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Review Article

Novel multitarget-directed tacrine derivatives as potential candidates for the treatment of Alzheimer’s disease

, , , , , , , & show all
Pages 572-587 | Received 14 Apr 2016, Accepted 28 Jun 2016, Published online: 29 Jan 2017

References

  • Querfurth HW, Laferla FM. Alzheimer's disease. N Engl J Med 2010;362:329–44.
  • Ritchie CW, Molinuevo JL, Truyen L, et al. Development of interventions for the secondary prevention of Alzheimer's dementia: the European Prevention of Alzheimer's Dementia (EPAD) project. Lancet Psychiatry 2016; 3:179–86.
  • Guzior N, Wieckowska A, Panek D, Malawska B. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease. Curr Med Chem 2015;22:373–404.
  • Leon R, Garcia AG, Marco-Contelles J. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease. Med Res Rev 2013;33:139–89.
  • Martinez A, Emerging drugs and targets for Alzheimer’s disease: Volume 1: Beta-amyloid, Tau protein and Glucose metabolism. Cambridge: Royal Society of Chemistry; 2010:938–939.
  • Cavalli A, Bolognesi ML, Minarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008;51:347–72.
  • Chen X, Decker M. Multi-target compounds acting in the central nervous system designed from natural products. Curr Med Chem 2013;20:1673–85.
  • Wang Y, Wang F, Yu JP, et al. Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca2+ overload. Bioorg Med Chem 2012;20:6513–22.
  • Decker M, Kraus B, Heilmann J. Design, synthesis and pharmacological evaluation of hybrid molecules out of quinazolinimines and lipoic acid lead to highly potent and selective butyrylcholinesterase inhibitors with antioxidant properties. Bioorg Med Chem 2008;16:4252–61.
  • Mohamed T, Rao PP. Alzheimer's disease: emerging trends in small molecule therapies. Curr Med Chem 2011;18:4299–320.
  • Romero A, Cacabelos R, Oset-Gasque MJ, et al. Novel tacrine- related drugs as potential candidates for the treatment of Alzheimer's disease. Bioorg Med Chem Lett 2013;23:1916–22.
  • Minarini A, Milelli A, Simoni E, et al. Multifunctional tacrine derivatives in Alzheimer's disease. Curr Top Med Chem 2013;13:1771–86.
  • Musial A, Bajda M, Malawska B. Recent developments in cholinesterases inhibitors for Alzheimer's disease treatment. Curr Med Chem 2007;14:2654–79.
  • Gupta RC. Tacrine. Encyclopedia of Toxicology 2005; 332:130–1.
  • Meng Q, Ru J, Zhang GL, et al. Re-evaluation of tacrine hepatotoxicity using gel entrapped hepatocytes. Toxicol Lett 2007;168:140–7.
  • Chen Y, Sun HP, Li W. Progress in novel multi-target-directed tacrine derivatives. Prog Pharm Sci 2014;38:656–64.
  • Tumiatti V, Minarini A, Bolognesi ML, et al. Tacrine derivatives and Alzheimer's disease. Curr Med Chem 2010;17:1825–38.
  • Ladner CJ, Lee JM. Pharmacological drug treatment of Alzheimer disease: the cholinergic hypothesis revisited. J Neuropathol Exp Neurol 1998;57:719–31.
  • Sussman JL, Harel M, Frolow F, et al. Atomic structure of acetylcholinesterase from Torpedo californica: a protopic acetylcholine-binding protein. Science 1991;253:827–79.
  • Bourne Y, Grassi J, Bougis PE, Marchot P. Conformational flexibility of the acetylcholinesterase tetramer suggested by x-ray crystallography. J Biol Chem 1999;274:30370–6.
  • Kryger G, Harel M, Giles K, et al. Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr D Biol Crystallogr 2000;56:1385–94.
  • Cheung J, Rudolph MJ, Burshteyn F, et al. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 2012;55:10282–6.
  • Dvir H, Silman I, Harel M, et al. Acetylcholinesterase: from 3D structure to function. Chem Biol Interact 2010;187:10–22.
  • Harel M, Sonoda LK, Silman I, et al. Crystal structure of thioflavin T bound to the peripheral site of Torpedo californica acetylcholinesterase reveals how thioflavin T acts as a sensitive flu. J Am Chem Soc 2008;130:7856–61.
