Abstract
Alzheimer's disease (AD) has become the fourth leading cause of death in the world. Due to its complex pathogenesis, there is still a lack of effective drug treatments. Studies have found that the metal dyshomeostasis is closely related to other pathogeneses of AD such as oxidative stress, β-amyloid protein deposits, etc. Therefore, it becomes an important target to find the appropriate metal chelating agents to regulate the metal homeostasis. At the same time, because of the complex pathogenesis, single target drugs cannot achieve good effects. Therefore, current studies are mainly focused on exploring multi-target therapy for AD. In this work, the multi-target studies based on metal chelators and other targets with synergistic anti-AD activities were reviewed. The structural characteristics of different chelating agents were summarized and the structure-activity relationship was analyzed, which provided some valuable clues for the subsequent development of anti-AD multi-target drugs based on metal chelating agents.
Keywords: Multi-target, Alzheimer’s disease, Metal ion, homeostasis, Metal, chelator
Graphical Abstract
[http://dx.doi.org/10.3233/JAD-190302] [PMID: 31306127]
[http://dx.doi.org/10.2174/0929867323666161213101126] [PMID: 30191777]
[http://dx.doi.org/10.1002/alz.12328] [PMID: 33756057]
[http://dx.doi.org/10.1016/j.jalz.2017.12.006] [PMID: 29433981]
[http://dx.doi.org/10.1038/ncomms11398] [PMID: 27092707]
[http://dx.doi.org/10.2174/1389450121999201209201004] [PMID: 33302832]
[http://dx.doi.org/10.1038/nrd2896] [PMID: 20431570]
[http://dx.doi.org/10.2174/1389450121999200819144544] [PMID: 32814524]
[http://dx.doi.org/10.1016/j.ejmech.2015.03.040] [PMID: 25812965]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00624] [PMID: 26181606]
[http://dx.doi.org/10.3233/JAD-170662] [PMID: 29562528]
[http://dx.doi.org/10.1016/S0022-510X(98)00092-6] [PMID: 9667777]
[http://dx.doi.org/10.1007/s10534-014-9728-5] [PMID: 24668390]
[http://dx.doi.org/10.2478/v10007-011-0006-6] [PMID: 21406339]
[http://dx.doi.org/10.1002/psc.2789] [PMID: 26018760]
[http://dx.doi.org/10.1038/nrn2168] [PMID: 17551515]
[http://dx.doi.org/10.1038/s41593-020-0687-6] [PMID: 32778792]
[http://dx.doi.org/10.1039/B912601E] [PMID: 21069156]
[http://dx.doi.org/10.1515/revneuro-2019-0052] [PMID: 31747384]
[http://dx.doi.org/10.1016/j.neuro.2020.07.003] [PMID: 32717200]
[http://dx.doi.org/10.1111/bph.14567] [PMID: 30632143]
[http://dx.doi.org/10.1021/acs.accounts.5b00119] [PMID: 25946460]
[http://dx.doi.org/10.1111/j.1742-4658.2007.06238.x] [PMID: 18205831]
[http://dx.doi.org/10.1111/j.1471-4159.2006.04079.x] [PMID: 17029598]
[http://dx.doi.org/10.1021/acs.inorgchem.7b00782] [PMID: 28485587]
[http://dx.doi.org/10.1016/j.ejmech.2017.09.057] [PMID: 29107423]
[http://dx.doi.org/10.1016/j.bcp.2005.09.003] [PMID: 16226724]
[http://dx.doi.org/10.1016/j.ejmech.2019.04.060] [PMID: 31042617]
[http://dx.doi.org/10.1002/cbdv.202000442] [PMID: 32692899]
