Novel Multitarget-directed Tacrine Derivatives As Potential Candidates for the Treatment of Alzheimer's Disease

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2017 Jan 31

PMID 28133981

Citations 23

Authors

Wen-Yu Wu

Yu-Chen Dai

Nian-Guang Li

Ze-Xi Dong

Ting Gu

Zhi-Hao Shi

Xin Xue

Yu-Ping Tang

Jin-Ao Duan

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, which is complex and progressive; it has not only threatened the health of elderly people, but also burdened the whole social medical and health system. The available therapy for AD is limited and the efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the design and development of efficacious and safe anti-AD agents has become a hotspot in the field of pharmaceutical research. Due to the multifactorial etiology of AD, the multitarget-directed ligands (MTDLs) approach is promising in search for new drugs for AD. Tacrine, which is the first acetylcholinesterase (AChE) inhibitor, has been selected as the ideal active fragment because of its simple structure, clear activity, and its superiority in the structural modification, thus it could be introduced into the overall molecular skeletons of the multi-target-directed anti-AD agents. In this review, we have summarized the recent advances (2012 to the present) in the chemical modification of tacrine, which could provide the reference for the further study of novel multi-target-directed tacrine derivatives to treat AD.

Citing Articles

Therapeutic Options in Alzheimer's Disease: From Classic Acetylcholinesterase Inhibitors to Multi-Target Drugs with Pleiotropic Activity.

Cacabelos R, Martinez-Iglesias O, Cacabelos N, Carrera I, Corzo L, Naidoo V Life (Basel). 2025; 14(12.

PMID: 39768263 PMC: 11678002. DOI: 10.3390/life14121555.

Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease.

Londhe S, Shenoy M, Kini S, Walhekar V, Kumar D Curr Top Med Chem. 2024; 24(19):1738-1753.

PMID: 38859777 DOI: 10.2174/0115680266295740240602122613.

Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer's Disease: AChE, MAO-B, and COX-2 as Molecular Targets.

Asghar S, Mushtaq N, Ahmed A, Anwar L, Munawar R, Akhtar S Molecules. 2024; 29(2).

PMID: 38276568 PMC: 10820890. DOI: 10.3390/molecules29020490.

Structural, harmonic force field and vibrational studies of cholinesterase inhibitor tacrine used for treatment of Alzheimer's disease.

Sundius T, Brandan S Heliyon. 2023; 9(6):e17280.

PMID: 37441405 PMC: 10333470. DOI: 10.1016/j.heliyon.2023.e17280.

A Multifunctional (-)-Meptazinol-Serotonin Hybrid Ameliorates Oxidative Stress-Associated Apoptotic Neuronal Death and Memory Deficits via Activating the Nrf2/Antioxidant Enzyme Pathway.

Zhao F, Zhao L, Zhou Y, Tan X, Yang Y, Ni W Oxid Med Cell Longev. 2023; 2023:6935947.

PMID: 36819782 PMC: 9935814. DOI: 10.1155/2023/6935947.

References

Querfurth H, LaFerla F . Alzheimer's disease. N Engl J Med. 2010; 362(4):329-44. DOI: 10.1056/NEJMra0909142. View

Bjorklund C, Oscarson S, Benkestock K, Borkakoti N, Jansson K, Lindberg J . Design and synthesis of potent and selective BACE-1 inhibitors. J Med Chem. 2010; 53(4):1458-64. DOI: 10.1021/jm901168f. View

De Ferrari G, Canales M, Shin I, Weiner L, Silman I, Inestrosa N . A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry. 2001; 40(35):10447-57. DOI: 10.1021/bi0101392. View

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; 62:745-53. DOI: 10.1016/j.ejmech.2013.01.039. View

Digiacomo M, Chen Z, Wang S, Lapucci A, Macchia M, Yang X . Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD. Bioorg Med Chem Lett. 2015; 25(4):807-10. DOI: 10.1016/j.bmcl.2014.12.084. View

