Design and synthesis of tacrine-phenothiazine hybrids as multitarget drugs for Alzheimer’s disease

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• 作者：Ai-ling Hui (1)
  Yan Chen (2)
  Shi-jing Zhu (1)
  Chang-sheng Gan (1)
  Jian Pan (1)
  An Zhou (3)
  
• 关键词：Alzheimer’s disease ; Acetylcholinesterase inhibitor (AChEI) ; Tau phosphorylation ; Beta amyloid ; Tacrine ; phenothiazine hybrids
• 刊名：Medicinal Chemistry Research
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：23
• 期：7
• 页码：3546-3557
• 全文大小：
• 参考文献：1. Bajda M, Guzior N, Ignasik M, Malawska B (2011) Multi-target-directed ligands in Alzheimer’s disease treatment. Curr Med Chem 18:4949-975 CrossRef
  2. Carlier PR, Han YF, Chow ES-H, Li CP-L, Wang H, Lieu TX, Wong HS, Pang Y-P (1997) Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis. Bioorg Med Chem 7:351-57 CrossRef
  3. Cavalli A, Bolognesi ML, Capsoni S, Andrisano V, Bartolini M, Margotti E, Cattaneo A, Recanatini M, Melchiorre C (2007) A small molecule targeting the multifactorial nature of Alzheimer’s disease. Angew Chem Int Ed 46:3689-692 CrossRef
  4. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C (2008) Multi-target-directed ligands to combated neurodegenerative diseases. J Med Chem 51:347-70 CrossRef
  5. Chitranshi N, Gupta S, Tripathi PK, Seth PK (2013) New molecular scaffolds for the design of Alzheimer’s acetylcholinesterase inhibitors identified using ligand and receptor-based virtual screening. Med Chem Res 22:2328-345 CrossRef
  6. Darvesh S, McDonald RS, Renwell A, Conrad S, Darvesh KV, Mataija D, Comez G, Caines A, Walsh R, Martin E (2005) Structure-activity relationships for inhibition of human cholinesterase’s by alkyl amide phenothiazine derivative. Bioorg Med Chem 13:211-22 CrossRef
  7. Fernández-Bachiller MI, Pérez C, González-Mu?oz GC, Conde S, López MG, Villarroya M, García AG, Rodríguez-Franco MI (2010) Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer’s diseases, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J Med Chem 53:4927-937 CrossRef
  8. Fu HJ, Li WM, Luo JL, Lee NTK, Li MT, Tsim KWK, Pang YP, Youdim MBH, Han YF (2008) Promising anti-Alzheimer’s dimer bis(7)-tacrine reduces β-amyloid generation by directly inhibiting BACE-1 activity. Biochem Biophys Res Commun 366:631-36 CrossRef
  9. Ghadami SA, Hossein-pour Z, Khodarahmi R, Ghobadi S, Adibi H (2013) Synthesis and in vitro characterization of some benzo thiazole and benzofuranone-derivatives for quantification of fibrillar aggregates and inhibition of amyloid-mediated peroxidase activity. Med Chem Res 22:115-26 CrossRef
  10. Hanger DP, Anderton BH, Noble W (2009a) Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 15:112-19 CrossRef
  11. Hanger DP, Seereeram A, Noble W (2009b) Mediators of Tau phosphorylation in the pathogenesis of Alzheimer’s disease. Exp Rev Neurother 9:1647-666 CrossRef
  12. Hu MK, Wu LJ, Hsiao G, Yen MH (2002) Homodimeric tacrine congener’s asacetylcholinesterase inhibitions. J Med Chem 45:2277-282 CrossRef
  13. Kapkov? P, Alptüzün V, Frey P, Erciyas E, Holzgrabe U (2006) Search for dual function inhibitors for Alzheimer’s disease: synthesis and biological activity of acetylcholinesterase inhibitors of pyridinium-type and their Aβ fibril formation inhibition capacity. Bioorg Med Chem 14:472-78 CrossRef
  14. Lee SK, Lee IH, Kim HJ, Chang GS, Chung JE, No KT (2003) The PreADME approach: web-based program for rapid prediction of physic-chemical, drug absorption and drug-like properties, Euro QSAR 2002 Designing drugs and crop protectants: processes, problems and solutions. Blackwell, Boston, pp 418-20
  15. Li WM, Pi RB, Chan HHN, Fu HJ, Lee NTK, Tsang HW, Pu YM, Chang DC, Li CC, Luo JL, Xiong KM, Li ZW, Xue H, Carlier PR, Pang YP, Tsim KWK, Li MT, Han YF (2005) Novel dimeric acetylcholinesterase inhibitor bis(7)-tarcrine, but not donepezil, prevents glutamate-induced neuronal apoptosis by blocking / N-methyl- / D-aspartate receptors. J Biol Chem 280:18179-8188 CrossRef
  16. Luo JL, Li WM, Liu YW, Zhang W, Fu HJ, Lee NTK, Yu H, Pang YP, Huang PB, Xia J, Li ZW, Li CY, Han YF (2007) Novel dimer bis(7)-tacrine proton-dependently inhibits NMDA-activated currents. Biochem Biophys Res Commun 361:505-09 CrossRef
  17. Massoud F, Guathier S (2010) Update on the pharmacological treatment of Alzheimer’s disease. Curr Neuropharmacol 8:69-0 CrossRef
  18. Minarini A, Milelli A, Rumiatti V, Rosini M, Simoni E, Bolognesi ML, Andrisano V, Bartolini M, Motori E, Angeloni C, Hrelia S (2012) Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer’s disease treatment. Neuropharmacology 62:997-003 CrossRef
  19. Morphy R, Rankovic Z (2009) Designing multiple ligands-medicinal chemistry strategies and challenges. Curr Pharm Des 15:587-00 CrossRef
  20. O’Leary JC, Li QY, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J, Jones JR, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwick JE, Dickey CA (2010) Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 5:45-5 CrossRef
  21. Ouberai M, Brannstrom K, Vestling M, Olofsson A, Dumy P, Chierici S, Garcia J (2011) Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds. Org Biomol Chem 9(4):1140-147 CrossRef
  22. Pang Y-P, Quiram P, Jelaric T, Hong F, Brimijoin S (1996) Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase: steps toward novel drugs for treating Alzheimer’s disease. J Biol Chem 271:23646-3649 CrossRef
  23. Rizzo S, Tarozzi A, Bartolini M, Costa GD, Bisi A, Gobbi S, Belluti F, Ligresti A, Allará M, Monti JP, Andrisano V, Marzo VD, Hrelia P, Rampa A (2012) 2-arylbenzofuran-based molecules as multipotent Alzheimer’s disease modifying agents. Eur J Med Chem 58:519-32 CrossRef
  24. Rosini M, Simoni E, Bartolini M, Cavalli A, Ceccarini L, Pascu N, McClymont DW, Tarozzi A, Bolognesi ML, Minarini A, Tumiatti V, Andrisano V, Mellor IR, Melchiorre C (2008) Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA acceptors in Alzheimer’s disease: a promising direction for the multi-target-directed ligands gold rush. J Med Chem 51:4381-384 CrossRef
  25. Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D, Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T, Toth G, Zagyva A, Zekany A, Lavian G, Gross A, Friedman R, Razin M, Huang W, Krais B, Chorev M, Youdim MB, Weinstock M (2002) Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer’s disease. J Med Chem 45:5260-279 CrossRef
  26. Su H (2011) Design and synthesis of dual-target-directed ligands as potential treatment for Alzheimer’s disease. M.S. Thesis, Hefei University of Technology
  27. Takashima A (2006) GSK-3β is essential in the pathogenesis of Alzheimer’s disease. J Alzheimer Dis 9:309-17
  28. Tang H, Zhao LZ, Zhao HT, Huang SL, Zhong SM, Qin JK, Chen ZF, Huang ZS, Liang H (2011) Hybrids of oxoisoaporphine-tacrine congener: novel acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation inhibitors. Eur J Med Chem 46:4970-979 CrossRef
  29. Taniguchi S, Suzuki N, Masuda M, Hisanaga S, Iwatsubo T, Goedert M, Hasegawa M (2005) Inhibition of heparin-induced tau filament formation by phenothiazine, polyphenols, and porphyrins. J Biol Chem 280:7614-623 CrossRef
  30. Tumiatti V, Milelli A, Minarini A, Rosini M, Bolognesi ML, Micco M, Andeisano V, Bartolini M, Mancini F, Recanatini M, Cavalli A, Melchiorre C (2008) Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone 4. Further investigation on the inner spacer. J Med Chem 51:7308-312 CrossRef
  31. Yan Y, Liu Y, Sorci M, Belfort G, Lusthader JW, Yan SS, Wang C (2007) Surface Plasmon resonance and unclear magnetic resonance studies of ABAD-A beta interaction. Biochemistry 46:1724-731 CrossRef
  32. Zhu YP, Xiao K, Ma LP, Xiong B, Fu Y, Yu HP, Wang W, Wang X, Hu DY, Heng HL, Li JY, Gong Q, Chai Q, Tang XC, Zhang HY, Li J, Shen JK (2009) Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase. Bioorg Med Chem 17:1600-613 CrossRef
  
