Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

The Hybrid Compounds as Multi-target Ligands for the Treatment of Alzheimer's Disease: Considerations on Donepezil

Author(s): Hayrettin Ozan Gulcan* and Muberra Kosar*

Volume 22, Issue 5, 2022

Published on: 11 November, 2021

Page: [395 - 407] Pages: 13

DOI: 10.2174/1568026621666211111153626

Price: $65

Abstract

The strategies to combat Alzheimer’s Disease (AD) have been changing with respect to the failures of many drug candidates assessed in clinical studies, the complex pathophysiology of AD, and the limitations of the current drugs employed. So far, none of the targets, either validated or nonvalidated, have been shown to be purely causative in the generation and development of AD. Considering the progressive and the neurodegenerative characteristics of the disease, the main strategy has been based on the design of molecules capable of showing activity on more than one receptor, and it is defined as multi-target ligand design strategy. The hybrid molecule concept is an outcome of this approach. Donepezil, as one of the currently employed drugs for AD therapy, has also been utilized in hybrid drug design studies. This review has aimed to present the promising donepezil-like hybrid molecules introduced in the recent period. Particularly, multi-target ligands with additional activities concomitant to cholinesterase inhibition are preferred.

Keywords: Donepezil, Hybrid drug design, Cholinesterase, MAO-B, Metal-chelation, Amyloid beta, Antioxidant.

« Previous Next »
[1]
Taylor, C.A.; Greenlund, S.F.; McGuire, L.C.; Lu, H.; Croft, J.B. Deaths from Alzheimer’s Disease - United States, 1999-2014. MMWR Morb. Mortal. Wkly. Rep., 2017, 66(20), 521-526.
[http://dx.doi.org/10.15585/mmwr.mm6620a1] [PMID: 28542120]
[2]
Jagust, W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci., 2018, 19(11), 687-700.
[http://dx.doi.org/10.1038/s41583-018-0067-3] [PMID: 30266970]
[3]
Kumar, A.; Singh, A. Ekavali, A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol. Rep., 2015, 67(2), 195-203.
[http://dx.doi.org/10.1016/j.pharep.2014.09.004] [PMID: 25712639]
[4]
Samanta, M.K.; Wilson, B.; Santhi, K.; Kumar, K.P.; Suresh, B. Alzheimer disease and its management: a review. Am. J. Ther., 2006, 13(6), 516-526.
[http://dx.doi.org/10.1097/01.mjt.0000208274.80496.f1] [PMID: 17122533]
[5]
Darvesh, S.; Walsh, R.; Kumar, R.; Caines, A.; Roberts, S.; Magee, D.; Rockwood, K.; Martin, E. Inhibition of human cholinesterases by drugs used to treat Alzheimer disease. Alzheimer Dis. Assoc. Disord., 2003, 17(2), 117-126.
[http://dx.doi.org/10.1097/00002093-200304000-00011] [PMID: 12794390]
[6]
Hansen, R.A.; Gartlehner, G.; Webb, A.P.; Morgan, L.C.; Moore, C.G.; Jonas, D.E. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin. Interv. Aging, 2008, 3(2), 211-225.
[PMID: 18686744]
[7]
Gulcan, H.O.; Mavideniz, A.; Sahin, M.F.; Orhan, I.E. Benzimidazole-derived compounds designed for different targets of Alzheimer’s disease. Curr. Med. Chem., 2019, 26(18), 3260-3278.
[http://dx.doi.org/10.2174/0929867326666190124123208] [PMID: 30678614]
[8]
Gulcan, H.O.; Orhan, I.E.; Sener, B. Chemical and molecular aspects on interactions of galanthamine and its derivatives with cholinesterases. Curr. Pharm. Biotechnol., 2015, 16(3), 252-258.
[http://dx.doi.org/10.2174/1389201015666141202105105] [PMID: 25483718]
[9]
Selkoe, D.J. Alzheimer disease and aducanumab: adjusting our approach. Nat. Rev. Neurol., 2019, 15(7), 365-366.
[http://dx.doi.org/10.1038/s41582-019-0205-1] [PMID: 31138932]
[10]
Sevigny, J.; Chiao, P.; Bussière, T.; Weinreb, P.H.; Williams, L.; Maier, M.; Dunstan, R.; Salloway, S.; Chen, T.; Ling, Y.; O’Gorman, J.; Qian, F.; Arastu, M.; Li, M.; Chollate, S.; Brennan, M.S.; Quintero-Monzon, O.; Scannevin, R.H.; Arnold, H.M.; Engber, T.; Rhodes, K.; Ferrero, J.; Hang, Y.; Mikulskis, A.; Grimm, J.; Hock, C.; Nitsch, R.M.; Sandrock, A. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, 2016, 537(7618), 50-56.
