Review Article

Study on Multi-Target Synergistic Treatment of Alzheimer’s Disease Based on Metal Chelators

Author(s): Aihong Yang, Jianhua Wu, Yuhong Chen, Rui Shen* and Xiaodi Kou*

Volume 24, Issue 2, 2023

Published on: 27 October, 2022

Page: [131 - 150] Pages: 20

DOI: 10.2174/1389450123666220926143920

Price: $65

conference banner
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 homeostasis, metal chelator, synergistic treatment, oxidative stress.

Graphical Abstract
[1]
Nance C, Ritter A, Miller JB, Lapin B, Banks SJ. The pathology of rapid cognitive decline in clinically diagnosed Alzheimer’s disease. J Alzheimers Dis 2019; 70(4): 983-93.
[http://dx.doi.org/10.3233/JAD-190302] [PMID: 31306127]
[2]
dos Santos PLC, Ozela PF, de Fatima BBM, et al. Alzheimer’s disease: A review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. Curr Med Chem 2018; 25(26): 3141-59.
[http://dx.doi.org/10.2174/0929867323666161213101126] [PMID: 30191777]
[3]
Alzheimer’s Association Report. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement 2021; 17(3): 327-406.
[http://dx.doi.org/10.1002/alz.12328] [PMID: 33756057]
[4]
Jia J, Wei C, Chen S, et al. The cost of Alzheimer’s disease in China and re‐estimation of costs worldwide. Alzheimers Dement 2018; 14(4): 483-91.
[http://dx.doi.org/10.1016/j.jalz.2017.12.006] [PMID: 29433981]
[5]
Matthews FE, Stephan BCM, Robinson L, et al. A two decade dementia incidence comparison from the cognitive function and ageing studies I and II. Nat Commun 2016; 7(1): 11398.
[http://dx.doi.org/10.1038/ncomms11398] [PMID: 27092707]
[6]
Iqubal A, Rahman SO, Ahmed M, et al. Current quest in natural bioactive compounds for Alzheimer’s disease: Multi-targeted-designed-ligand based approach with preclinical and clinical based evidence. Curr Drug Targets 2021; 22(6): 685-720.
[http://dx.doi.org/10.2174/1389450121999201209201004] [PMID: 33302832]
[7]
Citron M. Alzheimer’s disease: Strategies for disease modification. Nat Rev Drug Discov 2010; 9(5): 387-98.
[http://dx.doi.org/10.1038/nrd2896] [PMID: 20431570]
[8]
Pirolla NFF, Batista VS, Dias Viegas FP, et al. Alzheimer’s disease: Related targets, synthesis of available drugs, bioactive compounds under development and promising results obtained from multi-target approaches. Curr Drug Targets 2021; 22(5): 505-38.
[http://dx.doi.org/10.2174/1389450121999200819144544] [PMID: 32814524]
[9]
Xie SS, Wang X, Jiang N, et al. Multi-target tacrine-coumarin hybrids: Cholinesterase and monoamine oxidase B inhibition properties against Alzheimer’s disease. Eur J Med Chem 2015; 95: 153-65.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.040] [PMID: 25812965]
[10]
Sola I, Aso E, Frattini D, et al. Novel levetiracetam derivatives that are effective against the Alzheimer-like phenotype in mice: Synthesis, in vitro, ex vivo and in vivo efficacy studies. J Med Chem 2015; 58(15): 6018-32.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00624] [PMID: 26181606]
[11]
Adlard PA, Bush AI. Metals and Alzheimer’s disease: How far have we come in the clinic? J Alzheimers Dis 2018; 62(3): 1369-79.
[http://dx.doi.org/10.3233/JAD-170662] [PMID: 29562528]
[12]
Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 1998; 158(1): 47-52.
[http://dx.doi.org/10.1016/S0022-510X(98)00092-6] [PMID: 9667777]
[13]
González-Domínguez R, García-Barrera T, Gómez-Ariza JL. Homeostasis of metals in the progression of Alzheimer’s disease. Biometals 2014; 27(3): 539-49.
[http://dx.doi.org/10.1007/s10534-014-9728-5] [PMID: 24668390]
[14]
Budimir A. Metal ions, Alzheimer’s disease and chelation therapy. Acta Pharm 2011; 61(1): 1-14.
[http://dx.doi.org/10.2478/v10007-011-0006-6] [PMID: 21406339]
[15]
Qiu T, Liu Q, Chen YX, Zhao YF, Li YM A. β 42 and A β 40: Similarities and differences J Pept Sci 2015; 21(7): 522-9.