• 作者单位：Ai-ling Hui (1)
  Yan Chen (2)
  Shi-jing Zhu (1)
  Chang-sheng Gan (1)
  Jian Pan (1)
  An Zhou (3)
  
  1. Institute of Natural Medicine, Hefei University of Technology, No. 193, Tunxi Road, Hefei, 230009, Anhui, People’s Republic of China
  2. School of Life Science, Anhui University, Hefei, People’s Republic of China
  3. Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Traditional Chinese Medicine, Hefei, People’s Republic of China
  
• ISSN：1554-8120

文摘

Tacrine is well-known drug for Alzheimer’s disease as an acetylcholinesterase inhibitor. Rember is a bright and promising AD drugs targeting tau protein, and it is currently in Phase III clinical trials. Phenothiazine, the key pharmacophore of Rember, can prevent tau filament formation. In this work, several tacrine-phenothiazine hybrids (T1–T26) were designed for inhibiting acetylcholinesterase and tau protein involved in Alzheimer’s disease. After initial screening with the help of computational chemistry software and Molegro Virtual Docker, three molecules (T5, T18, and T22) were selected for further synthesis and biological evaluation. Next, T5, T18, and T22 were synthesized and evaluated for their acetylcholinesterase and tau hyperphosphorylation inhibition. All the tested compounds had better acetylcholinesterase inhibitory activity compared with tacrine. Among them, compound T5 was found to be the most potent compound with IC50 89 nM. Meanwhile, T5 markedly prevented tau hyperphosphorylation induced by okadaic acid in N2α cell. Its P-tau level was decreased with 39.5?% inhibition when tested at 10? M, lower than that Rember (55.7?%). Besides acetylcholinesterase and tau hyperphosphorylation inhibition, T5 can also interact with fibrill beta amyloid using surface plasmon resonance, the data of KD were 5.51?×?10??M. All the above results indicated that tacrine-phenothiazine hybrids are potential multitarget directed ligands targeting acetylcholinesterase, tau protein, and beta amyloid.