[http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]
[11]
Wilson, R.S.; Barnes, L.L.; Aggarwal, N.T.; Boyle, P.A.; Hebert, L.E.; Mendes de Leon, C.F.; Evans, D.A. Cognitive activity and the cognitive morbidity of Alzheimer disease. Neurology, 2010, 75(11), 990-996.
[http://dx.doi.org/10.1212/WNL.0b013e3181f25b5e] [PMID: 20811001]
[12]
Simard, M.; van Reekum, R. Memory assessment in studies of cognition-enhancing drugs for Alzheimer’s disease. Drugs Aging, 1999, 14(3), 197-230.
[http://dx.doi.org/10.2165/00002512-199914030-00004] [PMID: 10220105]
[13]
Dong, S.; Duan, Y.; Hu, Y.; Zhao, Z. Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis. Transl. Neurodegener., 2012, 1(1), 18.
[http://dx.doi.org/10.1186/2047-9158-1-18] [PMID: 23210692]
[14]
Norouzbahari, M.; Burgaz, E.V.; Ercetin, T.; Fallah, A.; Foroumadi, A.; Firoozpour, L.; Gulcan, H.O. Design, synthesis and characterization of novel urolithin derivatives as cholinesterase inhibitor agents. Lett. Drug Des. Discov., 2018, 15(11), 1131-1140.
[http://dx.doi.org/10.2174/1570180815666180115144608]
[15]
Castellani, R.J.; Plascencia-Villa, G.; Perry, G. The amyloid cascade and Alzheimer’s disease therapeutics: theory versus observation. Lab. Invest., 2019, 99(7), 958-970.
[http://dx.doi.org/10.1038/s41374-019-0231-z] [PMID: 30760863]
[16]
Whitesell, J.D.; Buckley, A.R.; Knox, J.E.; Kuan, L.; Graddis, N.; Pelos, A.; Mukora, A.; Wakeman, W.; Bohn, P.; Ho, A.; Hirokawa, K.E.; Harris, J.A. Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease. J. Comp. Neurol., 2019, 527(13), 2122-2145.
[http://dx.doi.org/10.1002/cne.24555] [PMID: 30311654]
[17]
Esteras, N.; Abramov, A.Y. Mitochondrial calcium deregulation in the mechanism of beta-amyloid and tau pathology. Cells, 2020, 9(9), 2135.
[http://dx.doi.org/10.3390/cells9092135] [PMID: 32967303]
[18]
Jang, H.; Arce, F.T.; Capone, R.; Ramachandran, S.; Lal, R.; Nussinov, R. Misfolded amyloid ion channels present mobile β-sheet subunits in contrast to conventional ion channels. Biophys. J., 2009, 97(11), 3029-3037.
[http://dx.doi.org/10.1016/j.bpj.2009.09.014] [PMID: 19948133]
[19]
Qiao, H.; Koya, R.C.; Nakagawa, K.; Tanaka, H.; Fujita, H.; Takimoto, M.; Kuzumaki, N. Inhibition of Alzheimer’s amyloid-β peptide-induced reduction of mitochondrial membrane potential and neurotoxicity by gelsolin. Neurobiol. Aging, 2005, 26(6), 849-855.
[http://dx.doi.org/10.1016/j.neurobiolaging.2004.08.003] [PMID: 15718043]
[20]
Chakraborty, S. Multi-potent natural scaffolds targeting amyloid cascade: in search of alzheimer’s disease therapeutics. Curr. Top. Med. Chem., 2017, 17(31), 3336-3348.
[http://dx.doi.org/10.2174/1568026618666180116122921] [PMID: 29345580]
[21]
Hillen, H. The beta amyloid dysfunction (BAD) hypothesis for Alzheimer’s disease. Front. Neurosci., 2019, 13, 1154.
[http://dx.doi.org/10.3389/fnins.2019.01154] [PMID: 31787864]
[22]
Ricciarelli, R.; Fedele, E. The amyloid cascade hypothesis in Alzheimer’s disease: it’s time to change our mind. Curr. Neuropharmacol., 2017, 15(6), 926-935.
[http://dx.doi.org/10.2174/1570159X15666170116143743] [PMID: 28093977]
[23]
Makin, S. The amyloid hypothesis on trial. Nature, 2018, 559(7715), S4-S7.
[http://dx.doi.org/10.1038/d41586-018-05719-4] [PMID: 30046080]
[24]
Modrego, P.; Lobo, A. A good marker does not mean a good target for clinical trials in Alzheimer’s disease: the amyloid hypothesis questioned. Neurodegener. Dis. Manag., 2019, 9(3), 119-121.