[http://dx.doi.org/10.1002/psc.2789] [PMID: 26018760]
[16]
LaFerla FM, Green KN, Oddo S. Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci 2007; 8(7): 499-509.
[http://dx.doi.org/10.1038/nrn2168] [PMID: 17551515]
[17]
Busche MA, Hyman BT. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci 2020; 23(10): 1183-93.
[http://dx.doi.org/10.1038/s41593-020-0687-6] [PMID: 32778792]
[18]
Brown DR. Metalloproteins and neuronal death. Metallomics 2010; 2(3): 186-94.
[http://dx.doi.org/10.1039/B912601E] [PMID: 21069156]
[19]
Isaev NK, Stelmashook EV, Genrikhs EE. Role of zinc and copper ions in the pathogenetic mechanisms of traumatic brain injury and Alzheimer’s disease. Rev Neurosci 2020; 31(3): 233-43.
[http://dx.doi.org/10.1515/revneuro-2019-0052] [PMID: 31747384]
[20]
Xie Z, Wu H, Zhao J. Multifunctional roles of zinc in Alzheimer’s disease. Neurotoxicology 2020; 80: 112-23.
[http://dx.doi.org/10.1016/j.neuro.2020.07.003] [PMID: 32717200]
[21]
Nikseresht S, Bush AI, Ayton S. Treating Alzheimer’s disease by targeting iron. Br J Pharmacol 2019; 176(18): 3622-35.
[http://dx.doi.org/10.1111/bph.14567] [PMID: 30632143]
[22]
Robert A, Liu Y, Nguyen M, Meunier B. Regulation of copper and iron homeostasis by metal chelators: A possible chemotherapy for Alzheimer’s disease. Acc Chem Res 2015; 48(5): 1332-9.
[http://dx.doi.org/10.1021/acs.accounts.5b00119] [PMID: 25946460]
[23]
Inestrosa NC, Dinamarca MC, Alvarez A. Amyloid-cholinesterase interactions. FEBS J 2008; 275(4): 625-32.
[http://dx.doi.org/10.1111/j.1742-4658.2007.06238.x] [PMID: 18205831]
[24]
Ghribi O, Golovko MY, Larsen B, Schrag M, Murphy EJ. Deposition of iron and? -amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets. J Neurochem 2006; 99(2): 438-49.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04079.x] [PMID: 17029598]
[25]
Ji Y, Lee HJ, Kim M, et al. Strategic design of 2,2′-bipyridine derivatives to modulate metal-amyloid-β aggregation. Inorg Chem 2017; 56(11): 6695-705.
[http://dx.doi.org/10.1021/acs.inorgchem.7b00782] [PMID: 28485587]
[26]
Iraji A, Firuzi O, Khoshneviszadeh M, et al. Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer’s disease. Eur J Med Chem 2017; 141: 690-702.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.057] [PMID: 29107423]
[27]
Zheng H, Youdim MBH, Weiner LM, Fridkin M. Novel potential neuroprotective agents with both iron chelating and amino acid-based derivatives targeting central nervous system neurons. Biochem Pharmacol 2005; 70(11): 1642-52.
[http://dx.doi.org/10.1016/j.bcp.2005.09.003] [PMID: 16226724]
[28]
Sestito S, Wang S, Chen Q, et al. Multi-targeted chei-copper chelating molecules as neuroprotective agents. Eur J Med Chem 2019; 174: 216-25.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.060] [PMID: 31042617]
[29]
Yang A, Yu Q, Ju H, Song L, Kou X, Shen R. Design, synthesis and biological evaluation of xanthone derivatives for possible treatment of Alzheimer’s disease based on multi-target strategy. Chem Biodivers 2020; 17(10): e2000442.
[http://dx.doi.org/10.1002/cbdv.202000442] [PMID: 32692899]
[30]
Haghighijoo Z, Akrami S, Saeedi M, et al. N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer’s disease. Bioorg Chem 2020; 103: 104146.
[http://dx.doi.org/10.1016/j.bioorg.2020.104146] [PMID: 32777579]
[31]
Unzeta M, Esteban G, Bolea I, et al. 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]
[32]
Sang Z, Li Y, Qiang X, et al. Multifunctional scutellarin–rivastigmine hybrids with cholinergic, antioxidant, biometal chelating and neuroprotective properties for the treatment of Alzheimer’s disease. Bioorg Med Chem 2015; 23(4): 668-80.