[http://dx.doi.org/10.1016/j.bioorg.2020.104146] [PMID: 32777579]
[http://dx.doi.org/10.3389/fnins.2016.00205] [PMID: 27252617]
[http://dx.doi.org/10.1016/j.bmc.2015.01.005] [PMID: 25614117]
[http://dx.doi.org/10.1016/j.bmcl.2017.09.057] [PMID: 29033233]
[http://dx.doi.org/10.1016/j.bioorg.2018.10.065] [PMID: 30412794]
[http://dx.doi.org/10.1002/ardp.202000258] [PMID: 33226157]
[http://dx.doi.org/10.1016/j.ejmech.2013.03.051] [PMID: 23685572]
[http://dx.doi.org/10.1016/j.bioorg.2019.103499] [PMID: 31838287]
[http://dx.doi.org/10.1016/j.bioorg.2019.103006] [PMID: 31158577]
[http://dx.doi.org/10.1080/14756366.2016.1186019]
[http://dx.doi.org/10.1080/14756366.2016.1256883] [PMID: 28585866]
[http://dx.doi.org/10.1186/s13065-020-00715-0] [PMID: 33134975]
[http://dx.doi.org/10.1016/j.bmcl.2020.127477] [PMID: 32781220]
[http://dx.doi.org/10.1016/j.ejmech.2019.04.038] [PMID: 31055149]
[http://dx.doi.org/10.1016/j.bioorg.2019.03.058] [PMID: 30928879]
[http://dx.doi.org/10.1016/j.jinorgbio.2012.05.016] [PMID: 22819647]
[http://dx.doi.org/10.1021/jm3003813] [PMID: 22663067]
[http://dx.doi.org/10.1021/acs.chemrestox.9b00168] [PMID: 31402645]
[http://dx.doi.org/10.1016/j.ejmech.2014.10.004] [PMID: 25290683]
[http://dx.doi.org/10.1016/j.bmc.2017.05.027] [PMID: 28549891]
[http://dx.doi.org/10.1021/jm300978h] [PMID: 22978824]
[http://dx.doi.org/10.1155/2013/567128] [PMID: 24159420]
[http://dx.doi.org/10.1016/j.neuron.2008.06.018] [PMID: 18614028]
[http://dx.doi.org/10.3233/JAD-2010-1390] [PMID: 20164561]
[http://dx.doi.org/10.1016/j.bmc.2018.04.043] [PMID: 29729985]
[http://dx.doi.org/10.1002/chem.201402143] [PMID: 24797103]
[http://dx.doi.org/10.1039/C5IB00064E] [PMID: 25968625]
[http://dx.doi.org/10.1039/C4MT00161C] [PMID: 25144522]
[http://dx.doi.org/10.1039/B712377A] [PMID: 18092106]
[http://dx.doi.org/10.1016/j.fct.2018.03.035] [PMID: 29596976]
[http://dx.doi.org/10.1038/srep21826] [PMID: 26911795]
[http://dx.doi.org/10.1016/j.bmc.2018.08.019] [PMID: 30181028]
[http://dx.doi.org/10.1016/j.bmc.2017.08.048] [PMID: 28988627]
[http://dx.doi.org/10.1016/j.bmc.2016.06.012] [PMID: 27316544]
[http://dx.doi.org/10.3390/molecules25163610] [PMID: 32784464]
[http://dx.doi.org/10.1016/j.ejmech.2021.113821] [PMID: 34517222]
[http://dx.doi.org/10.1016/j.bmc.2014.07.009] [PMID: 25082512]
[http://dx.doi.org/10.4155/fmc-2019-0106] [PMID: 31838895]
[http://dx.doi.org/10.1016/j.bmc.2014.08.035] [PMID: 25282654]
[http://dx.doi.org/10.1016/j.ejmech.2019.111916] [PMID: 31812794]
[http://dx.doi.org/10.1016/j.bioorg.2019.103524] [PMID: 31918396]
[http://dx.doi.org/10.1016/j.bmcl.2014.12.084] [PMID: 25597007]
[http://dx.doi.org/10.1016/j.ejmech.2017.10.006] [PMID: 29031070]
[http://dx.doi.org/10.1016/j.bmc.2015.08.024] [PMID: 26337018]
[http://dx.doi.org/10.1016/j.bmc.2016.07.025] [PMID: 27460699]
[http://dx.doi.org/10.1016/j.ejmech.2018.04.058] [PMID: 29763808]
[http://dx.doi.org/10.1016/j.jinorgbio.2016.05.001] [PMID: 27230386]
[http://dx.doi.org/10.1016/j.bioorg.2020.103977] [PMID: 32485470]