[http://dx.doi.org/10.2217/nmt-2019-0006] [PMID: 31116074]
[25]
Mehta, D.; Jackson, R.; Paul, G.; Shi, J.; Sabbagh, M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin. Investig. Drugs, 2017, 26(6), 735-739.
[http://dx.doi.org/10.1080/13543784.2017.1323868] [PMID: 28460541]
[26]
Gülcan, H.O.; Orhan, I.E. The main targets involved in neuroprotection for the treatment of Alzheimer’s disease and Parkinson disease. Curr. Pharm. Des., 2020, 26(4), 509-516.
[http://dx.doi.org/10.2174/1381612826666200131103524] [PMID: 32003681]
[27]
Kuruva, C.S.; Reddy, P.H. Amyloid beta modulators and neuroprotection in Alzheimer’s disease: a critical appraisal. Drug Discov. Today, 2017, 22(2), 223-233.
[http://dx.doi.org/10.1016/j.drudis.2016.10.010] [PMID: 27794478]
[28]
Jellinger, K.A.; Attems, J. Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathol., 2007, 113(2), 107-117.
[http://dx.doi.org/10.1007/s00401-006-0156-7] [PMID: 17089134]
[29]
Farber, N.B.; Rubin, E.H.; Newcomer, J.W.; Kinscherf, D.A.; Miller, J.P.; Morris, J.C.; Olney, J.W.; McKeel, D.W. Jr Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis. Arch. Gen. Psychiatry, 2000, 57(12), 1165-1173.
[http://dx.doi.org/10.1001/archpsyc.57.12.1165] [PMID: 11115331]
[30]
Lue, L.F.; Brachova, L.; Civin, W.H. Rogers, J. Inflammation, A β deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J. Neuropathol. Exp. Neurol., 1996, 55(10), 1083-1088.
[http://dx.doi.org/10.1097/00005072-199655100-00008] [PMID: 8858005]
[31]
Boimel, M.; Grigoriadis, N.; Lourbopoulos, A.; Touloumi, O.; Rosenmann, D.; Abramsky, O.; Rosenmann, H. Statins reduce the neurofibrillary tangle burden in a mouse model of tauopathy. J. Neuropathol. Exp. Neurol., 2009, 68(3), 314-325.
[http://dx.doi.org/10.1097/NEN.0b013e31819ac3cb] [PMID: 19225406]
[32]
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]
[33]
Tell, V.; Hilgeroth, A. Recent developments of protein kinase inhibitors as potential AD therapeutics. Front. Cell. Neurosci., 2013, 7, 189.
[http://dx.doi.org/10.3389/fncel.2013.00189] [PMID: 24312003]
[34]
Hiremathad, A. A review: natural compounds as anti-Alzheimer’s disease agents. Curr. Nutr. Food Sci., 2017, 13(4), 247-254.
[http://dx.doi.org/10.2174/1573401313666170725103932]
[35]
Cuajungco, M.P.; Fagét, K.Y.; Huang, X.; Tanzi, R.E.; Bush, A.I. Metal chelation as a potential therapy for Alzheimer’s disease. Ann. N. Y. Acad. Sci., 2000, 920(1), 292-304.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb06938.x] [PMID: 11193167]
[36]
Bush, A.I. The metallobiology of Alzheimer’s disease. Trends Neurosci., 2003, 26(4), 207-214.
[http://dx.doi.org/10.1016/S0166-2236(03)00067-5] [PMID: 12689772]
[37]
Domingo, J.L. Aluminum and other metals in Alzheimer’s disease: a review of potential therapy with chelating agents. J. Alzheimers Dis., 2006, 10(2-3), 331-341.
[http://dx.doi.org/10.3233/JAD-2006-102-315] [PMID: 17119296]
[38]
Orhan, I.E.; Gulcan, H.O. Coumarins: auspicious cholinesterase and monoamine oxidase inhibitors. Curr. Top. Med. Chem., 2015, 15(17), 1673-1682.
[http://dx.doi.org/10.2174/1568026615666150427113103] [PMID: 25915613]
[39]
Gulcan, H.O.; Orhan, I.E. Amendatory effect of flavonoids in Alzheimer’s disease against mitochondrial dysfunction. Curr. Drug Targets, 2021, 22(14), 1618-1628.
[http://dx.doi.org/10.2174/1389450122666210120144921]
[40]
Gulcan, H.O.; Orhan, I.E. A Recent look into natural products that have potential to inhibit cholinesterases and monoamine oxidase b: update for 2010-2019. Comb. Chem. High Throughput Screen., 2020, 23(9), 862-876.
[http://dx.doi.org/10.2174/1386207323666200127145246] [PMID: 31985374]
[41]
Riederer, P.; Danielczyk, W.; Grünblatt, E. Monoamine oxidase-B inhibition in Alzheimer’s disease. Neurotoxicology, 2004, 25(1-2), 271-277.