[http://dx.doi.org/10.1016/j.bmc.2015.01.005] [PMID: 25614117]
[33]
Sang Z, Wang K, Wang H, et al. Design, synthesis and biological evaluation of 2-acetyl-5- O -(amino-alkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 2017; 27(22): 5046-52.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.057] [PMID: 29033233]
[34]
Rastegari A, Nadri H, Mahdavi M, et al. 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]
[35]
Saeedi M, Felegari P, Iraji A, et al. Novel N ‐benzylpiperidine derivatives of 5‐arylisoxazole‐3‐carboxamides as anti‐Alzheimer’s agents. Arch Pharm 2021; 354(3): 2000258.
[http://dx.doi.org/10.1002/ardp.202000258] [PMID: 33226157]
[36]
Xie SS, Wang XB, Li JY, Yang L, Kong LY. Design, synthesis and evaluation of novel tacrine–coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease. Eur J Med Chem 2013; 64: 540-53.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.051] [PMID: 23685572]
[37]
El-Sayed NF, El-Hussieny M, Ewies EF, Fouad MA, Boulos LS. New phosphazine and phosphazide derivatives as multifunctional ligands targeting acetylcholinesterase and β-Amyloid aggregation for treatment of Alzheimer’s disease. Bioorg Chem 2020; 95: 103499.
[http://dx.doi.org/10.1016/j.bioorg.2019.103499] [PMID: 31838287]
[38]
Riazimontazer E, Sadeghpour H, Nadri H, et al. Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives. Bioorg Chem 2019; 89: 103006.
[http://dx.doi.org/10.1016/j.bioorg.2019.103006] [PMID: 31158577]
[39]
Koca M, Yerdelen KO, Anil B, et al. Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents. J Enzyme Inhib Med Chem 2016; 31(S2): 13-23.
[http://dx.doi.org/10.1080/14756366.2016.1186019]
[40]
Lan JS, Hou JW, Liu Y, et al. Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N -benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer’s disease. J Enzyme Inhib Med Chem 2017; 32(1): 776-88.
[http://dx.doi.org/10.1080/14756366.2016.1256883] [PMID: 28585866]
[41]
Karimi Askarani H, Iraji A, Rastegari A, et al. Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer’s disease. BMC Chem 2020; 14(1): 64.
[http://dx.doi.org/10.1186/s13065-020-00715-0] [PMID: 33134975]
[42]
Singh A, Sharma S, Arora S, et al. New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation. Bioorg Med Chem Lett 2020; 30(20): 127477.
[http://dx.doi.org/10.1016/j.bmcl.2020.127477] [PMID: 32781220]
[43]
Umar T, Shalini S, Raza MK, et al. A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer’s disease. Eur J Med Chem 2019; 175: 2-19.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.038] [PMID: 31055149]
[44]
Kaur A, Mann S, Kaur A, et al. Multi-target-directed triazole derivatives as promising agents for the treatment of Alzheimer’s disease. Bioorg Chem 2019; 87: 572-84.
[http://dx.doi.org/10.1016/j.bioorg.2019.03.058] [PMID: 30928879]
[45]
Noël S, Perez F, Pedersen JT, et al. A new water-soluble Cu(II) chelator that retrieves Cu from Cu(amyloid-β) species, stops associated ROS production and prevents Cu(II)‐induced Aβ aggregation. J Inorg Biochem 2012; 117: 322-5.
[http://dx.doi.org/10.1016/j.jinorgbio.2012.05.016] [PMID: 22819647]
[46]
Geng J, Li M, Wu L, Ren J, Qu X. Liberation of copper from amyloid plaques: Making a risk factor useful for Alzheimer’s disease treatment. J Med Chem 2012; 55(21): 9146-55.
[http://dx.doi.org/10.1021/jm3003813] [PMID: 22663067]
[47]
Kaur A, Narang SS, Kaur A, et al. Multifunctional mono-triazole derivatives inhibit Aβ42 aggregation and Cu2+-mediated Aβ42 aggregation and protect against Aβ42-induced cytotoxicity. Chem Res Toxicol 2019; 32(9): 1824-39.
[http://dx.doi.org/10.1021/acs.chemrestox.9b00168] [PMID: 31402645]
[48]
Jiang N, Li SY, Xie SS, et al. Design, synthesis and evaluation of multifunctional salphen derivatives for the treatment of Alzheimer’s disease. Eur J Med Chem 2014; 87: 540-51.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.004] [PMID: 25290683]
[49]
Li F, Wu JJ, Wang J, et al. Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer’s disease. Bioorg Med Chem 2017; 25(14): 3815-26.
[http://dx.doi.org/10.1016/j.bmc.2017.05.027] [PMID: 28549891]
[50]
Huang L, Lu C, Sun Y, et al. Multitarget-directed benzylideneindanone derivatives: Anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer’s disease. J Med Chem 2012; 55(19): 8483-92.