[http://dx.doi.org/10.1111/j.1471-4159.2006.04258.x] [PMID: 17144902]
[http://dx.doi.org/10.1111/j.1471-4159.2005.03340.x] [PMID: 16181413]
[http://dx.doi.org/10.1089/ars.2011.4279] [PMID: 22360429]
[http://dx.doi.org/10.1016/j.bbagen.2014.05.005] [PMID: 24821011]
[http://dx.doi.org/10.1016/j.bmc.2015.01.042] [PMID: 25678013]
[http://dx.doi.org/10.1016/j.bioorg.2019.103477] [PMID: 31818478]
[http://dx.doi.org/10.1016/j.ejmech.2018.02.023] [PMID: 29466775]
[http://dx.doi.org/10.1016/j.ejmech.2016.09.052] [PMID: 27736684]
[http://dx.doi.org/10.1021/jacs.1c05470] [PMID: 34213901]
[http://dx.doi.org/10.1021/acschemneuro.0c00114] [PMID: 32310630]
[http://dx.doi.org/10.1016/j.ejmech.2019.02.001] [PMID: 30772605]
[http://dx.doi.org/10.1016/0891-5849(92)90144-6] [PMID: 1334028]
[http://dx.doi.org/10.1111/j.1471-4159.2008.05332.x] [PMID: 18331585]
[http://dx.doi.org/10.3233/JAD-2012-111346] [PMID: 22406440]
[http://dx.doi.org/10.3389/fnagi.2014.00218] [PMID: 25309423]
[http://dx.doi.org/10.1021/jm400567s] [PMID: 23799643]
[http://dx.doi.org/10.3233/JAD-131031] [PMID: 24413613]
[http://dx.doi.org/10.1080/14786419.2018.1496429] [PMID: 30345819]
[http://dx.doi.org/10.1016/j.cbi.2008.05.003] [PMID: 18547552]
[http://dx.doi.org/10.1002/biof.1504] [PMID: 31018024]
[http://dx.doi.org/10.1111/j.1755-5949.2010.00147.x] [PMID: 20406252]
[http://dx.doi.org/10.1016/j.ejmech.2015.02.063] [PMID: 25778991]
[http://dx.doi.org/10.3233/JAD-170188] [PMID: 28527218]
[http://dx.doi.org/10.1007/s00253-020-10461-x] [PMID: 32095862]
[http://dx.doi.org/10.1016/j.ejmech.2019.07.021] [PMID: 31310916]
[http://dx.doi.org/10.1016/j.ejmech.2019.06.026] [PMID: 31229875]
[http://dx.doi.org/10.1021/acschemneuro.9b00232] [PMID: 31199606]
[http://dx.doi.org/10.1177/2156587215610032] [PMID: 26438716]
[http://dx.doi.org/10.1007/s12640-019-00142-7] [PMID: 31853730]
[http://dx.doi.org/10.3390/biom10010059] [PMID: 31905923]
[http://dx.doi.org/10.1007/s13765-016-0217-0]
[http://dx.doi.org/10.1016/j.etp.2012.05.003] [PMID: 22739358]
[http://dx.doi.org/10.1016/j.lfs.2003.09.074] [PMID: 15051420]
[http://dx.doi.org/10.3390/molecules23123225] [PMID: 30563286]
[http://dx.doi.org/10.3390/molecules23040869] [PMID: 29642616]
[http://dx.doi.org/10.1002/mnfr.200500156] [PMID: 16470637]
[http://dx.doi.org/10.1159/000085385] [PMID: 15956814]
[http://dx.doi.org/10.3390/ijms19010173] [PMID: 29316635]
[http://dx.doi.org/10.2174/1389450118666170328122527] [PMID: 28356027]
[http://dx.doi.org/10.1021/acschemneuro.7b00071] [PMID: 28650631]
[http://dx.doi.org/10.1016/j.isci.2020.101005] [PMID: 32272441]
[http://dx.doi.org/10.1007/s11030-013-9452-z] [PMID: 23703159]
[http://dx.doi.org/10.1016/j.jchromb.2009.02.013] [PMID: 19237321]
[http://dx.doi.org/10.1016/j.ejps.2021.105976] [PMID: 34419572]
[http://dx.doi.org/10.1016/j.bmcl.2021.128316] [PMID: 34391893]
[http://dx.doi.org/10.1016/j.molstruc.2021.130459]
[http://dx.doi.org/10.1016/j.saa.2021.120587] [PMID: 34782268]