[http://dx.doi.org/10.1016/S0161-813X(03)00106-2] [PMID: 14697902]
[42]
García-Osta, A.; Cuadrado-Tejedor, M.; García-Barroso, C.; Oyarzábal, J.; Franco, R. Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem. Neurosci., 2012, 3(11), 832-844.
[http://dx.doi.org/10.1021/cn3000907] [PMID: 23173065]
[43]
Fisher, A. Muscarinic receptor agonists in Alzheimer’s disease. CNS Drugs, 1999, 12(3), 197-214.
[http://dx.doi.org/10.2165/00023210-199912030-00004]
[44]
Kemppainen, N.; Laine, M.; Laakso, M.P.; Kaasinen, V.; Någren, K.; Vahlberg, T.; Kurki, T.; Rinne, J.O. Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer’s disease. Eur. J. Neurosci., 2003, 18(1), 149-154.
[http://dx.doi.org/10.1046/j.1460-9568.2003.02716.x] [PMID: 12859348]
[45]
Benhamú, B.; Martín-Fontecha, M.; Vázquez-Villa, H.; Pardo, L.; López-Rodríguez, M.L. Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer’s disease. J. Med. Chem., 2014, 57(17), 7160-7181.
[http://dx.doi.org/10.1021/jm5003952] [PMID: 24850589]
[46]
Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B. Multi-target-directed ligands in Alzheimer’s disease treatment. Curr. Med. Chem., 2011, 18(32), 4949-4975.
[http://dx.doi.org/10.2174/092986711797535245] [PMID: 22050745]
[47]
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]
[48]
Rampa, A.; Belluti, F.; Gobbi, S.; Bisi, A. Hybrid-based multi-target ligands for the treatment of Alzheimer’s disease. Curr. Top. Med. Chem., 2011, 11(22), 2716-2730.
[http://dx.doi.org/10.2174/156802611798184409] [PMID: 22039875]
[49]
González, J.F.; Alcántara, A.R.; Doadrio, A.L.; Sánchez-Montero, J.M. Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches. Expert Opin. Drug Discov., 2019, 14(9), 879-891.
[http://dx.doi.org/10.1080/17460441.2019.1623201] [PMID: 31165654]
[50]
Gontijo, V.S.; Viegas, F.P.D.; Ortiz, C.J.C.; de Freitas Silva, M.; Damasio, C.M.; Rosa, M.C.; Campos, T.G.; Couto, D.S.; Tranches Dias, K.S.; Viegas, C. Molecular hybridization as a tool in the design of multi-target directed drug candidates for neurodegenerative diseases. Curr. Neuropharmacol., 2020, 18(5), 348-407.
[http://dx.doi.org/10.2174/1385272823666191021124443] [PMID: 31631821]
[51]
Uliassi, E.; Prati, F.; Bongarzone, S.; Bolognesi, M.L. Medicinal chemistry of hybrids for neurodegenerative diseases. In: Design of Hybrid Molecules for Drug Development; Elsevier, 2017; pp. 259-277.
[http://dx.doi.org/10.1016/B978-0-08-101011-2.00010-6]
[52]
Ibrar, A.; Shehzadi, S.A.; Saeed, F.; Khan, I. Developing hybrid molecule therapeutics for diverse enzyme inhibitory action: active role of coumarin-based structural leads in drug discovery. Bioorg. Med. Chem., 2018, 26(13), 3731-3762.
[http://dx.doi.org/10.1016/j.bmc.2018.05.042] [PMID: 30017112]
[53]
Rosini, M. Polypharmacology: the rise of multitarget drugs over combination therapies. Future Med. Chem., 2014, 6(5), 485-487.
[http://dx.doi.org/10.4155/fmc.14.25] [PMID: 24649950]
[54]
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]
[55]
Bell, D.S.H. Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. Diabetes Obes. Metab., 2013, 15(4), 291-300.
[http://dx.doi.org/10.1111/dom.12015] [PMID: 23013323]
[56]
Shaveta.; Mishra, S.; Singh, P. Hybrid molecules: The privileged scaffolds for various pharmaceuticals. Eur. J. Med. Chem., 2016, 124, 500-536.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.039] [PMID: 27598238]
[57]
Meunier, B. Hybrid molecules with a dual mode of action: dream or reality? Acc. Chem. Res., 2008, 41(1), 69-77.
[http://dx.doi.org/10.1021/ar7000843] [PMID: 17665872]
[58]
Bérubé, G. An overview of molecular hybrids in drug discovery. Expert Opin. Drug Discov., 2016, 11(3), 281-305.
