Abstract
Alzheimer's disease (AD) is a neurodegenerative disease and one of the leading causes of progressive dementia, affecting 50 million people worldwide. Many pathogenic processes, including amyloid β aggregation, tau hyperphosphorylation, oxidative stress, neuronal death, and deterioration of the function of cholinergic neurons, are associated with its progression. The one-compound-one-target treatment paradigm was unsuccessful in treating AD due to the multifaceted nature of Alzheimer's disease. The recent develop-ment of multitarget-directed ligand research has been explored to target the complemen-tary pathways associated with the disease. We aimed to find the key role and progress of MTDLs in treating AD; thus, we searched for the past ten years of literature on “Pub-Med”, “ScienceDirect”, “ACS” and “Bentham Science” using the keywords neurodegen-erative diseases, Alzheimer’s disease, and multitarget-directed ligands. The literature was further filtered based on the quality of work and relevance to AD. Thus, this review high-lights the current advancement and advantages of multitarget-directed ligands over tradi-tional single-targeted drugs and recent progress in their development to treat AD.
[http://dx.doi.org/10.1021/acschemneuro.0c00448] [PMID: 33073564]
[http://dx.doi.org/10.1039/C9MD00337A] [PMID: 32206241]
[http://dx.doi.org/10.1155/2020/7039138] [PMID: 32411333]
[http://dx.doi.org/10.1016/B978-0-12-813796-3.00008-0]
[http://dx.doi.org/10.1021/acs.jmedchem.0c00528] [PMID: 32706255]
[http://dx.doi.org/10.1021/acschemneuro.1c00235] [PMID: 34019757]
[http://dx.doi.org/10.1021/acschemneuro.0c00621] [PMID: 33322892]
[http://dx.doi.org/10.1016/j.bcp.2021.114651] [PMID: 34118220]
[http://dx.doi.org/10.1002/alz.12638] [PMID: 35289055]
[http://dx.doi.org/10.2174/1568026024607490] [PMID: 11966460]
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[http://dx.doi.org/10.3390/ph14010033] [PMID: 33466332]
[http://dx.doi.org/10.1111/jphp.13244] [PMID: 32149402]
[http://dx.doi.org/10.3233/JAD-190744] [PMID: 31594236]
[http://dx.doi.org/10.4103/1673-5374.274329] [PMID: 31997800]
[http://dx.doi.org/10.1002/alz.12192] [PMID: 33075193]
[http://dx.doi.org/10.1093/oxfordjournals.bmb.a072632] [PMID: 8221024]
[http://dx.doi.org/10.1021/acschemneuro.9b00216] [PMID: 31140779]
[http://dx.doi.org/10.3892/br.2016.630] [PMID: 27123241]
[http://dx.doi.org/10.3389/fnagi.2021.617588] [PMID: 33679375]
[http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]
[PMID: 30569080]
[http://dx.doi.org/10.1016/j.nlm.2021.107484] [PMID: 34175450]
[http://dx.doi.org/10.7150/thno.56059] [PMID: 34093845]
[http://dx.doi.org/10.1016/j.jphysparis.2005.12.080] [PMID: 16448808]
[http://dx.doi.org/10.1002/anie.201410456] [PMID: 25504761]
[http://dx.doi.org/10.1111/j.1745-7254.2008.00819.x] [PMID: 18565274]
[http://dx.doi.org/10.1002/alz.12398] [PMID: 34151525]
[http://dx.doi.org/10.1007/s00775-019-01712-y] [PMID: 31486954]
[http://dx.doi.org/10.3233/JAD-201556] [PMID: 34219710]
[http://dx.doi.org/10.1016/j.nurt.2008.05.001] [PMID: 18625454]
[http://dx.doi.org/10.3389/fnmol.2017.00339] [PMID: 29114205]
[http://dx.doi.org/10.1016/S0022-510X(98)00092-6] [PMID: 9667777]
[http://dx.doi.org/10.1016/j.tins.2016.01.003] [PMID: 26833257]
[http://dx.doi.org/10.1186/alzrt82] [PMID: 21639952]
[http://dx.doi.org/10.2174/1570159X19666211201094031] [PMID: 34852746]
[http://dx.doi.org/10.1186/1756-6606-4-3] [PMID: 21214928]
[http://dx.doi.org/10.2174/156720507781788837] [PMID: 17908044]
[http://dx.doi.org/10.1186/alzrt60] [PMID: 21190552]
[http://dx.doi.org/10.1186/s13195-017-0279-1] [PMID: 28764767]
[http://dx.doi.org/10.1021/acschemneuro.8b00220] [PMID: 30296051]