[http://dx.doi.org/10.1021/jm300978h] [PMID: 22978824]
[51]
Singh SK, Sinha P, Mishra L, Srikrishna S. Neuroprotective role of a novel copper chelator against Aβ42 induced neurotoxicity. Int J Alzheimers Dis 2013; 2013: 1-9.
[http://dx.doi.org/10.1155/2013/567128] [PMID: 24159420]
[52]
Adlard PA, Cherny RA, Finkelstein DI, et al. Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 2008; 59(1): 43-55.
[http://dx.doi.org/10.1016/j.neuron.2008.06.018] [PMID: 18614028]
[53]
Faux NG, Ritchie CW, Gunn A, et al. PBT2 rapidly improves cognition in Alzheimer’s Disease: Additional phase II analyses. J Alzheimers Dis 2010; 20(2): 509-16.
[http://dx.doi.org/10.3233/JAD-2010-1390] [PMID: 20164561]
[54]
Yang X, Cai P, Liu Q, et al. Novel 8-hydroxyquinoline derivatives targeting β-amyloid aggregation, metal chelation and oxidative stress against Alzheimer’s disease. Bioorg Med Chem 2018; 26(12): 3191-201.
[http://dx.doi.org/10.1016/j.bmc.2018.04.043] [PMID: 29729985]
[55]
Nguyen M, Robert A, Sournia-Saquet A, Vendier L, Meunier B. Characterization of new specific copper chelators as potential drugs for the treatment of Alzheimer’s disease. Chemistry 2014; 20(22): 6771-85.
[http://dx.doi.org/10.1002/chem.201402143] [PMID: 24797103]
[56]
Yang Y, Chen T, Zhu S, et al. Two macrocyclic polyamines as modulators of metal-mediated Aβ 40 aggregation. Integr Biol 2015; 7(6): 655-62.
[http://dx.doi.org/10.1039/C5IB00064E] [PMID: 25968625]
[57]
Gonzalez P, da Costa VCP, Hyde K, et al. Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer’s disease. Metallomics 2014; 6(11): 2072-82.
[http://dx.doi.org/10.1039/C4MT00161C] [PMID: 25144522]
[58]
Jiang W, Fu Q, Fan H, Wang W. An NBD fluorophore-based sensitive and selective fluorescent probe for zinc ion. Chem Commun 2008; 14(2): 259-61.
[http://dx.doi.org/10.1039/B712377A] [PMID: 18092106]
[59]
Chen T, Zhang Y, Shang Y, Gu X, Zhu Y, Zhu L. NBD-BPEA regulates Zn2+- or Cu2+-induced Aβ40 aggregation and cytotoxicity. Food Chem Toxicol 2018; 119: 260-7.
[http://dx.doi.org/10.1016/j.fct.2018.03.035] [PMID: 29596976]
[60]
Su T, Zhang T, Xie S, et al. Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease. Sci Rep 2016; 6(1): 21826.
[http://dx.doi.org/10.1038/srep21826] [PMID: 26911795]
[61]
Martínez A, Zahran M, Gomez M, et al. Novel multi-target compounds in the quest for new chemotherapies against Alzheimer’s disease: An experimental and theoretical study. Bioorg Med Chem 2018; 26(17): 4823-40.
[http://dx.doi.org/10.1016/j.bmc.2018.08.019] [PMID: 30181028]
[62]
Yang HL, Cai P, Liu QH, et al. Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer’s disease. Bioorg Med Chem 2017; 25(21): 5917-28.
[http://dx.doi.org/10.1016/j.bmc.2017.08.048] [PMID: 28988627]
[63]
Martínez A, Alcendor R, Rahman T, Podgorny M, Sanogo I, Mccurdy R. Ionophoric polyphenols selectively bind Cu2+, display potent antioxidant and anti-amyloidogenic properties, and are non-toxic toward Tetrahymena thermophila. Bioorg Med Chem 2016; 24(16): 3657-70.
[http://dx.doi.org/10.1016/j.bmc.2016.06.012] [PMID: 27316544]
[64]
Bowroju SK, Mainali N, Ayyadevara S, et al. Design and synthesis of novel hybrid 8-hydroxy quinoline-indole derivatives as inhibitors of Aβ self-aggregation and metal chelation-induced Aβ aggregation. Molecules 2020; 25(16): 3610.