[http://dx.doi.org/10.1517/17460441.2016.1135125] [PMID: 26727036]
[59]
Morphy, R.; Rankovic, Z. The physicochemical challenges of designing multiple ligands. J. Med. Chem., 2006, 49(16), 4961-4970.
[http://dx.doi.org/10.1021/jm0603015] [PMID: 16884308]
[60]
Prati, F.; Cavalli, A.; Bolognesi, M.L. Navigating the chemical space of multitarget-directed ligands: from hybrids to fragments in Alzheimer’s disease. Molecules, 2016, 21(4), 466.
[http://dx.doi.org/10.3390/molecules21040466] [PMID: 27070562]
[61]
Breen, E.C.; Walsh, J.J. Tubulin-targeting agents in hybrid drugs. Curr. Med. Chem., 2010, 17(7), 609-639.
[http://dx.doi.org/10.2174/092986710790416254] [PMID: 20088764]
[62]
Ivasiv, V.; Albertini, C.; Gonçalves, A.E.; Rossi, M.; Bolognesi, M.L. Molecular hybridization as a tool for designing multitarget drug candidates for complex diseases. Curr. Top. Med. Chem., 2019, 19(19), 1694-1711.
[http://dx.doi.org/10.2174/1568026619666190619115735] [PMID: 31237210]
[63]
Lu, C.; Zhou, Q.; Yan, J.; Du, Z.; Huang, L.; Li, X. A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2013, 62, 745-753.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.039] [PMID: 23454517]
[64]
Jeřábek, J.; Uliassi, E.; Guidotti, L.; Korábečný, J.; Soukup, O.; Sepsova, V.; Hrabinova, M.; Kuča, K.; Bartolini, M.; Peña-Altamira, L.E.; Petralla, S.; Monti, B.; Roberti, M.; Bolognesi, M.L. Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer’s disease. Eur. J. Med. Chem., 2017, 127, 250-262.
[http://dx.doi.org/10.1016/j.ejmech.2016.12.048] [PMID: 28064079]
[65]
Mahdavi, M.; Hariri, R.; Mirfazli, S.S.; Lotfian, H.; Rastergari, A.; Firuzi, O.; Edraki, N.; Larijani, B.; Akbarzadeh, T.; Saeedi, M. Synthesis and biological activity of some Benzochromenoquinolinones: tacrine analogs as potent anti‐Alzheimer’s agents. Chem. Biodivers., 2019, 16(4), e1800488.
[http://dx.doi.org/10.1002/cbdv.201800488] [PMID: 30720917]
[66]
Chen, X.; Decker, M. Multi-target compounds acting in the central nervous system designed from natural products. Curr. Med. Chem., 2013, 20(13), 1673-1685.
[http://dx.doi.org/10.2174/0929867311320130007] [PMID: 23410166]
[67]
Stockwell, J.; Abdi, N.; Lu, X.; Maheshwari, O.; Taghibiglou, C. Novel central nervous system drug delivery systems. Chem. Biol. Drug Des., 2014, 83(5), 507-520.
[http://dx.doi.org/10.1111/cbdd.12268] [PMID: 24325540]
[68]
Das, S.; Basu, S. Multi-targeting strategies for Alzheimer’s disease therapeutics: pros and cons. Curr. Top. Med. Chem., 2017, 17(27), 3017-3061.
[http://dx.doi.org/10.2174/1568026617666170707130652] [PMID: 28685694]
[69]
Zimmermann, G.R.; Lehár, J.; Keith, C.T. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov. Today, 2007, 12(1-2), 34-42.
[http://dx.doi.org/10.1016/j.drudis.2006.11.008] [PMID: 17198971]
[70]
Bansal, Y.; Silakari, O. Multifunctional compounds: smart molecules for multifactorial diseases. Eur. J. Med. Chem., 2014, 76, 31-42.
[http://dx.doi.org/10.1016/j.ejmech.2014.01.060] [PMID: 24565571]
[71]
Kása, P.; Rakonczay, Z.; Gulya, K. The cholinergic system in Alzheimer’s disease. Prog. Neurobiol., 1997, 52(6), 511-535.
[http://dx.doi.org/10.1016/S0301-0082(97)00028-2] [PMID: 9316159]
[72]
Rosini, M.; Simoni, E.; Minarini, A.; Melchiorre, C. Multi-target design strategies in the context of Alzheimer’s disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. Neurochem. Res., 2014, 39(10), 1914-1923.
[http://dx.doi.org/10.1007/s11064-014-1250-1] [PMID: 24493627]
[73]
Singh, M.; Kaur, M.; Chadha, N.; Silakari, O. Hybrids: a new paradigm to treat Alzheimer’s disease. Mol. Divers., 2016, 20(1), 271-297.