[http://dx.doi.org/10.3389/fnmol.2019.00143] [PMID: 31191248]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01457] [PMID: 26502061]
[http://dx.doi.org/10.1517/14728222.12.8.921] [PMID: 18620516]
[http://dx.doi.org/10.1155/2012/649079] [PMID: 22792454]
[http://dx.doi.org/10.1007/s12035-015-9369-x] [PMID: 26227906]
[http://dx.doi.org/10.1016/j.arr.2014.03.008] [PMID: 24726823]
[http://dx.doi.org/10.1016/j.ejmech.2016.04.075] [PMID: 27423119]
[http://dx.doi.org/10.1038/s41419-018-0688-5] [PMID: 29844403]
[http://dx.doi.org/10.1073/pnas.172504199] [PMID: 12244210]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01370] [PMID: 29363967]
[PMID: 10529898]
[http://dx.doi.org/10.1016/j.neulet.2020.134741] [PMID: 31927055]
[http://dx.doi.org/10.1042/BSR20170862] [PMID: 29222348]
[http://dx.doi.org/10.1038/sj.npp.1300330] [PMID: 14571255]
[http://dx.doi.org/10.2174/1381612821666150605112105] [PMID: 26044973]
[http://dx.doi.org/10.1016/j.ejmech.2017.02.043] [PMID: 28282613]
[http://dx.doi.org/10.1016/S0092-8674(00)80748-5] [PMID: 10319819]
[http://dx.doi.org/10.1016/j.conb.2006.05.004] [PMID: 16698262]
[http://dx.doi.org/10.1111/epi.14482] [PMID: 30159880]
[http://dx.doi.org/10.1016/j.mcn.2008.07.010] [PMID: 18706502]
[http://dx.doi.org/10.1038/srep45701] [PMID: 28361919]
[http://dx.doi.org/10.1056/NEJMoa1211103] [PMID: 23150908]
[http://dx.doi.org/10.1016/j.jalz.2014.12.009] [PMID: 25936935]
[http://dx.doi.org/10.1155/2011/143269]
[http://dx.doi.org/10.1038/nrm3293] [PMID: 22395773]
[http://dx.doi.org/10.1039/C4CS00337C] [PMID: 25622714]
[http://dx.doi.org/10.1038/nbt0505-552] [PMID: 15877070]
[http://dx.doi.org/10.2174/09298673113209990216] [PMID: 23992340]
[http://dx.doi.org/10.1016/j.apsb.2014.12.006] [PMID: 26579421]
[http://dx.doi.org/10.1002/cpt.1104] [PMID: 29717478]
[http://dx.doi.org/10.1016/S1474-4422(03)00502-7] [PMID: 12941576]
[PMID: 12137632]
[http://dx.doi.org/10.1177/08919887211044746] [PMID: 34476990]
[http://dx.doi.org/10.3390/ijms21093272] [PMID: 32380758]
[http://dx.doi.org/10.2147/DDDT.S86463] [PMID: 27757016]
[http://dx.doi.org/10.1097/01.wad.0000213859.35355.59] [PMID: 17132971]
[http://dx.doi.org/10.1185/03007995.2011.582484] [PMID: 21561398]
[http://dx.doi.org/10.1185/03007990903434914] [PMID: 19929593]
[http://dx.doi.org/10.1038/d41586-021-01546-2] [PMID: 34103732]
[http://dx.doi.org/10.1136/bmj.p73] [PMID: 36631154]
[http://dx.doi.org/10.1017/9781108975759]
[http://dx.doi.org/10.1016/j.drudis.2006.11.008] [PMID: 17198971]
[http://dx.doi.org/10.1038/437942a] [PMID: 16222266]
[http://dx.doi.org/10.1016/S1359-6446(04)03163-0] [PMID: 15279847]
[http://dx.doi.org/10.1021/acs.jmedchem.9b00017] [PMID: 31082225]
[http://dx.doi.org/10.2174/138161209787315594] [PMID: 19199984]
[http://dx.doi.org/10.1016/j.sbi.2006.01.013] [PMID: 16442279]
[http://dx.doi.org/10.1021/jm058225d] [PMID: 16220969]
[http://dx.doi.org/10.1021/acs.chemrev.8b00138] [PMID: 30095897]
[http://dx.doi.org/10.1016/j.pneurobio.2015.12.003] [PMID: 26797191]
[http://dx.doi.org/10.1111/j.1471-4159.2004.02899.x] [PMID: 15686476]
[http://dx.doi.org/10.1016/j.bmc.2016.02.023] [PMID: 26917219]
[PMID: 31257471]
[http://dx.doi.org/10.2174/1570159X11311030005] [PMID: 24179465]
[http://dx.doi.org/10.1021/acschemneuro.7b00270] [PMID: 28737885]
[http://dx.doi.org/10.1016/j.neuropharm.2006.04.007] [PMID: 16762377]
[http://dx.doi.org/10.1021/jm3009458] [PMID: 23033965]
[http://dx.doi.org/10.2147/ciia.2007.2.1.17] [PMID: 18044073]
[http://dx.doi.org/10.1002/trc2.12106] [PMID: 33614888]
[http://dx.doi.org/10.1021/jm020120c] [PMID: 12431053]
[http://dx.doi.org/10.2174/138945012799499794] [PMID: 22280345]