[http://dx.doi.org/10.3390/molecules25163610] [PMID: 32784464]
[65]
Wang XX, Xie F, Jia CC, et al. Synthesis and biological evaluation of selective histone deacetylase 6 inhibitors as multifunctional agents against Alzheimer’s disease. Eur J Med Chem 2021; 225: 113821.
[http://dx.doi.org/10.1016/j.ejmech.2021.113821] [PMID: 34517222]
[66]
Li Y, Peng P, Tang L, Hu Y, Hu Y, Sheng R. Design, synthesis and evaluation of rivastigmine and curcumin hybrids as site-activated multitarget-directed ligands for Alzheimer’s disease therapy. Bioorg Med Chem 2014; 22(17): 4717-25.
[http://dx.doi.org/10.1016/j.bmc.2014.07.009] [PMID: 25082512]
[67]
Swetha R, Kumar D, Gupta SK, et al. Multifunctional hybrid sulfonamides as novel therapeutic agents for Alzheimer’s disease. Future Med Chem 2019; 11(24): 3161-78.
[http://dx.doi.org/10.4155/fmc-2019-0106] [PMID: 31838895]
[68]
Lan JS, Xie SS, Li SY, Pan LF, Wang XB, Kong LY. Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 2014; 22(21): 6089-104.
[http://dx.doi.org/10.1016/j.bmc.2014.08.035] [PMID: 25282654]
[69]
Wichur T. Więckowska A, Więckowski K, et al. 1-Benzylpyrrolidine-3-amine-based BuChE inhibitors with anti-aggregating, antioxidant and metal-chelating properties as multifunctional agents against Alzheimer’s disease. Eur J Med Chem 2020; 187: 111916.
[http://dx.doi.org/10.1016/j.ejmech.2019.111916] [PMID: 31812794]
[70]
Mishra CB, Gusain S, Shalini S, et al. Development of novel carbazole derivatives with effective multifunctional action against Alzheimer’s diseases: Design, synthesis, in silico, in vitro and in vivo investigation. Bioorg Chem 2020; 95: 103524.
[http://dx.doi.org/10.1016/j.bioorg.2019.103524] [PMID: 31918396]
[71]
Digiacomo M, Chen Z, Wang S, et al. Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD. Bioorg Med Chem Lett 2015; 25(4): 807-10.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.084] [PMID: 25597007]
[72]
Nesi G, Chen Q, Sestito S, et al. Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer’s disease. Eur J Med Chem 2017; 141: 232-9.
[http://dx.doi.org/10.1016/j.ejmech.2017.10.006] [PMID: 29031070]
[73]
Manral A, Saini V, Meena P, Tiwari M. Multifunctional novel Diallyl disulfide (DADS) derivatives with β-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer’s disease. Bioorg Med Chem 2015; 23(19): 6389-403.
[http://dx.doi.org/10.1016/j.bmc.2015.08.024] [PMID: 26337018]
[74]
Wang J, Wang ZM, Li XM, et al. 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): 4324-38.
[http://dx.doi.org/10.1016/j.bmc.2016.07.025] [PMID: 27460699]
[75]
Jalili-Baleh L, Forootanfar H. Küçükkılınç TT, et al. Design, synthesis and evaluation of novel multi-target-directed ligands for treatment of Alzheimer’s disease based on coumarin and lipoic acid scaffolds. Eur J Med Chem 2018; 152: 600-14.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.058] [PMID: 29763808]
[76]
Hamulakova S, Poprac P, Jomova K, et al. Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer’s disease using multifunctional tacrine-coumarin hybrid molecules. J Inorg Biochem 2016; 161: 52-62.
[http://dx.doi.org/10.1016/j.jinorgbio.2016.05.001] [PMID: 27230386]
[77]
Patel DV, Patel NR, Kanhed AM, et al. Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents. Bioorg Chem 2020; 101: 103977.
[http://dx.doi.org/10.1016/j.bioorg.2020.103977] [PMID: 32485470]
[78]
Avramovich-Tirosh Y, Amit T, Bar-Am O, Zheng H, Fridkin M, Youdim MBH. Therapeutic targets and potential of the novel brain- permeable multifunctional iron chelator?monoamine oxidase inhibitor drug, M-30, for the treatment of Alzheimer’s disease. J Neurochem 2007; 100(2): 490-502.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04258.x] [PMID: 17144902]
[79]
Zheng H, Gal S, Weiner LM, et al. Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: In vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. J Neurochem 2005; 95(1): 68-78.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03340.x] [PMID: 16181413]
[80]
Kupershmidt L, Amit T, Bar-Am O, Youdim MBH, Weinreb O. The novel multi-target iron chelating-radical scavenging compound M30 possesses beneficial effects on major hallmarks of Alzheimer’s disease. Antioxid Redox Signal 2012; 17(6): 860-77.