  • Bourne Y, Taylor P, Radic Z, Marchot P. Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site. EMBO J 2003;22:1–12.
  • Harel M, Quinn DM, Nair HK, et al. The X-ray structure of a transition state analog complex reveals the molecular origins of the catalytic power and substrate specificity of acetylcholinesterase. J Am Chem Soc 1996;118:2340–6.
  • Colletier JP, Fournier D, Greenblatt HM, et al. Structural insights into substrate traffic and inhibition in acetylcholinesterase. EMBO J 2006;25:2746–56.
  • Szegletes T, Mallender WD, Rosenberry TL. Nonequilibrium analysis alters the mechanistic interpretation of inhibition of acetylcholinesterase by peripheral site ligands. Biochemistry 1998;37:4206–16.
  • De Ferrari GV, Canales MA, Shin I, et al. A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry 2001;40:10447–57.
  • Chambers C, Luo C, Tong M, et al. Probing the role of amino acids in oxime-mediated reactivation of nerve agent-inhibited human acetylcholinesterase. Toxicol In Vitro 2015;29:408–14.
  • Bartolini M, Bertucci C, Cavrini V, Andrisano V. beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 2003;65:407–16.
  • Dinamarca MC, Sagal JP, Quintanilla RA, et al. Amyloid-beta-acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Abeta peptide. Implications for the pathogenesis of Alzheimer's disease. Mol Neurodegener 2010;5:4.
  • Reale M, Di Nicola M, Velluto L, et al. Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-beta ex vivo activation of peripheral chemo-cytokines from Alzheimer’s disease subjects: exploring the cholinergic anti-inflammatory pathway. Curr Alzheimer Res 2014;11:608–22.
  • Ballard CG, Greig NH, Guillozet-Bongaarts AL, et al. Cholinesterases: roles in the brain during health and disease. Curr Alzheimer Res 2005;2:307–18.
  • Greig NH, Utsuki T, Ingram DK, et al. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc Natl Acad Sci USA 2005;102:17213–18.
  • Furukawahibi Y, Alkam T, Nitta A, et al. Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-beta peptide in mice. Behav Brain Res 2011;225:222–9.
  • Anand P, Singh B. A review on cholinesterase inhibitors for Alzheimer's disease. Arch Pharm Res 2013;36:375–99.
  • Harel M, Schalk I, Ehret-Sabatier L, et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 1993;90:9031–5.
  • Pang YP, Quiram P, Jelacic T, et al. Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease. J Biol Chem 1996;271:23646–9.
  • Cappelli A, Gallelli A, Manini M, et al. Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands. Development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties. J Med Chem 2005;48:3564–75.
  • Hu MK, Wu LJ, Hsiao G, Yen MH. Homodimeric tacrine congeners as acetylcholinesterase inhibitors. J Med Chem 2002;45:2277–82.
  • Shao D, Zou C, Luo C, et al. Synthesis and evaluation of tacrine-E2020 hybrids as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease. Bioorg Med Chem Lett 2004;14:4639–42.
  • Camps P, Formosa X, Galdeano C, et al. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. J Med Chem 2008;51:3588–98.
  • Alonso D, Dorronsoro I, Rubio L, et al. Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorg Med Chem 2005;13:6588–97.
  • Munoz-Ruiz P, Rubio L, Garcia-Palomero E, et al. Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer’s disease. J Med Chem 2005;48:7223–33.
  • Krasinski A, Radic Z, Manetsch R, et al. In situ selection of lead compounds by click chemistry: target-guided optimization of acetylcholinesterase inhibitors. J Am Chem Soc 2005;127:6686–92.
  • Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci USA 1994;91:12243–7.
  • Thorsett ED, Latimer LH. Therapeutic approaches to Alzheimer's disease. Curr Opin Chem Biol 2000;4:377–82.
  • Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353–6.
  • Paul S, Planque S, Nishiyama Y. Beneficial catalytic immunity to Aβ peptide. Rejuvenation Res 2010;13:179–87.
  • Schott Y, Decker M, Rommelspacher H, Lehmann J. 6-Hydroxy- and 6-methoxy-beta-carbolines as acetyl- and butyrylcholinesterase inhibitors. Bioorg Med Chem Lett 2006;16:5840–3.
