenberger, S.M.; Stauffer, S.R.; Coburn, C.A.; Stachel, S.J.; Yang, W.; Barrow, J.C.; Neilson, L.A.; McWherter, M.; Perlow, D.; Fahr, B.; Munshi, S.; Allison, T.J.; Holloway, K.; Selnick, H.G.; Yang, Z.; Swestock, J.; Simon, A.J.; Sankaranarayanan, S.; Colussi, D.; Tugusheva, K.; Lai, M.T.; Pietrak, B.; Haugabook, S.; Jin, L.; Chen, I.W.; Holahan, M.; Stranieri-Michener, M.; Cook, J.J.; Vacca, J.; Graham, S.L. Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency. Bioorg. Med. Chem. Lett.,  2015, 25(21), 4812-4819.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.082] [PMID:  26195137] 
[180] 
Mandal, M.; Wu, Y.; Misiaszek, J.; Li, G.; Buevich, A.; Caldwell, J.P.; Liu, X.; Mazzola, R.D.; Orth, P.; Strickland, C.; Voigt, J.; Wang, H.; Zhu, Z.; Chen, X.; Grzelak, M.; Hyde, L.A.; Kuvelkar, R.; Leach, P.T.; Terracina, G.; Zhang, L.; Zhang, Q.; Michener, M.S.; Smith, B.; Cox, K.; Grotz, D.; Favreau, L.; Mitra, K.; Kazakevich, I.; McKittrick, B.A.; Greenlee, W.; Kennedy, M.E.; Parker, E.M.; Cumming, J.N.; Stamford, A.W. Structure-based design of an iminoheterocyclic β-site amyloid precursor protein cleaving Enzyme (BACE) inhibitor that lowers central Aβ in nonhuman primates. J. Med. Chem.,  2016, 59(7), 3231-3248.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01995] [PMID:  26937601] 
[181] 
Scott, J.D. Discovery of the 3-imino-1, 2, 4-thiadiazinane 1, 1-dioxide derivative verubecestat (MK-8931)–A β-site amyloid precursor protein cleaving enzyme 1 inhibitor for the treatment of Alzheimer’s disease. J. Med. Chem.,  59(23), 10435-10450.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00307] 
[182] 
Eketjäll, S.; Janson, J.; Kaspersson, K.; Bogstedt, A.; Jeppsson, F.; Fälting, J.; Haeberlein, S.B.; Kugler, A.R.; Alexander, R.C.; Cebers, G. AZD3293: A novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J. Alzheimers Dis.,  2016, 50(4), 1109-1123.
[http://dx.doi.org/10.3233/JAD-150834] [PMID:  26890753] 
[183] 
Butler, C.R.; Ogilvie, K.; Martinez-Alsina, L.; Barreiro, G.; Beck, E.M.; Nolan, C.E.; Atchison, K.; Benvenuti, E.; Buzon, L.; Doran, S.; Gonzales, C.; Helal, C.J.; Hou, X.; Hsu, M.H.; Johnson, E.F.; Lapham, K.; Lanyon, L.; Parris, K.; O’Neill, B.T.; Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M.A. Aminomethyl-derived beta secretase (BACE1) inhibitors: engaging Gly230 without an anilide functionality. J. Med. Chem.,  2017, 60(1), 386-402.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01451] [PMID:  27997172] 
[184] 
Yazdani, M.; Edraki, N.; Badri, R.; Khoshneviszadeh, M.; Iraji, A.; Firuzi, O. Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design, synthesis and biological evaluation. Bioorg. Chem.,  2019, 84, 363-371.
[http://dx.doi.org/10.1016/j.bioorg.2018.11.038] [PMID:  30530107] 
[185] 
Bhaskar, V.; Chowdary, R.; Dixit, S.R.; Joshi, S.D. Synthesis, molecular modeling and BACE-1 inhibitory study of tetrahydrobenzo[b] pyran derivatives. Bioorg. Chem.,  2019, 84, 202-210.
[http://dx.doi.org/10.1016/j.bioorg.2018.11.023] [PMID:  30502632] 
[186] 
Rastegari, A.; Nadri, H.; Mahdavi, M.; Moradi, A.; Mirfazli, S.S.; Edraki, N.; Moghadam, F.H.; Larijani, B.; Akbarzadeh, T.; Saeedi, M. Design, synthesis and anti-alzheimer’s activity of novel 1,2,3-triazole-chromenone carboxamide derivatives. Bioorg. Chem.,  2019, 83, 391-401.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.065] [PMID:  30412794] 