[http://dx.doi.org/10.1089/ars.2011.4279] [PMID: 22360429]
[81]
Liu J, Qiu J, Wang M, et al. Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer’s disease. Biochim Biophys Acta, Gen Subj 2014; 1840(9): 2886-903.
[http://dx.doi.org/10.1016/j.bbagen.2014.05.005] [PMID: 24821011]
[82]
Liu Q, Qiang X, Li Y, et al. Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 2015; 23(5): 911-23.
[http://dx.doi.org/10.1016/j.bmc.2015.01.042] [PMID: 25678013]
[83]
Tian C, Qiang X, Song Q, et al. Flurbiprofen-chalcone hybrid mannich base derivatives as balanced multifunctional agents against Alzheimer’s disease: Design, synthesis and biological evaluation. Bioorg Chem 2020; 94: 103477.
[http://dx.doi.org/10.1016/j.bioorg.2019.103477] [PMID: 31818478]
[84]
Hiremathad A, Keri RS, Esteves AR, Cardoso SM, Chaves S, Santos MA. Novel tacrine-hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer’s disease. Eur J Med Chem 2018; 148: 255-67.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.023] [PMID: 29466775]
[85]
Chen Z, Digiacomo M, Tu Y, et al. Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer’s disease. Eur J Med Chem 2017; 125: 784-92.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.052] [PMID: 27736684]
[86]
Sun L, Cho HJ, Sen S, et al. Amphiphilic distyrylbenzene derivatives as potential therapeutic and imaging agents for soluble and insoluble amyloid β aggregates in Alzheimer’s disease. J Am Chem Soc 2021; 143(27): 10462-76.
[http://dx.doi.org/10.1021/jacs.1c05470] [PMID: 34213901]
[87]
Cho HJ, Sharma AK, Zhang Y, Gross ML, Mirica LM. A multifunctional chemical agent as an attenuator of amyloid burden and neuroinflammation in Alzheimer’s disease. ACS Chem Neurosci 2020; 11(10): 1471-81.
[http://dx.doi.org/10.1021/acschemneuro.0c00114] [PMID: 32310630]
[88]
Shi XL, Wu JD, Liu P, Liu ZP. Synthesis and evaluation of novel GSK-3β inhibitors as multifunctional agents against Alzheimer’s disease. Eur J Med Chem 2019; 167: 211-25.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.001] [PMID: 30772605]
[89]
Morel I, Cillard J, Lescoat G, et al. Antioxidant and free radical scavenging activities of the iron chelators pyoverdin and hydroxypyrid-4-ones in iron-loaded hepatocyte cultures: Comparison of their mechanism of protection with that of desferrioxamine. Free Radic Biol Med 1992; 13(5): 499-508.
[http://dx.doi.org/10.1016/0891-5849(92)90144-6] [PMID: 1334028]
[90]
Molina-Holgado F, Gaeta A, Francis PT, Williams RJ, Hider RC. Neuroprotective actions of deferiprone in cultured cortical neurones and SHSY-5Y cells. J Neurochem 2008; 105(6): 2466-76.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05332.x] [PMID: 18331585]
[91]
Prasanthi JRP, Schrag M, Dasari B, et al. Deferiprone reduces amyloid-β and tau phosphorylation levels but not reactive oxygen species generation in hippocampus of rabbits fed a cholesterol-enriched diet. J Alzheimers Dis 2012; 30(1): 167-82.
[http://dx.doi.org/10.3233/JAD-2012-111346] [PMID: 22406440]
[92]
Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci 2014; 6: 218.
[http://dx.doi.org/10.3389/fnagi.2014.00218] [PMID: 25309423]
[93]
Lu C, Guo Y, Yan J, et al. Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer’s disease. J Med Chem 2013; 56(14): 5843-59.
[http://dx.doi.org/10.1021/jm400567s] [PMID: 23799643]
[94]
Solberg NO, Chamberlin R, Vigil JR, et al. Optical and SPION-enhanced MR imaging shows that trans-stilbene inhibitors of NF-κB concomitantly lower Alzheimer’s disease plaque formation and microglial activation in AβPP/PS-1 transgenic mouse brain. J Alzheimers Dis 2014; 40(1): 191-212.
[http://dx.doi.org/10.3233/JAD-131031] [PMID: 24413613]
[95]
Cao Y, Xu W, Huang Y, Zeng X. Licochalcone B, a chalcone derivative from Glycyrrhiza inflata, as a multifunctional agent for the treatment of Alzheimer’s disease. Nat Prod Res 2020; 34(5): 736-9.