  • Rook Y, Schmidtke KU, Gaube F, et al. Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents. J Med Chem 2010;53:3611–17.
  • Herraiz T, Galisteo J. Tetrahydro-β-carboline alkaloids that occur in foods and biological systems act as radical scavengers and antioxidants in the ABTS assay. Free Radic Res 2002;36:923–8.
  • Herraiz T, Galisteo J. Tetrahydro-beta-carboline alkaloids occur in fruits and fruit juices. Activity as antioxidants and radical scavengers. J Agric Food Chem 2003;51:7156–61.
  • Matsutomo T, Stark TD, Hofmann T. In vitro activity-guided identification of antioxidants in aged garlic extract. J Agric Food Chem 2013;61:3059–67.
  • Lan JS, Xie SS, Li SY, et al. Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease. Bioorg Med Chem 2014;22:6089–104.
  • Choi MM, Kim EA, Hahn HG, et al. Protective effect of benzothiazole derivative KHG21834 on amyloid beta-induced neurotoxicity in PC12 cells and cortical and mesencephalic neurons. Toxicology 2007;239:156–66.
  • Keri RS, Quintanova C, Marques SM, et al. Design, synthesis and neuroprotective evaluation of novel tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer's disease. Bioorg Med Chem 2013;21:4559–69.
  • Zhang WT, Ruan JL, Wu PF, et al. Design, synthesis, and cytoprotective effect of 2-aminothiazole analogues as potent poly (ADP-ribose) polymerase-1 inhibitors. J Med Chem 2009;52:718–25.
  • Elsinghorst PW, Tanarro CMG, Gutschow M. Novel heterobivalent tacrine derivatives as cholinesterase inhibitors with no table selectivity toward butyrylcholinesterase. J Med Chem 2006;49:7540–4.
  • Ucar G, Gokhan N, Yesilada A, Bilgin AA. 1-N-substituted thiocarbomoyl-3-phenyl-5-thienyl-2-prozolines: a novel cholinesterase and selected monoamine oxidase B inhibitors for the treatment of Parkinson’s and Alzheimer’s diseases. Neurosci Lett 2005;382:327–31.
  • Zhang C, Du QY, Chen LD, et al. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease. Eur J Med Chem 2016;116:200–9.
  • Bolognesi ML, Chiriano G, Bartolini M, et al. Synthesis of monomeric derivatives to probe memoquin's bivalent interactions. J Med Chem 2011;54:8299–304.
  • Prati F, Uliassi E, Bolognesi ML. Two diseases, one approach: multitarget drug discovery in Alzheimer’s and neglected tropical diseases. Med Chem Comm 2014;5:853–61.
  • Bartolini M, Bertucci C, Bolognesi ML, et al. Insight into the kinetic of amyloid beta (1-42) peptide self-aggregation: elucidation of inhibitors' mechanism of action. Chembiochem 2007;8:2152–61.
  • Scherzer-Attali R, Pellarin R, Convertino M, et al. Complete phenotypic recovery of an Alzheimer’s disease model by a quinone-tryptophan hybrid aggregation inhibitor. PLoS One 2010;5:e11101.
  • Nepovimova E, Uliassi E, Korabecny J, et al. Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-beta aggregation and to exert anticholinesterase and antioxidant effects. J Med Chem 2014;57:8576–89.
  • Klaver DW, Wilce MC, Cui H, et al. Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions. Biol Chem 2010;391:849–59.
  • Luo X, Yan R. Inhibition of BACE1 for therapeutic use in Alzheimer's disease. Int J Clin Exp Pathol 2010;3:618–28.
  • Bjorklund C, Oscarson S, Benkestock K, et al. Design and synthesis of potent and selective BACE-1 inhibitors. J Med Chem 2010;53:1458–64.
  • Venugopal C, Demos CM, Rao KS, et al. Beta-secretase: structure, function, and evolution. CNS Neurol Disord Drug Targets 2008;7:278–94.
  • Galdeano C, Viayna E, Sola I, et al. Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases. J Med Chem 2012;55:661–9.
  • Spencer JP. The impact of flavonoids on memory: physiological and molecular considerations. Chem Soc Rev 2009;38:1152–61.
  • Spencer JP. Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain. Proc Nutr Soc 2010;69:244–60.