[187] 
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.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.008] [PMID:  30771601] 
[188] 
Zhang, X.; Yu, Y.; Sun, P.; Fan, Z.; Zhang, W.; Feng, C. Royal jelly peptides: potential inhibitors of β-secretase in N2a/APP695swe cells. Sci. Rep.,  2019, 9(1), 168.
[http://dx.doi.org/10.1038/s41598-018-35801-w] [PMID:  30655564] 
[189] 
Youn, K.; Jun, M. Biological evaluation and docking analysis of potent BACE1 inhibitors from Boesenbergia rotunda. Nutrients,  2019, 11(3)E662
[http://dx.doi.org/10.3390/nu11030662] [PMID:  30893825] 
[190] 
Zhu, B.L.; Long, Y.; Luo, W.; Yan, Z.; Lai, Y.J.; Zhao, L.G.; Zhou, W.H.; Wang, Y.J.; Shen, L.L.; Liu, L.; Deng, X.J.; Wang, X.F.; Sun, F.; Chen, G.J. MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation. Brain,  2019, 142(1), 176-192.
[http://dx.doi.org/10.1093/brain/awy305] [PMID:  30596903] 
[191] 
Kissinger, C.R.; Rejto, P.A.; Pelletier, L.A.; Thomson, J.A.; Showalter, R.E.; Abreo, M.A.; Agree, C.S.; Margosiak, S.; Meng, J.J.; Aust, R.M.; Vanderpool, D.; Li, B.; Tempczyk-Russell, A.; Villafranca, J.E. Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer’s disease therapeutics. J. Mol. Biol.,  2004, 342(3), 943-952.
[http://dx.doi.org/10.1016/j.jmb.2004.07.071] [PMID:  15342248] 
[192] 
Lauretti, E.; Li, J.G.; Di Meco, A.; Praticò, D. Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model. Transl. Psychiatry,  2017, 7(1)e1020
[http://dx.doi.org/10.1038/tp.2016.296] [PMID:  28140402] 
[193] 
Yan, S.D.; Fu, J.; Soto, C.; Chen, X.; Zhu, H.; Al-Mohanna, F.; Collison, K.; Zhu, A.; Stern, E.; Saido, T.; Tohyama, M.; Ogawa, S.; Roher, A.; Stern, D. An intracellular protein that binds amyloid-β peptide and mediates neurotoxicity in Alzheimer’s disease. Nature,  1997, 389(6652), 689-695.
[http://dx.doi.org/10.1038/39522] [PMID:  9338779] 
[194] 
Oppermann, U.C.T.; Salim, S.; Tjernberg, L.O.; Terenius, L.; Jörnvall, H. Binding of amyloid beta-peptide to mitochondrial hydroxyacyl-CoA dehydrogenase (ERAB): regulation of an SDR enzyme activity with implications for apoptosis in Alzheimer’s disease. FEBS Lett.,  1999, 451(3), 238-242.
[http://dx.doi.org/10.1016/S0014-5793(99)00586-4] [PMID:  10371197] 
[195] 
Yan, S.D.; Shi, Y.; Zhu, A.; Fu, J.; Zhu, H.; Zhu, Y.; Gibson, L.; Stern, E.; Collison, K.; Al-Mohanna, F.; Ogawa, S.; Roher, A.; Clarke, S.G.; Stern, D.M. Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in Abeta-induced cytotoxicity. J. Biol. Chem.,  1999, 274(4), 2145-2156.
[http://dx.doi.org/10.1074/jbc.274.4.2145] [PMID:  9890977] 
[196] 
Oppermann, U.C.; Salim, S.; Tjernberg, L.O.; Terenius, L.; Jörnvall, H. Binding of amyloid β-peptide to mitochondrial hydroxyacyl-CoA dehydrogenase (ERAB): regulation of an SDR enzyme activity with implications for apoptosis in Alzheimer’s disease. FEBS Lett.,  1999, 451(3), 238-242.
[http://dx.doi.org/10.1016/S0014-5793(99)00586-4] [PMID:  10371197] 
[197] 