[http://dx.doi.org/10.1007/s11030-015-9628-9] [PMID: 26328942]
[74]
Spilovska, K.; Korabecny, J.; Nepovimova, E.; Dolezal, R.; Mezeiova, E.; Soukup, O.; Kuca, K. Multitarget tacrine hybrids with neuroprotective properties to confront Alzheimer’s disease. Curr. Top. Med. Chem., 2017, 17(9), 1006-1026.
[http://dx.doi.org/10.2174/1568026605666160927152728] [PMID: 27697055]
[75]
Mezeiova, E.; Spilovska, K.; Nepovimova, E.; Gorecki, L.; Soukup, O.; Dolezal, R.; Malinak, D.; Janockova, J.; Jun, D.; Kuca, K.; Korabecny, J. Profiling donepezil template into multipotent hybrids with antioxidant properties. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 583-606.
[http://dx.doi.org/10.1080/14756366.2018.1443326] [PMID: 29529892]
[76]
Ahmad, M. Donepezil: A review of the recent structural modifications and their impact on anti-Alzheimer activity. Braz. J. Pharm. Sci., 2020, 56, e18325.
[http://dx.doi.org/10.1590/s2175-97902019000418325]
[77]
Korabecny, J.; Spilovska, K.; Mezeiova, E.; Benek, O.; Juza, R.; Kaping, D.; Soukup, O. A systematic review on donepezil-based derivatives as potential cholinesterase inhibitors for Alzheimer’s disease. Curr. Med. Chem., 2019, 26(30), 5625-5648.
[http://dx.doi.org/10.2174/0929867325666180517094023] [PMID: 29768996]
[78]
Benchekroun, M.; Ismaili, L.; Pudlo, M.; Luzet, V.; Gharbi, T.; Refouvelet, B.; Marco-Contelles, J. Donepezil-ferulic acid hybrids as anti-Alzheimer drugs. Future Med. Chem., 2015, 7(1), 15-21.
[http://dx.doi.org/10.4155/fmc.14.148] [PMID: 25582330]
[79]
Ismaili, L.; Refouvelet, B.; Benchekroun, M.; Brogi, S.; Brindisi, M.; Gemma, S.; Campiani, G.; Filipic, S.; Agbaba, D.; Esteban, G.; Unzeta, M.; Nikolic, K.; Butini, S.; Marco-Contelles, J. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer’s disease. Prog. Neurobiol., 2017, 151, 4-34.
[http://dx.doi.org/10.1016/j.pneurobio.2015.12.003] [PMID: 26797191]
[80]
Kryger, G.; Silman, I.; Sussman, J.L. Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure, 1999, 7(3), 297-307.
[http://dx.doi.org/10.1016/S0969-2126(99)80040-9] [PMID: 10368299]
[81]
Sugimoto, H.; Yamanishi, Y.; Iimura, Y.; Kawakami, Y. Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr. Med. Chem., 2000, 7(3), 303-339.
[http://dx.doi.org/10.2174/0929867003375191] [PMID: 10637367]
[82]
Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V. β-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem. Pharmacol., 2003, 65(3), 407-416.
[http://dx.doi.org/10.1016/S0006-2952(02)01514-9] [PMID: 12527333]
[83]
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]
[84]
Kimura, M.; Komatsu, H.; Ogura, H.; Sawada, K. Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons. Neurosci. Lett., 2005, 391(1-2), 17-21.
[http://dx.doi.org/10.1016/j.neulet.2005.08.036] [PMID: 16154269]
[85]
Tahmasebinia, F.; Emadi, S. Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron. Biometals, 2017, 30(2), 285-293.
[http://dx.doi.org/10.1007/s10534-017-0005-2] [PMID: 28281098]
[86]
Joppe, K.; Roser, A.E.; Maass, F.; Lingor, P. The contribution of iron to protein aggregation disorders in the central nervous system. Front. Neurosci., 2019, 13, 15.
[http://dx.doi.org/10.3389/fnins.2019.00015] [PMID: 30723395]
[87]
Costa, M.; Josselin, R.; Silva, D.F.; Cardoso, S.M.; May, N.V.; Chaves, S.; Santos, M.A. Donepezil-based hybrids as multifunctional anti-Alzheimer’s disease chelating agents: effect of positional isomerization. J. Inorg. Biochem., 2020, 206, 111039.
[http://dx.doi.org/10.1016/j.jinorgbio.2020.111039] [PMID: 32171933]
[88]
Piemontese, L.; Tomás, D.; Hiremathad, A.; Capriati, V.; Candeias, E.; Cardoso, S.M.; Chaves, S.; Santos, M.A. Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 1212-1224.
[http://dx.doi.org/10.1080/14756366.2018.1491564] [PMID: 30160188]
[89]
Du, H.; Liu, X.; Xie, J.; Ma, F. Novel deoxyvasicinone-donepezil hybrids as potential multitarget drug candidates for Alzheimer’s disease. ACS Chem. Neurosci., 2019, 10(5), 2397-2407.