  • Shimmyo Y, Kihara T, Akaike A, et al. Flavonols and flavones as BACE-1 inhibitors: structure-activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features. Biochim Biophys Acta 2008;1780:819–25.
  • Fernandez-Bachiller MI, Perez C, Monjas L, et al. New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and β-amyloid-reducing properties. J Med Chem 2012;55:1303–17.
  • Baharloo F, Moslemin MH, Nadri H, et al. Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors. Eur J Med Chem 2015;93:196–201.
  • Howlett DR, Perry AE, Godfrey F, et al. Inhibition of fibril formation in beta-amyloid peptide by a novel series of benzofurans. Biochem J 1999;340:283–9.
  • Byun JH, Kim H, Kim Y, et al. Aminostyrylbenzofuran derivatives as potent inhibitors for Abeta fibril formation. Bioorg Med Chem Lett 2008;18:5591–3.
  • Ono M, Kung MP, Hou C, Kung HF. Benzofuran derivatives as Abeta-aggregate-specific imaging agents for Alzheimer's disease. Nucl Med Biol 2002;29:633–42.
  • Allsop D, Gibson G, Martin IK, et al. 3-p-Toluoyl-2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran and 2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran do not act as surfactants or micelles when inhibiting the aggregation of beta-amyloid peptide. Bioorg Med Chem Lett 2001;11:255–7.
  • Zha XM, Lamba D, Zhang LL, et al. Novel tacrine-benzofuran hybrids as potent multitarget-directed ligands for the treatment of Alzheimer’s disease: design, synthesis, biological evaluation, and X-ray crystallography. J Med Chem 2016;59:114–31.
  • Ghosh AK, Brindisi M, Tang J. Developing beta-secretase inhibitors for treatment of Alzheimer’s disease. J Neurochem 2012;120:71–83.
  • Padurariu M, Ciobica A, Lefter R, et al. The oxidative stress hypothesis in Alzheimer's disease. Psychiatr Danub 2013;25:401–9.
  • Skrzydlewska E, Farbiszewski R. Trolox-derivative antioxidant protects against methanol-induced damage. Fundam Clin Pharmacol 1997;11:460–5.
  • Quintanilla RA, Munoz FJ, Metcalfe MJ, et al. 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;280:11615–25.
  • Dogterom P, Nagelkerke JF, Mulder GJ. Hepatotoxicity of tetrahydroaminoacridine in isolated rat hepatocytes: effect of glutathione and vitamin E. Biochem Pharmacol 1988;37:2311–13.
  • Xie SS, Lan JS, Wang XB, et al. Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties. Eur J Med Chem 2015;93:42–50.
  • Tang YZ, Liu ZQ. Free-radical-scavenging effect of carbazole derivatives on AAPH-induced hemolysis of human erythrocytes. Bioorg Med Chem 2007;15:1903–13.
  • Thiratmatrakul S, Yenjai C, Waiwut P, et al. Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem 2014;75:21–30.
  • Sharma S, Rakoczy S, Brown-Borg H. Assessment of spatial memory in mice. Life Sci 2010;87:521–36.
  • Rosini M, Andrisano V, Bartolini M, et al. Rational approach to discover multipotent anti-Alzheimer drugs. J Med Chem 2005;48:360–3.
  • Fang L, Kraus B, Lehmann J, et al. Design and synthesis of tacrine-ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates. Bioorg Med Chem Lett 2008;18:2905–9.
  • Chao X, He X, Yang Y, et al. Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg Med Chem Lett 2012;22:6498–502.
  • 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;25:807–10.
  • Quintanova C, Keri RS, Marques SM, et al. Design, synthesis and bioevaluation of tacrine hybrids with cinnamate and cinnamylideneacetate derivatives as potential anti-Alzheimer drugs. Med Chem Comm 2015;6:1969–77.
  • Hayashi K, Hayashi T, Otsuka H, Takeda YJ. Antiviral activity of 5,6,7-trimethoxyflavone and its potentiation of the antiherpes activity of acyclovir. J Antimicrob Chemother 1997;39:821–4.
  • Nakajima A, Ohizumi Y, Yamada K. Anti-dementia activity of nobiletin, a citrus flavonoid: a review of animal studies. Clin Psychopharmacol Neurosci 2014;12:75–82.