Lustbader, J.W.; Cirilli, M.; Lin, C.; Xu, H.W.; Takuma, K.; Wang, N.; Caspersen, C.; Chen, X.; Pollak, S.; Chaney, M.; Trinchese, F.; Liu, S.; Gunn-Moore, F.; Lue, L.F.; Walker, D.G.; Kuppusamy, P.; Zewier, Z.L.; Arancio, O.; Stern, D.; Yan, S.S.; Wu, H. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science,  2004, 304(5669), 448-452.
[http://dx.doi.org/10.1126/science.1091230] [PMID:  15087549] 
[198] 
Valaasani, K.R.; Sun, Q.; Hu, G.; Li, J.; Du, F.; Guo, Y.; Carlson, E.A.; Gan, X.; Yan, S.S. Identification of human ABAD inhibitors for rescuing Aβ-mediated mitochondrial dysfunction. Curr. Alzheimer Res.,  2014, 11(2), 128-136.
[http://dx.doi.org/10.2174/1567205011666140130150108] [PMID:  24479630] 
[199] 
Hroch, L.; Benek, O.; Guest, P.; Aitken, L.; Soukup, O.; Janockova, J.; Musil, K.; Dohnal, V.; Dolezal, R.; Kuca, K.; Smith, T.K.; Gunn-Moore, F.; Musilek, K. Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment. Bioorg. Med. Chem. Lett.,  2016, 26(15), 3675-3678.
[http://dx.doi.org/10.1016/j.bmcl.2016.05.087] [PMID:  27287370] 
[200] 
Aitken, L.; Benek, O.; McKelvie, B.E.; Hughes, R.E.; Hroch, L.; Schmidt, M.; Major, L.L.; Vinklarova, L.; Kuca, K.; Smith, T.K.; Musilek, K.; Gunn-Moore, F.J. Novel benzothiazole-based ureas as 17β-HSD10 inhibitors, a potential alzheimer’s disease treatment. Molecules,  2019, 24(15), 2757.
[http://dx.doi.org/10.3390/molecules24152757] [PMID:  31362457] 
[201] 
Hroch, L.; Guest, P.; Benek, O.; Soukup, O.; Janockova, J.; Dolezal, R.; Kuca, K.; Aitken, L.; Smith, T.K.; Gunn-Moore, F.; Zala, D.; Ramsay, R.R.; Musilek, K. Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment. Bioorg. Med. Chem.,  2017, 25(3), 1143-1152.
[http://dx.doi.org/10.1016/j.bmc.2016.12.029] [PMID:  28082069] 
[202] 
Benek, O.; Hroch, L.; Aitken, L.; Gunn-Moore, F.; Vinklarova, L.; Kuca, K.; Perez, D.I.; Perez, C.; Martinez, A.; Fisar, Z.; Musilek, K. 1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders. J. Enzyme Inhib. Med. Chem.,  2018, 33(1), 665-670.
[http://dx.doi.org/10.1080/14756366.2018.1445736] [PMID:  29536773] 
[203] 
Eisenhofer, G.; Kopin, I.J.; Goldstein, D.S. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol. Rev.,  2004, 56(3), 331-349.
[http://dx.doi.org/10.1124/pr.56.3.1] [PMID:  15317907] 
[204] 
Hauger, R.L.; Scheinin, M.; Siever, L.J.; Linnoila, M.; Potter, W.Z. Dissociation of norepinephrine turnover from alpha-2 responses after clorgiline. Clin. Pharmacol. Ther.,  1988, 43(1), 32-38.
[http://dx.doi.org/10.1038/clpt.1988.8] [PMID:  2826065] 
[205] 
Chiba, K.; Trevor, A.; Castagnoli, N., Jr Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun.,  1984, 120(2), 574-578.
[http://dx.doi.org/10.1016/0006-291X(84)91293-2] [PMID:  6428396] 
[206] 
Garrick, N.A.; Murphy, D.L. Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain. Psychopharmacology (Berl.),  1980, 72(1), 27-33.
[http://dx.doi.org/10.1007/BF00433804] [PMID:  6781004] 
[207] 
Green, A.R.; Mitchell, B.D.; Tordoff, A.F.; Youdim, M.B. Evidence for dopamine deamination by both type A and type B monoamine oxidase in rat brain in vivo and for the degree of inhibition of enzyme necessary for increased functional activity of dopamine and 5-hydroxytryptamine. Br. J. Pharmacol.,  1977, 60(3), 343-349.
[http://dx.doi.org/10.1111/j.1476-5381.1977.tb07506.x] [PMID:  890205] 