[http://dx.doi.org/10.1080/14786419.2018.1496429] [PMID: 30345819]
[96]
Ak T. Gülçin İ Antioxidant and radical scavenging properties of curcumin. Chem Biol Interact 2008; 174(1): 27-37.
[http://dx.doi.org/10.1016/j.cbi.2008.05.003] [PMID: 18547552]
[97]
Shakeri A, Panahi Y, Johnston TP, Sahebkar A. Biological properties of metal complexes of curcumin. Biofactors 2019; 45(3): 304-17.
[http://dx.doi.org/10.1002/biof.1504] [PMID: 31018024]
[98]
Hamaguchi T, Ono K, Yamada M. Review: Curcumin and Alzheimer’s disease. CNS Neurosci Ther 2010; 16(5): 285-97.
[http://dx.doi.org/10.1111/j.1755-5949.2010.00147.x] [PMID: 20406252]
[99]
Sang Z, Qiang X, Li Y, et al. Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 2015; 94: 348-66.
[http://dx.doi.org/10.1016/j.ejmech.2015.02.063] [PMID: 25778991]
[100]
Tang M, Taghibiglou C. The mechanisms of action of curcumin in Alzheimer’s disease. J Alzheimers Dis 2017; 58(4): 1003-16.
[http://dx.doi.org/10.3233/JAD-170188] [PMID: 28527218]
[101]
Sun ZZ, Li XY, Wang S, Shen L, Ji HF. Bidirectional interactions between curcumin and gut microbiota in transgenic mice with Alzheimer’s disease. Appl Microbiol Biotechnol 2020; 104(8): 3507-15.
[http://dx.doi.org/10.1007/s00253-020-10461-x] [PMID: 32095862]
[102]
Sang Z, Wang K, Zhang P, Shi J, Liu W, Tan Z. Design, synthesis, in-silico and biological evaluation of novel chalcone derivatives as multi-function agents for the treatment of Alzheimer’s disease. Eur J Med Chem 2019; 180: 238-52.
[http://dx.doi.org/10.1016/j.ejmech.2019.07.021] [PMID: 31310916]
[103]
Sang Z, Wang K, Shi J, Liu W, Tan Z. Design, synthesis, in-silico and biological evaluation of novel chalcone-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 2019; 178: 726-39.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.026] [PMID: 31229875]
[104]
Nam G, Ji Y, Lee HJ, et al. Orobol: An isoflavone exhibiting regulatory multifunctionality against four pathological features of Alzheimer’s disease. ACS Chem Neurosci 2019; 10(8): 3386-90.
[http://dx.doi.org/10.1021/acschemneuro.9b00232] [PMID: 31199606]
[105]
Ademosun AO, Oboh G, Bello F, Ayeni PO. Antioxidative properties and effect of quercetin and its glycosylated form (rutin) on acetylcholinesterase and butyrylcholinesterase activities. J Evid Based Complementary Altern Med 2016; 21(4): NP11-7.
[http://dx.doi.org/10.1177/2156587215610032] [PMID: 26438716]
[106]
da Silva WMB, de Oliveira PS, Alves DR, et al. Synthesis of quercetin-metal complexes, in vitro and in silico anticholinesterase and antioxidant evaluation, and in vivo toxicological and anxiolitic activities. Neurotox Res 2020; 37(4): 893-903.
[http://dx.doi.org/10.1007/s12640-019-00142-7] [PMID: 31853730]
[107]
Khan H, Ullah H, Aschner M, Cheang WS, Akkol EK. Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules 2019; 10(1): 59.
[http://dx.doi.org/10.3390/biom10010059] [PMID: 31905923]
[108]
Kim JH, Lee J, Lee S, Cho EJ. Quercetin and quercetin-3-β-d-glucoside improve cognitive and memory function in Alzheimer’s disease mouse. Applied Biol Chem 2016; 59(5): 721-8.
[http://dx.doi.org/10.1007/s13765-016-0217-0]
[109]
Guo LL, Guan ZZ, Huang Y, Wang YL, Shi JS. The neurotoxicity of β-amyloid peptide toward rat brain is associated with enhanced oxidative stress, inflammation and apoptosis, all of which can be attenuated by scutellarin. Exp Toxicol Pathol 2013; 65(5): 579-84.
[http://dx.doi.org/10.1016/j.etp.2012.05.003] [PMID: 22739358]
[110]
Hong H, Liu GQ. Protection against hydrogen peroxide-induced cytotoxicity in PC12 cells by scutellarin. Life Sci 2004; 74(24): 2959-73.