  • Liao S, Deng H, Huang S, et al. Design, synthesis and evaluation of novel 5, 6, 7-trimethoxyflavone-6-chlorotacrine hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 2015;25:1541–5.
  • Lu C, Guo Y, Yan J, et al. Synthesis and evaluation of multi-target-directed ligands against alzheimer's disease based on the fusion of donepezil and ebselen. J Med Chem 2013;56:9089–99.
  • Masumoto H, Sies H. The reaction of ebselen with peroxynitrite. Chem Res Toxicol 1996;9:262–7.
  • Centuriao FB, Corte CL, Paixao MW, et al. Effect of ebselen and organochalcogenides on excitotoxicity induced by glutamate in isolated chick retina. Brain Res 2005;1039:146–52.
  • Yamagata K, Ichinose S, Miyashita A, Tagami M. Protective effects of ebselen, a seleno-organic antioxidant on neurodegeneration induced by hypoxia and reperfusion in stroke-prone spontaneously hypertensive rat. Neuroscience 2008;153:428–35.
  • Mao F, Chen J, Zhou Q, et al. Novel tacrine-ebselen hybrids with improved cholinesterase inhibitory, hydrogen peroxide and peroxynitrite scavenging activity. Bioorg Med Chem Lett 2013;23:6737–42.
  • Calabrese V, Mancuso C, Calvani M, et al. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 2007;8:766–75.
  • Thatcher GR, Bennett BM, Reynolds JN. Nitric oxide mimetic molecules as therapeutic agents in Alzheimer's disease. Curr Alzheimer Res 2005;2:171–82.
  • Chen Y, Sun J, Fang L, et al. Tacrine-ferulic acid-nitric oxide (NO) donor trihybrids as potent, multifunctional acetyl- and butyrylcholinesterase inhibitors. J Med Chem 2012;55:4309–21.
  • Fang L, Appenroth D, Decker M, et al. NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity. J Med Chem 2008;51:7666–9.
  • Chen Y, Sun J, Huang Z, et al. Design, synthesis and evaluation of tacrine-flurbiprofen-nitrate trihybrids as novel anti-Alzheimer's disease agents. Bioorg Med Chem 2013;21:2462–70.
  • Mohan IK, Khan M, Wisel S, et al. Cardioprotection by HO-4038, a novel verapamil derivative, targeted against ischemia and reperfusion-mediated acute myocardial infarction. Am J Physiol Heart Circ Physiol 2009;296:140–51.
  • Kalai T, Balog M, Szabo A, et al. New poly(ADP-ribose) polymerase-1 inhibitors with antioxidant activity based on 4-carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine nitroxides and their precursors. J Med Chem 2009;52:1619–29.
  • Kalai T, Mugesh G, Roy G, et al. Combining benzo[d] isoselenazol-3-ones with sterically hindered alicyclic amines and nitroxides: enhanced activity as glutathione peroxidase mimics. Org Biomol Chem 2005;3:3564–9.
  • Kalai T, Altman R, Maezawa I, et al. Synthesis and functional survey of new tacrine analogs modified with nitroxides or their precursors. Eur J Med Chem 2014;77:343–50.
  • Minarini A, Milelli A, Tumiatti V, et al. Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer's disease treatment. Neuropharmacology 2012;62:997–1003.
  • Yong-Seok L, Silva AJ. The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 2009;10:126–40.
  • Cai F, Wang F, Lin FK, et al. Redox modulation of long-term potentiation in the hippocampus via regulation of the glycogen synthase kinase-3beta pathway. Free Radic Biol Med 2008;45:964–70.
  • Yang YJ, Wu PF, Long LH, et al. Reversal of aging-associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function. Aging Cell 2010;9:709–21.
  • Robillard JM, Gordon GR, Choi HB, et al. Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult. PLos One 2011;6:e20676.
  • Wang Y, Guan XL, Wu PF, et al. Multifunctional mercapto-tacrine derivatives for treatment of age-related neurodegenerative diseases. J Med Chem 2012;55:3588–92.
  • Keri RS, Quintanova C, Chaves S, et al. New tacrine hybrids with natural based cysteine derivatives as multi-targeted drugs for potential treatment of Alzheimer's disease. Chem Biol Drug Des 2016;87:101–11.