[208] 
Sherif, F.; Gottfries, C.G.; Alafuzoff, I.; Oreland, L. Brain gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO) in patients with Alzheimer’s disease. J. Neural Transm. Park. Dis. Dement. Sect.,  1992, 4(3), 227-240.
[http://dx.doi.org/10.1007/BF02260906] [PMID:  1627256] 
[209] 
Naoi, M.; Maruyama, W.; Akao, Y.; Yi, H.; Yamaoka, Y. Involvement of type A monoamine oxidase in neurodegeneration: regulation of mitochondrial signaling leading to cell death or neuroprotection. J. Neural Transm. Suppl.,  2006, (71), 67-77.
[http://dx.doi.org/10.1007/978-3-211-33328-0_8] [PMID:  17447417] 
[210] 
Cai, Z. Monoamine oxidase inhibitors: promising therapeutic agents for alzheimer’s disease (Review). Mol. Med. Rep.,  2014, 9(5), 1533-1541.
[http://dx.doi.org/10.3892/mmr.2014.2040] [PMID:  24626484] 
[211] 
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.
[http://dx.doi.org/10.1186/s13195-017-0279-1] [PMID:  28764767] 
[212] 
Jo, S.; Yarishkin, O.; Hwang, Y.J.; Chun, Y.E.; Park, M.; Woo, D.H.; Bae, J.Y.; Kim, T.; Lee, J.; Chun, H.; Park, H.J.; Lee, D.Y.; Hong, J.; Kim, H.Y.; Oh, S.J.; Park, S.J.; Lee, H.; Yoon, B.E.; Kim, Y.; Jeong, Y.; Shim, I.; Bae, Y.C.; Cho, J.; Kowall, N.W.; Ryu, H.; Hwang, E.; Kim, D.; Lee, C.J. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat. Med.,  2014, 20(8), 886-896.
[http://dx.doi.org/10.1038/nm.3639] [PMID:  24973918] 
[213] 
Riederer, P.; Youdim, M.B. Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl. J. Neurochem.,  1986, 46(5), 1359-1365.
[http://dx.doi.org/10.1111/j.1471-4159.1986.tb01747.x] [PMID:  2420928] 
[214] 
Pizzinat, N.; Copin, N.; Vindis, C.; Parini, A.; Cambon, C. Reactive oxygen species production by monoamine oxidases in intact cells. Naunyn Schmiedebergs Arch. Pharmacol.,  1999, 359(5), 428-431.
[http://dx.doi.org/10.1007/PL00005371] [PMID:  10498294] 
[215] 
Kristal, B.S.; Conway, A.D.; Brown, A.M.; Jain, J.C.; Ulluci, P.A.; Li, S.W.; Burke, W.J. Selective dopaminergic vulnerability: 3,4-dihydroxyphenylacetaldehyde targets mitochondria. Free Radic. Biol. Med.,  2001, 30(8), 924-931.
[http://dx.doi.org/10.1016/S0891-5849(01)00484-1] [PMID:  11295535] 
[216] 
Hroudová, J.; Fisar, Z.; Korábečný, J.; Kuča, K. In vitro effects of acetylcholinesterase inhibitors and reactivators on Complex I of electron transport chain. Neuroendocrinol. Lett.,  2011, 32(3), 259-263.
[PMID:  21712782] 
[217] 
Fišar, Z.; Hroudová, J.; Korábečný, J.; Musílek, K.; Kuča, K. In vitro effects of acetylcholinesterase reactivators on monoamine oxidase activity. Toxicol. Lett.,  2011, 201(2), 176-180.
[http://dx.doi.org/10.1016/j.toxlet.2010.12.023] [PMID:  21195145] 
[218] 
Amrein, R.; Martin, J.R.; Cameron, A.M. Moclobemide in patients with dementia and depression. Adv. Neurol.,  1999, 80, 509-519.
[PMID:  10410765] 
[219] 
Foley, P.; Gerlach, M.; Youdim, M.B.; Riederer, P. MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders? Parkinsonism Relat. Disord.,  2000, 6(1), 25-47.
[http://dx.doi.org/10.1016/S1353-8020(99)00043-7] [PMID:  18591148] 
[220] 
Volz, H.P.; Gleiter, C.H. Monoamine oxidase inhibitors. A perspective on their use in the elderly. Drugs Aging,  1998, 13(5), 341-355.