[http://dx.doi.org/10.1021/acschemneuro.8b00699] [PMID: 30720268]
[90]
Queda, F.; Calò, S.; Gwizdala, K.; Magalhães, J.D.; Cardoso, S.M.; Chaves, S.; Piemontese, L.; Santos, M.A. Novel donepezil-arylsulfonamide hybrids as multitarget-directed ligands for potential treatment of Alzheimer’s disease. Molecules, 2021, 26(6), 1658.
[http://dx.doi.org/10.3390/molecules26061658] [PMID: 33809771]
[91]
Lan, J.S.; Zhang, T.; Liu, Y.; Yang, J.; Xie, S.S.; Liu, J.; Miao, Z.Y.; Ding, Y. Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2017, 133, 184-196.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.045] [PMID: 28388521]
[92]
Yan, J.; Hu, J.; Liu, A.; He, L.; Li, X.; Wei, H. Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer’s disease based on the fusion of donepezil and curcumin. Bioorg. Med. Chem., 2017, 25(12), 2946-2955.
[http://dx.doi.org/10.1016/j.bmc.2017.02.048] [PMID: 28454848]
[93]
Cai, P.; Fang, S.Q.; Yang, H.L.; Yang, X.L.; Liu, Q.H.; Kong, L.Y.; Wang, X.B. Donepezil-butylated hydroxytoluene (BHT) hybrids as Anti-Alzheimer’s disease agents with cholinergic, antioxidant, and neuroprotective properties. Eur. J. Med. Chem., 2018, 157, 161-176.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.005] [PMID: 30096650]
[94]
Wang, J.; Cai, P.; Yang, X.L.; Li, F.; Wu, J.J.; Kong, L.Y.; Wang, X.B. Novel cinnamamide-dibenzylamine hybrids: Potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer’s disease. Eur. J. Med. Chem., 2017, 139, 68-83.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.077] [PMID: 28800459]
[95]
Dias, K.S.T.; de Paula, C.T.; Dos Santos, T.; Souza, I.N.; Boni, M.S.; Guimarães, M.J.; da Silva, F.M.; Castro, N.G.; Neves, G.A.; Veloso, C.C.; Coelho, M.M.; de Melo, I.S.; Giusti, F.C.; Giusti-Paiva, A.; da Silva, M.L.; Dardenne, L.E.; Guedes, I.A.; Pruccoli, L.; Morroni, F.; Tarozzi, A.; Viegas, C. Jr Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2017, 130, 440-457.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.043] [PMID: 28282613]
[96]
Pachón-Angona, I.; Refouvelet, B.; Andrýs, R.; Martin, H.; Luzet, V.; Iriepa, I.; Moraleda, I.; Diez-Iriepa, D.; Oset-Gasque, M.J.; Marco-Contelles, J.; Musilek, K.; Ismaili, L. Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer’s disease therapy. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 479-489.
[http://dx.doi.org/10.1080/14756366.2018.1545766] [PMID: 30712420]
[97]
Estrada Valencia, M.; Herrera-Arozamena, C.; de Andrés, L.; Pérez, C.; Morales-García, J.A.; Pérez-Castillo, A.; Ramos, E.; Romero, A.; Viña, D.; Yáñez, M.; Laurini, E.; Pricl, S.; Rodríguez-Franco, M.I. Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer’s disease. Eur. J. Med. Chem., 2018, 156, 534-553.
[http://dx.doi.org/10.1016/j.ejmech.2018.07.026] [PMID: 30025348]
[98]
Mishra, C.B.; Manral, A.; Kumari, S.; Saini, V.; Tiwari, M. Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease. Bioorg. Med. Chem., 2016, 24(16), 3829-3841.
[http://dx.doi.org/10.1016/j.bmc.2016.06.027] [PMID: 27353888]
[99]
Mishra, C.B.; Kumari, S.; Manral, A.; Prakash, A.; Saini, V.; Lynn, A.M.; Tiwari, M. Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2017, 125, 736-750.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.057] [PMID: 27721157]
[100]
Gabr, M.T.; Abdel-Raziq, M.S. Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors. Bioorg. Chem., 2018, 80, 245-252.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.031] [PMID: 29966870]
[101]
Green, K.D.; Fosso, M.Y.; Garneau-Tsodikova, S. Multifunctional donepezil analogues as cholinesterase and BACE1 inhibitors. Molecules, 2018, 23(12), 3252.