  • Chen X, Zenger K, Lupp A, et al. Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo. J Med Chem 2012;55:5231–42.
  • Dong J, Atwood CS, Anderson VE, et al. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry 2003;42:2768–73.
  • Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev 2013;2013:316523.
  • Budimir A. Metal ions, Alzheimer's disease and chelation therapy. Acta Pharm 2011;61:1–14.
  • Li S, Jiang N, Xie S, et al. Design, synthesis and evaluation of novel tacrine-rhein hybrids as multifunctional agents for the treatment of Alzheimer's disease. Org Biomol Chem 2014;12:801–14.
  • Fernandezbachiller MI, Perez C, Gonzalezmunoz GC, et al. 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;53:4927–37.
  • Antequera D, Bolos M, Spuch C, et al. Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Aβ accumulation and cell death: Involvement in hippocampal neuronal loss in Alzheimer's disease. Neurobiol Dis 2012;46:682–91.
  • Kozikowski AP, Campiani G, Sun LQ, et al. Identification of a more potent analogue of the naturally occurring alkaloid huperzine A. Predictive molecular modeling of its interaction with AChE. J Am Chem Soc 1996;118:11357–62.
  • 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 2014;33:227–33.
  • Wall ME. Camptothecin and taxol: discovery to clinic. Med Res Rev 1998;18:299–314.
  • Torres M, Gil S, Parra M. New synthetic methods to 2-pyridone rings. Curr Org Chem 2005;9:1757–79.
  • Chand K, Alsoghier HM, Chaves S, Santos MA. Tacrine-(hydroxybenzoyl-pyridone) hybrids as potential multifunctional anti-Alzheimer’s agents: AChE inhibition, antioxidant activity and metal chelating capacity. J Inorg Biochem 2016;163:266–77.
  • Lin HC, Tsai SH, Chen CS, et al. Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities. Biochem Pharm 2008;75:1416–25.
  • Kostova I, Bhatia S, Grigorov P, et al. Coumarins as Antioxidants. Curr Med Chem 2011;18:3929–51.
  • Hornick A, Lieb A, Vo NP, et al. The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory. Neuroscience 2011;197:280–92.
  • 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.
  • Chaurasiya ND, Ganesan S, Nanayakkara NP, et al. Inhibition of human monoamine oxidase A and B by 5-phenoxy 8-aminoquinoline analogs. Bioorg Med Chem Lett 2012;22:1701–4.
  • Saura J, Luque JM, Cesura AM, et al. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 1994;62:15–30.
  • Nebbioso M, Pascarella A, Cavallotti C, Pescosolido N. Monoamine oxidase enzymes and oxidative stress in the rat optic nerve: age-related changes. Int J Exp Pathol 2012;93:401–5.
  • Bar-Am O, Amit T, Weinreb O, et al. Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein precursor: involvement of MAPK and PKC activation. J Alzheimers Dis 2010;21:361–71.
  • Lu C, Zhou Q, Yan J, et al. 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.
  • Sun Y, Chen J, Chen X, et al. Inhibition of cholinesterase and monoamine oxidase-B activity by tacrine-homoisoflavonoid hybrids. Bioorg Med Chem 2013;21:7406–17.
  • Desideri N, Bolasco A, Fioravanti R, et al. Homoisoflavonoids: natural scaffolds with potent and selective monoamine oxidase-B inhibition properties. J Med Chem 2011;54:2155–64.
  • 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.
  • Reynolds CH, Garwood CJ, Wray S, et al. Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases. J Biol Chem 2008;283:18177–86.
  • Spires-Jones TL, Stoothoff WH, de Calignon A, et al. Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci 2009;32:150–9.
  • Iqbal K, Liu F, Gong CX, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 2010;7:656–64.
  • Pietro OD, Perezareales FJ, Juarezjimenez J, et al. Munoztorrero D. Tetrahydrobenzo [h] [1,6] naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies. Eur J Med Chem 2014;84:107–17.
  • O’Leary JC, Li Q, Marinec P, et al. Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 2010;1:45–55.
  • Hui AL, Chen Y, Zhu SJ, et al. Design and synthesis of tacrine-phenothiazine hybrids as multitarget drugs for Alzheimer’s disease. Med Chem Res 2014;23:3546–57.
  • Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014;6:37.