[http://dx.doi.org/10.2165/00002512-199813050-00002] [PMID:  9829163] 
[221] 
Bortolato, M.; Chen, K.; Shih, J.C. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv. Drug Deliv. Rev.,  2008, 60(13-14), 1527-1533.
[http://dx.doi.org/10.1016/j.addr.2008.06.002] [PMID:  18652859] 
[222] 
Weinstock, M.; Bejar, C.; Wang, R.H.; Poltyrev, T.; Gross, A.; Finberg, J.P.; Youdim, M.B. TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease. J. Neural Transm. Suppl.,  2000, (60), 157-169.
[http://dx.doi.org/10.1007/978-3-7091-6301-6_10] [PMID:  11205137] 
[223] 
Weinreb, O.; Amit, T.; Bar-Am, O.; Youdim, M.B. 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.
[http://dx.doi.org/10.2174/138945012799499794] [PMID:  22280345] 
[224] 
Tripathi, A.C.; Upadhyay, S.; Paliwal, S.; Saraf, S.K. Privileged scaffolds as MAO inhibitors: Retrospect and prospects. Eur. J. Med. Chem.,  2018, 145, 445-497.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.003] [PMID:  29335210] 
[225] 
Tavari, M.; Malan, S.F.; Joubert, J. Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors. MedChemComm,  2016, 7(8), 1628-1639.
[http://dx.doi.org/10.1039/C6MD00228E] 
[226] 
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.
[http://dx.doi.org/10.3389/fnins.2016.00294] [PMID:  27445665] 
[227] 
Liu, W.; Lang, M.; Youdim, M.B.H.; Amit, T.; Sun, Y.; Zhang, Z.; Wang, Y.; Weinreb, O. Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer’s disease. Neuropharmacology,  2016, 109, 376-385.
[http://dx.doi.org/10.1016/j.neuropharm.2016.06.013] [PMID:  27318273] 
[228] 
Xu, Y.X.; Wang, H.; Li, X.K.; Dong, S.N.; Liu, W.W.; Gong, Q.; Wang, T.D.; Tang, Y.; Zhu, J.; Li, J.; Zhang, H.Y.; Mao, F. Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur. J. Med. Chem.,  2018, 143, 33-47.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.025] [PMID:  29172081] 
[229] 
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.
[http://dx.doi.org/10.1021/acschemneuro.8b00220] [PMID:  30296051] 
[230] 
Hamulakova, S.; Kozurkova, M.; Kuca, K. Coumarin derivatives in pharmacotherapy of alzheimer’s disease. Curr. Org. Chem.,  2017, 21(7), 602-612.
[http://dx.doi.org/10.2174/1385272820666160601155411] 
[231] 
Repsold, B.P.; Malan, S.F.; Joubert, J.; Oliver, D.W. Multi-targeted directed ligands for alzheimer’s disease: design of novel lead coumarin conjugates. SAR QSAR Environ. Res.,  2018, 29(3), 231-255.
[http://dx.doi.org/10.1080/1062936X.2018.1423641] [PMID:  29390885] 
[232] 
Yang, H.L.; Cai, P.; Liu, Q.H.; Yang, X.L.; Li, F.; Wang, J.; Wu, J.J.; Wang, X.B.; Kong, L.Y. Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of alzheimer’s disease. Eur. J. Med. Chem.,  2017, 138, 715-728.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.008] [PMID:  28728104] 
[233] 
Pisani, L.; Farina, R.; Catto, M.; Iacobazzi, R.M.; Nicolotti, O.; Cellamare, S.; Mangiatordi, G.F.; Denora, N.; Soto-Otero, R.; Siragusa, L.; Altomare, C.D.; Carotti, A. Exploring basic tail modifications of coumarin-based dual acetylcholinesterase-monoamine oxidase b inhibitors: identification of water-soluble, brain-permeant neuroprotective multitarget agents. J. Med. Chem.,  2016, 59(14), 6791-6806.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00562] [PMID:  27347731] 