[http://dx.doi.org/10.1021/jm900504c] [PMID: 19485411]
[http://dx.doi.org/10.1517/14656566.1.1.121] [PMID: 11249555]
[http://dx.doi.org/10.1056/NEJM199101313240525] [PMID: 1986300]
[http://dx.doi.org/10.1017/S1461145701002528] [PMID: 11602028]
[http://dx.doi.org/10.1039/C1MD00221J]
[http://dx.doi.org/10.1016/j.ejmech.2013.09.024] [PMID: 24095756]
[http://dx.doi.org/10.1016/j.nurt.2008.10.030] [PMID: 19110207]
[http://dx.doi.org/10.1038/ncomms14727] [PMID: 28367951]
[http://dx.doi.org/10.1371/journal.pone.0031921] [PMID: 22384101]
[http://dx.doi.org/10.1155/2014/350516] [PMID: 25525597]
[http://dx.doi.org/10.1007/s40263-016-0399-3] [PMID: 27914038]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01417] [PMID: 29420891]
[http://dx.doi.org/10.7717/peerj.2140] [PMID: 27441112]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01917] [PMID: 26978477]
[http://dx.doi.org/10.1016/j.ejmech.2018.02.023] [PMID: 29466775]
[http://dx.doi.org/10.1016/j.bmcl.2014.12.006] [PMID: 25537270]
[http://dx.doi.org/10.1016/j.ejmech.2019.02.008] [PMID: 30771601]
[PMID: 16437529]
[http://dx.doi.org/10.3390/molecules21040466] [PMID: 27070562]
[http://dx.doi.org/10.1080/14756366.2017.1406485] [PMID: 29210299]
[http://dx.doi.org/10.1016/j.ejmech.2019.02.021] [PMID: 30851693]
[http://dx.doi.org/10.3390/molecules25245891] [PMID: 33322783]
[PMID: 34121977]
[http://dx.doi.org/10.1016/j.bmc.2014.06.057] [PMID: 25088549]
[http://dx.doi.org/10.1016/j.bmcl.2014.12.084] [PMID: 25597007]
[http://dx.doi.org/10.1016/j.ejmech.2016.09.078] [PMID: 27721153]
[http://dx.doi.org/10.1016/j.bbadis.2016.11.020] [PMID: 27865910]
[http://dx.doi.org/10.1021/acschemneuro.7b00461] [PMID: 29345897]
[http://dx.doi.org/10.1016/j.bioorg.2020.104201] [PMID: 32890999]
[http://dx.doi.org/10.1016/j.ejmech.2014.04.078] [PMID: 24813882]
[http://dx.doi.org/10.1002/cmdc.201500383] [PMID: 26427608]
[http://dx.doi.org/10.3389/fnins.2016.00294] [PMID: 27445665]
[http://dx.doi.org/10.1016/j.bioorg.2020.103722] [PMID: 32155491]
[http://dx.doi.org/10.1080/14756366.2018.1491564] [PMID: 30160188]
[http://dx.doi.org/10.1021/acschemneuro.9b00409] [PMID: 31697472]
[http://dx.doi.org/10.1021/acs.jmedchem.8b00610] [PMID: 30078314]
[http://dx.doi.org/10.1016/j.ejmech.2020.112874] [PMID: 33017743]
[http://dx.doi.org/10.3390/biom11010111] [PMID: 33467709]
[http://dx.doi.org/10.1016/j.bmcl.2019.126927] [PMID: 31901382]
[http://dx.doi.org/10.1021/acs.jmedchem.0c01940] [PMID: 33769811]
[http://dx.doi.org/10.1016/j.ejmech.2022.114630] [PMID: 35987018]
[http://dx.doi.org/10.1021/acs.jmedchem.1c02150] [PMID: 35271276]
[http://dx.doi.org/10.1021/acschemneuro.1c00535] [PMID: 35195392]
[http://dx.doi.org/10.3390/molecules27030958] [PMID: 35164223]
[http://dx.doi.org/10.1021/acsmedchemlett.1c00445] [PMID: 35059126]
[http://dx.doi.org/10.1039/D3RA00297G] [PMID: 36950709]
[http://dx.doi.org/10.1007/s11164-022-04908-1]
[http://dx.doi.org/10.1080/14756366.2023.2169682] [PMID: 36688444]
[http://dx.doi.org/10.1016/j.ejmech.2023.115216] [PMID: 36857812]
[http://dx.doi.org/10.1016/j.ejmech.2023.115288] [PMID: 37031527]
[http://dx.doi.org/10.1016/j.ejmech.2023.115354] [PMID: 37043996]
[http://dx.doi.org/10.1016/j.bmc.2022.117146] [PMID: 36580744]
[http://dx.doi.org/10.1016/j.bmc.2023.117333] [PMID: 37236021]
[http://dx.doi.org/10.1016/j.bmc.2023.117178] [PMID: 36706609]
[http://dx.doi.org/10.1016/j.ejmech.2023.115120] [PMID: 36682173]
[http://dx.doi.org/10.3390/ijms24032285] [PMID: 36768608]
[http://dx.doi.org/10.1038/s41594-020-0505-6] [PMID: 32989305]
[http://dx.doi.org/10.1056/NEJMoa1705971] [PMID: 29365294]
[http://dx.doi.org/10.1186/s13195-017-0318-y] [PMID: 29221491]