Sui X, Gao C . Huperzine A ameliorates damage induced by acute myocardial infarction in rats through antioxidant, anti-apoptotic and anti-inflammatory mechanisms. Int J Mol Med. 2013; 33(1):227-33. DOI: 10.3892/ijmm.2013.1546. View

Centuriao F, Corte C, Paixao M, Braga A, Zeni G, Emanuelli T . Effect of ebselen and organochalcogenides on excitotoxicity induced by glutamate in isolated chick retina. Brain Res. 2005; 1039(1-2):146-52. DOI: 10.1016/j.brainres.2005.01.062. View

Luo Z, Sheng J, Sun Y, Lu C, Yan J, Liu A . Synthesis and evaluation of multi-target-directed ligands against Alzheimer's disease based on the fusion of donepezil and ebselen. J Med Chem. 2013; 56(22):9089-99. DOI: 10.1021/jm401047q. View

Dogterom P, Nagelkerke J, Mulder G . Hepatotoxicity of tetrahydroaminoacridine in isolated rat hepatocytes: effect of glutathione and vitamin E. Biochem Pharmacol. 1988; 37(12):2311-3. DOI: 10.1016/0006-2952(88)90356-5. View

10.

Quintanilla R, Munoz F, Metcalfe M, Hitschfeld M, Olivares G, Godoy J . Trolox and 17beta-estradiol protect against amyloid beta-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway. J Biol Chem. 2005; 280(12):11615-25. DOI: 10.1074/jbc.M411936200. View

11.

Cai F, Wang F, Lin F, Liu C, Ma L, Liu J . Redox modulation of long-term potentiation in the hippocampus via regulation of the glycogen synthase kinase-3beta pathway. Free Radic Biol Med. 2008; 45(7):964-70. DOI: 10.1016/j.freeradbiomed.2008.06.014. View

12.

Ono M, Kung M, Hou C, Kung H . Benzofuran derivatives as Abeta-aggregate-specific imaging agents for Alzheimer's disease. Nucl Med Biol. 2002; 29(6):633-42. DOI: 10.1016/s0969-8051(02)00326-8. View

13.

Greig N, Utsuki T, Ingram D, Wang Y, Pepeu G, Scali C . Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc Natl Acad Sci U S A. 2005; 102(47):17213-8. PMC: 1288010. DOI: 10.1073/pnas.0508575102. View

14.

Fernandez-Bachiller M, Perez C, Gonzalez-Munoz G, Conde S, Lopez M, Villarroya M . Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J Med Chem. 2010; 53(13):4927-37. DOI: 10.1021/jm100329q. View

15.

Klaver D, Wilce M, Cui H, Hung A, Gasperini R, Foa L . Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions. Biol Chem. 2010; 391(8):849-59. DOI: 10.1515/BC.2010.089. View

16.

Keri R, Quintanova C, Marques S, Esteves A, Cardoso S, Santos M . Design, synthesis and neuroprotective evaluation of novel tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer's disease. Bioorg Med Chem. 2013; 21(15):4559-69. DOI: 10.1016/j.bmc.2013.05.028. View

17.

Kalai T, Mugesh G, Roy G, Sies H, Berente Z, Hideg K . Combining benzo[d]isoselenazol-3-ones with sterically hindered alicyclic amines and nitroxides: enhanced activity as glutathione peroxidase mimics. Org Biomol Chem. 2005; 3(19):3564-9. DOI: 10.1039/b509865c. View

18.

Leon R, Garcia A, Marco-Contelles J . Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease. Med Res Rev. 2011; 33(1):139-89. DOI: 10.1002/med.20248. View

19.

Meng Q, Ru J, Zhang G, Shen C, Schmitmeier S, Bader A . Re-evaluation of tacrine hepatotoxicity using gel entrapped hepatocytes. Toxicol Lett. 2006; 168(2):140-7. DOI: 10.1016/j.toxlet.2006.11.009. View

20.

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View