[http://dx.doi.org/10.3390/molecules23123252] [PMID: 30544832]
[102]
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]
[103]
Bautista-Aguilera, O.M.; Samadi, A.; Chioua, M.; Nikolic, K.; Filipic, S.; Agbaba, D.; Soriano, E.; de Andrés, L.; Rodríguez-Franco, M.I.; Alcaro, S.; Ramsay, R.R.; Ortuso, F.; Yañez, M.; Marco-Contelles, J. N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor. J. Med. Chem., 2014, 57(24), 10455-10463.
[http://dx.doi.org/10.1021/jm501501a] [PMID: 25418133]
[104]
Wang, L.; Esteban, G.; Ojima, M.; Bautista-Aguilera, O.M.; Inokuchi, T.; Moraleda, I.; Iriepa, I.; Samadi, A.; Youdim, M.B.; Romero, A.; Soriano, E.; Herrero, R.; Fernández Fernández, A.P. Ricardo-Martínez-Murillo; Marco-Contelles, J.; Unzeta, M. Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2014, 80, 543-561.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.078] [PMID: 24813882]
[105]
Samadi, A.; Chioua, M.; Bolea, I.; de Los Ríos, C.; Iriepa, I.; Moraleda, I.; Bastida, A.; Esteban, G.; Unzeta, M.; Gálvez, E.; Marco-Contelles, J. Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2011, 46(9), 4665-4668.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.048] [PMID: 21669479]
[106]
Shukur, K.T.; Ercetin, T.; Luise, C.; Sippl, W.; Sirkecioglu, O.; Ulgen, M.; Coskun, G.P.; Yarim, M.; Gazi, M.; Gulcan, H.O. Design, synthesis, and biological evaluation of new urolithin amides as multitarget agents against Alzheimer’s disease. Arch. Pharm. (Weinheim), 2021, 354(5), e2000467.
[http://dx.doi.org/10.1002/ardp.202000467] [PMID: 33511649]
[107]
Xie, S.S.; Lan, J.S.; Wang, X.; Wang, Z.M.; Jiang, N.; Li, F.; Wu, J.J.; Wang, J.; Kong, L.Y. Design, synthesis and biological evaluation of novel donepezil-coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease. Bioorg. Med. Chem., 2016, 24(7), 1528-1539.
[http://dx.doi.org/10.1016/j.bmc.2016.02.023] [PMID: 26917219]
[108]
Pieczenik, S.R.; Neustadt, J. Mitochondrial dysfunction and molecular pathways of disease. Exp. Mol. Pathol., 2007, 83(1), 84-92.
[http://dx.doi.org/10.1016/j.yexmp.2006.09.008] [PMID: 17239370]
[109]
Tamás, M.J.; Sharma, S.K.; Ibstedt, S.; Jacobson, T.; Christen, P. Heavy metals and metalloids as a cause for protein misfolding and aggregation. Biomolecules, 2014, 4(1), 252-267.
[http://dx.doi.org/10.3390/biom4010252] [PMID: 24970215]
[110]
Zhu, G.; Wang, K.; Shi, J.; Zhang, P.; Yang, D.; Fan, X.; Zhang, Z.; Liu, W.; Sang, Z. The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2019, 29(19), 126625.
[http://dx.doi.org/10.1016/j.bmcl.2019.126625] [PMID: 31444085]
[111]
Wu, M.Y.; Esteban, G.; Brogi, S.; Shionoya, M.; Wang, L.; Campiani, G.; Unzeta, M.; Inokuchi, T.; Butini, S.; Marco-Contelles, J. Donepezil-like multifunctional agents: design, synthesis, molecular modeling and biological evaluation. Eur. J. Med. Chem., 2016, 121, 864-879.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.001] [PMID: 26471320]
[112]
Wang, Z.M.; Cai, P.; Liu, Q.H.; Xu, D.Q.; Yang, X.L.; Wu, J.J.; Kong, L.Y.; Wang, X.B. Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2016, 123, 282-297.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.052] [PMID: 27484514]
[113]
Wang, J.; Wang, Z.M.; Li, X.M.; Li, F.; Wu, J.J.; Kong, L.Y.; Wang, X.B. Synthesis and evaluation of multi-target-directed ligands for the treatment of Alzheimer’s disease based on the fusion of donepezil and melatonin. Bioorg. Med. Chem., 2016, 24(18), 4324-4338.
[http://dx.doi.org/10.1016/j.bmc.2016.07.025] [PMID: 27460699]
[114]
Li, F.; Wang, Z.M.; Wu, J.J.; Wang, J.; Xie, S.S.; Lan, J.S.; Wang, X.B. Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer’s disease. J. Enzyme Inhib. Med. Chem., 2016, 31(sup3), 41-53.
[http://dx.doi.org/10.1080/14756366.2016] [PMID: 27384289]

Rights & Permissions Print Cite
Article Metrics
34
1
© 2024 Bentham Science Publishers | Privacy Policy