[234] 
He, Q.; Liu, J.; Lan, J.S.; Ding, J.; Sun, Y.; Fang, Y.; Jiang, N.; Yang, Z.; Sun, L.; Jin, Y.; Xie, S.S. Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against alzheimer’s disease: Design, synthesis and biological evaluation. Bioorg. Chem.,  2018, 81, 512-528.
[http://dx.doi.org/10.1016/j.bioorg.2018.09.010] [PMID:  30245233] 
[235] 
Hussain, G.; Zhang, L.; Rasul, A.; Anwar, H.; Sohail, M.U.; Razzaq, A.; Aziz, N.; Shabbir, A.; Ali, M.; Sun, T. Role of plant-derived flavonoids and their mechanism in attenuation of alzheimer’s and parkinson’s diseases: an update of recent data. Molecules,  2018, 23(4)E814
[http://dx.doi.org/10.3390/molecules23040814] [PMID:  29614843] 
[236] 
Wang, Y.; Sun, Y.; Guo, Y.; Wang, Z.; Huang, L.; Li, X. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. J. Enzyme Inhib. Med. Chem.,  2016, 31(3), 389-397.
[PMID:  25798687] 
[237] 
Li, Y.; Qiang, X.; Luo, L.; Yang, X.; Xiao, G.; Zheng, Y.; Cao, Z.; Sang, Z.; Su, F.; Deng, Y. Multitarget drug design strategy against Alzheimer’s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties. Bioorg. Med. Chem.,  2017, 25(2), 714-726.
[http://dx.doi.org/10.1016/j.bmc.2016.11.048] [PMID:  27923535] 
[238] 
Borroni, E.; Bohrmann, B.; Grueninger, F.; Prinssen, E.; Nave, S.; Loetscher, H.; Chinta, S.J.; Rajagopalan, S.; Rane, A.; Siddiqui, A.; Ellenbroek, B.; Messer, J.; Pähler, A.; Andersen, J.K.; Wyler, R.; Cesura, A.M. Sembragiline: A Novel, selective monoamine oxidase type B inhibitor for the treatment of alzheimer’s disease. J. Pharmacol. Exp. Ther.,  2017, 362(3), 413-423.
[http://dx.doi.org/10.1124/jpet.117.241653] [PMID:  28642233] 
[239] 
Chen, Q.H. Anti-amnesic effect of leea indica extract in scopolamine-induced amnesia of alzheimer’s type in rats. Int. J. Pharmacol.,  2019, 15(1), 116-123.
[http://dx.doi.org/10.1016/j.ijpharm.2019.01.074] 
[240] 
Park, J.H.; Ju, Y.H.; Choi, J.W.; Song, H.J.; Jang, B.K.; Woo, J.; Chun, H.; Kim, H.J.; Shin, S.J.; Yarishkin, O.; Jo, S.; Park, M.; Yeon, S.K.; Kim, S.; Kim, J.; Nam, M.H.; Londhe, A.M.; Kim, J.; Cho, S.J.; Cho, S.; Lee, C.; Hwang, S.Y.; Kim, S.W.; Oh, S.J.; Cho, J.; Pae, A.N.; Lee, C.J.; Park, K.D. Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease. Sci. Adv.,  2019, 5(3)eaav0316
[http://dx.doi.org/10.1126/sciadv.aav0316] [PMID:  30906861] 
[241] 
Zhao, Z.; Nelson, A.R.; Betsholtz, C.; Zlokovic, B.V. Establishment and dysfunction of the blood-brain barrier. Cell,  2015, 163(5), 1064-1078.
[http://dx.doi.org/10.1016/j.cell.2015.10.067] [PMID:  26590417] 
[242] 
Montagne, A.; Zhao, Z.; Zlokovic, B.V. Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J. Exp. Med.,  2017, 214(11), 3151-3169.
[http://dx.doi.org/10.1084/jem.20171406] [PMID:  29061693] 
[243] 
Bennett, R.E.; Robbins, A.B.; Hu, M.; Cao, X.; Betensky, R.A.; Clark, T.; Das, S.; Hyman, B.T. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proc. Natl. Acad. Sci. USA,  2018, 115(6), E1289-E1298.
[http://dx.doi.org/10.1073/pnas.1710329115] [PMID:  29358399] 
[244] 
Blair, L.J.; Frauen, H.D.; Zhang, B.; Nordhues, B.A.; Bijan, S.; Lin, Y.C.; Zamudio, F.; Hernandez, L.D.; Sabbagh, J.J.; Selenica, M.L.; Dickey, C.A. Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol. Commun.,  2015, 3(1), 8.
[http://dx.doi.org/10.1186/s40478-015-0186-2] [PMID:  25775028] 
[245] 
Sweeney, M.D.; Sagare, A.P.; Zlokovic, B.V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol.,  2018, 14(3), 133-150.
[http://dx.doi.org/10.1038/nrneurol.2017.188] [PMID:  29377008] 
[246] 
Pardridge, W.M. CSF, blood-brain barrier, and brain drug delivery. Expert Opin. Drug Deliv.,  2016, 13(7), 963-975.
[http://dx.doi.org/10.1517/17425247.2016.1171315] [PMID:  27020469] 
[247] 
Hendricks, B.K.; Cohen-Gadol, A.A.; Miller, J.C. Novel delivery methods bypassing the blood-brain and blood-tumor barriers. Neurosurg. Focus,  2015, 38(3)E10
[http://dx.doi.org/10.3171/2015.1.FOCUS14767] [PMID:  25727219] 
[248] 
Gill, S.S.; Patel, N.K.; Hotton, G.R.; O’Sullivan, K.; McCarter, R.; Bunnage, M.; Brooks, D.J.; Svendsen, C.N.; Heywood, P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med.,  2003, 9(5), 589-595.
[http://dx.doi.org/10.1038/nm850] [PMID:  12669033] 
[249] 
Yin, D.; Forsayeth, J.; Bankiewicz, K.S. Optimized cannula design and placement for convection-enhanced delivery in rat striatum. J. Neurosci. Methods,  2010, 187(1), 46-51.
[http://dx.doi.org/10.1016/j.jneumeth.2009.12.008] [PMID:  20026357] 
[250] 
Ohshima-Hosoyama, S.; Simmons, H.A.; Goecks, N.; Joers, V.; Swanson, C.R.; Bondarenko, V.; Velotta, R.; Brunner, K.; Wood, L.D.; Hruban, R.H.; Emborg, M.E. A monoclonal antibody-GDNF fusion protein is not neuroprotective and is associated with proliferative pancreatic lesions in parkinsonian monkeys. PLoS One,  2012, 7(6)e39036
[http://dx.doi.org/10.1371/journal.pone.0039036] [PMID:  22745701] 
[251] 
Lipsman, N.; Meng, Y.; Bethune, A.J.; Huang, Y.; Lam, B.; Masellis, M.; Herrmann, N.; Heyn, C.; Aubert, I.; Boutet, A.; Smith, G.S.; Hynynen, K.; Black, S.E. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun.,  2018, 9(1), 2336.
[http://dx.doi.org/10.1038/s41467-018-04529-6] [PMID:  30046032] 
[252] 
Agrawal, M.; Saraf, S.; Saraf, S.; Antimisiaris, S.G.; Chougule, M.B.; Shoyele, S.A.; Alexander, A. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J. Control. Release,  2018, 281, 139-177.
[http://dx.doi.org/10.1016/j.jconrel.2018.05.011] [PMID:  29772289] 
Rights & Permissions Print Cite
Article Metrics
77
5
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568026619666191203113745	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294
Current Topics in Medicinal Chemistry

Progress in Target Drug Molecules for Alzheimer's Disease

Abstract

Graphical Abstract

Chemistry Based on Natural Products for Therapeutic Purposes

Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design

Drug Discovery in the Age of Artificial Intelligence

From Biodiversity to Chemical Diversity: Focus of Flavonoids

Current Topics in Medicinal Chemistry

Progress in Target Drug Molecules for Alzheimer's Disease

Abstract

Graphical Abstract

Call for Papers in Thematic Issues

Chemistry Based on Natural Products for Therapeutic Purposes

Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design

Drug Discovery in the Age of Artificial Intelligence

From Biodiversity to Chemical Diversity: Focus of Flavonoids

Related Journals

Related Books

Related Articles