[http://dx.doi.org/10.1016/j.lfs.2003.09.074] [PMID: 15051420]
[111]
Liu Q, Li X, Ouyang X, Chen D. Dual effect of glucuronidation of a pyrogallol-type phytophenol antioxidant: A comparison between scutellarein and scutellarin. Molecules 2018; 23(12): 3225.
[http://dx.doi.org/10.3390/molecules23123225] [PMID: 30563286]
[112]
Zeng YQ, Cui YB, Gu JH, Liang C, Zhou XF. Scutellarin mitigates Aβ-induced neurotoxicity and improves behavior impairments in AD mice. Molecules 2018; 23(4): 869.
[http://dx.doi.org/10.3390/molecules23040869] [PMID: 29642616]
[113]
Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MBH. Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol Nutr Food Res 2006; 50(2): 229-34.
[http://dx.doi.org/10.1002/mnfr.200500156] [PMID: 16470637]
[114]
Mandel SA, Avramovich-Tirosh Y, Reznichenko L, et al. Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals 2005; 14(1-2): 46-60.
[http://dx.doi.org/10.1159/000085385] [PMID: 15956814]
[115]
Kim E, Hwang K, Lee J, et al. Skin protective effect of epigallocatechin gallate. Int J Mol Sci 2018; 19(1): 173.
[http://dx.doi.org/10.3390/ijms19010173] [PMID: 29316635]
[116]
Syarifah-Noratiqah SB, Naina-Mohamed I, Zulfarina MS, Qodriyah HMS. Natural polyphenols in the treatment of Alzheimer’s disease. Curr Drug Targets 2018; 19(8): 927-37.
[http://dx.doi.org/10.2174/1389450118666170328122527] [PMID: 28356027]
[117]
Kantham S, Chan S, McColl G, et al. Effect of the biphenyl neolignan honokiol on Aβ42-induced toxicity in caenorhabditis elegans, Aβ42 fibrillation, cholinesterase activity, DPPH radicals, and iron(II) chelation. ACS Chem Neurosci 2017; 8(9): 1901-12.
[http://dx.doi.org/10.1021/acschemneuro.7b00071] [PMID: 28650631]
[118]
Rajasekhar K, Samanta S, Bagoband V, Murugan NA, Govindaraju T. Antioxidant berberine-derivative inhibits multifaceted amyloid toxicity. iScience 2020; 23(4): 101005.
[http://dx.doi.org/10.1016/j.isci.2020.101005] [PMID: 32272441]
[119]
Cao YY, Wang L, Ge H, et al. Salvianolic acid A, a polyphenolic derivative from Salvia miltiorrhiza bunge, as a multifunctional agent for the treatment of Alzheimer’s disease. Mol Divers 2013; 17(3): 515-24.
[http://dx.doi.org/10.1007/s11030-013-9452-z] [PMID: 23703159]
[120]
Sun Y, Zhu H, Wang J, Liu Z, Bi J. Isolation and purification of salvianolic acid A and salvianolic acid B from Salvia miltiorrhiza by high-speed counter-current chromatography and comparison of their antioxidant activity. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877(8-9): 733-7.
[http://dx.doi.org/10.1016/j.jchromb.2009.02.013] [PMID: 19237321]
[121]
Liu C, Kou X, Wang X, Wu J, Yang A, Shen R. Novel chrysin derivatives as hidden multifunctional agents for anti-Alzheimer’s disease: Design, synthesis and in vitro evaluation. Eur J Pharm Sci 2021; 166: 105976.
[http://dx.doi.org/10.1016/j.ejps.2021.105976] [PMID: 34419572]
[122]
Wu J, Kou X, Ju H, Zhang H, Yang A, Shen R. Design, synthesis and biological evaluation of naringenin carbamate derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 2021; 49: 128316.
[http://dx.doi.org/10.1016/j.bmcl.2021.128316] [PMID: 34391893]
[123]
Kou X, Liu J, Chen Y, Yang A, Shen R. Emodin derivatives with multi-factor anti-AD activities: AChE inhibitor, anti-oxidant and metal chelator. J Mol Struct 2021; 1239: 130459.
[http://dx.doi.org/10.1016/j.molstruc.2021.130459]
[124]
Kou X, Li X, Hu C, et al. Multifunctional fluorescence sensor as a potential theranostic agent against Alzheimer’s disease. Spectrochim Acta A Mol Biomol Spectrosc 2022; 267(Pt 2): 120587.
[http://dx.doi.org/10.1016/j.saa.2021.120587] [PMID: 34782268]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy