Development of Phthalimide-Donepezil Hybrids as Potent Multitarget- Directed Ligands for the Treatment of Alzheimer’s Disease

Author(s): Lintao Yu, Jian Shi, Xinfeng Cheng, Keren Wang, Shuang Liu, Wenmin Liu, Zhipei Sang*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 9 , 2020

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Graphical Abstract:


Abstract:

Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs), combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD.

Methods: To test their biological activities, including AChE/BChE inhibitory activity and MAOA/ MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode.

Results and Discussions: The results displayed that compound 4c showed the best AChE inhibitory activity with an IC50 value of 4.2 μM, which was supported by the kinetic study and docking study. Compound 4c was also a selective MAO-B inhibitor (IC50 = 8.2 μM). Moreover, compound 4c could cross the blood-brain barrier in vitro.

Conclusion: Compound 4c deserved to further study as a potential multifunctional agent for the treatment of Alzheimer’s disease.

Keywords: Alzheimer`s disease (A.D), phthalimide-donepezil hybrids, design, synthesis, AChE inhibitor, MAO-B inhibitor, blood-brain barrier, in vitro.

[1]
Lane, C.A.; Hardy, J.; Schott, J.M. Alzheimer’s disease. Eur. J. Neurol., 2018, 25(1), 59-70.
[http://dx.doi.org/10.1111/ene.13439] [PMID: 28872215]
[2]
Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement., 2016, 12(4), 459-509.
[http://dx.doi.org/10.1016/j.jalz.2016.03.001] [PMID: 27570871]
[3]
Kumar, A.; Singh, A. Ekavali, A review on Alzheimer’s disease pathophysiology and its management: An update. Pharmacol. Rep., 2015, 67(2), 195-203.
[http://dx.doi.org/10.1016/j.pharep.2014.09.004] [PMID: 25712639]
[4]
Viña, J.; Sanz-Ros, J. Alzheimer’s disease: Only prevention makes sense. Eur. J. Clin. Invest., 2018, 48(10)e13005
[http://dx.doi.org/10.1111/eci.13005] [PMID: 30028503]
[5]
de Freitas Silva, M.; Dias, K.S.T.; Gontijo, V.S.; Ortiz, C.J.C.; Viegas, C., Jr Multi-target directed drugs as a modern approach for drug design towards Alzheimer’s disease: An update. Curr. Med. Chem., 2018, 25(29), 3491-3525.
[http://dx.doi.org/10.2174/0929867325666180111101843] [PMID: 29332563]
[6]
Umar, T.; Hoda, N. Alzheimer’s disease: A systemic review of substantial therapeutic targets and the leading multi-functional molecules. Curr. Top. Med. Chem., 2017, 17(31), 3370-3389.
[http://dx.doi.org/10.2174/1568026618666180112161024] [PMID: 29332579]
[7]
Ibrahim, M.M.; Gabr, M.T. Multitarget therapeutic strategies for Alzheimer’s disease. Neural Regen. Res., 2019, 14(3), 437-440.
[http://dx.doi.org/10.4103/1673-5374.245463] [PMID: 30539809]
[9]
Anand, P.; Singh, B. A review on cholinesterase inhibitors for Alzheimer’s disease. Arch. Pharm. Res., 2013, 36(4), 375-399.
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[10]
Mesulam, M.M.; Guillozet, A.; Shaw, P.; Levey, A.; Duysen, E.G.; Lockridge, O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience, 2002, 110(4), 627-639.
[http://dx.doi.org/10.1016/S0306-4522(01)00613-3] [PMID: 11934471]
[11]
Yeung, A.W.K.; Georgieva, M.G.; Atanasov, A.G.; Tzvetkov, N.T. Monoamine oxidases (MAOs) as privileged molecular targets in neuroscience: Research literature analysis. Front. Mol. Neurosci., 2019, 12, 143.
[http://dx.doi.org/10.3389/fnmol.2019.00143] [PMID: 31191248]
[12]
Borroni, E.; Bohrmann, B.; Grueninger, F.; Prinssen, E.; Nave, S.; Loetscher, H.; Chinta, S.J.; Rajagopalan, S.; Rane, A.; Siddiqui, A.; Ellenbroek, B.; Messer, J.; Pähler, A.; Andersen, J.K.; Wyler, R.; Cesura, A.M. Sembragiline: A novel, selective monoamine oxidase type B inhibitor for the treatment of Alzheimer’s disease. J. Pharmacol. Exp. Ther., 2017, 362(3), 413-423.
[http://dx.doi.org/10.1124/jpet.117.241653] [PMID: 28642233]
[13]
Panek, D.; Więckowska, A.; Wichur, T.; Bajda, M.; Godyń, J.; Jończyk, J.; Mika, K.; Janockova, J.; Soukup, O.; Knez, D.; Korabecny, J.; Gobec, S.; Malawska, B. Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation. Eur. J. Med. Chem., 2017, 125, 676-695.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.078] [PMID: 27721153]
[14]
Panek, D.; Więckowska, A.; Pasieka, A.; Godyń, J.; Jończyk, J.; Bajda, M.; Knez, D.; Gobec, S.; Malawska, B. Design, synthesis, and biological evaluation of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones derivatives as potential disease-modifying multifunctional anti-Alzheimer agents. Molecules, 2018, 23(2)E347
[http://dx.doi.org/10.3390/molecules23020347] [PMID: 29414887]
[15]
Sang, Z.; Wang, K.; Wang, H.; Yu, L.; Wang, H.; Ma, Q.; Ye, M.; Han, X.; Liu, W. Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2017, 27(22), 5053-5059.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.055] [PMID: 29033232]
[16]
Li, Q.; He, S.; Chen, Y.; Feng, F.; Qu, W.; Sun, H. Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2018, 158, 463-477.
[http://dx.doi.org/10.1016/j.ejmech.2018.09.031] [PMID: 30243151]
[17]
Manley-King, C.I.; Bergh, J.J.; Petzer, J.P. Inhibition of monoamine oxidase by C5-substituted phthalimide analogues. Bioorg. Med. Chem., 2011, 19(16), 4829-4840.
[http://dx.doi.org/10.1016/j.bmc.2011.06.070] [PMID: 21778064]
[18]
Sang, Z.; Wang, K.; Han, X.; Cao, M.; Tan, Z.; Liu, W. Design, synthesis, and evaluation of novel ferulic acid derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. ACS Chem. Neurosci., 2019, 10(2), 1008-1024.
[http://dx.doi.org/10.1021/acschemneuro.8b00530] [PMID: 30537804]
[19]
Sang, Z.; Qiang, X.; Li, Y.; Yuan, W.; Liu, Q.; Shi, Y.; Ang, W.; Luo, Y.; Tan, Z.; Deng, Y. Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2015, 94, 348-366.
[http://dx.doi.org/10.1016/j.ejmech.2015.02.063] [PMID: 25778991]
[20]
Zhang, X.; Song, Q.; Cao, Z.; Li, Y.; Tian, C.; Yang, Z.; Zhang, H.; Deng, Y. Design, synthesis and evaluation of chalcone Mannich base derivatives as multifunctional agents for the potential treatment of Alzheimer’s disease. Bioorg. Chem., 2019, 87, 395-408.
[http://dx.doi.org/10.1016/j.bioorg.2019.03.043] [PMID: 30921741]
[21]
Li, Y.; Qiang, X.; Luo, L.; Yang, X.; Xiao, G.; Zheng, Y.; Cao, Z.; Sang, Z.; Su, F.; Deng, Y. Multitarget drug design strategy against Alzheimer’s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties. Bioorg. Med. Chem., 2017, 25(2), 714-726.
[http://dx.doi.org/10.1016/j.bmc.2016.11.048] [PMID: 27923535]
[22]
Hepnarova, V.; Korabecny, J.; Matouskova, L.; Jost, P.; Muckova, L.; Hrabinova, M.; Vykoukalova, N.; Kerhartova, M.; Kucera, T.; Dolezal, R.; Nepovimova, E.; Spilovska, K.; Mezeiova, E.; Pham, N.L.; Jun, D.; Staud, F.; Kaping, D.; Kuca, K.; Soukup, O. The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer’s disease. Eur. J. Med. Chem., 2018, 150, 292-306.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.083] [PMID: 29533874]
[23]
Di, L.; Kerns, E.H.; Fan, K.; McConnell, O.J.; Carter, G.T. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem., 2003, 38(3), 223-232.
[http://dx.doi.org/10.1016/S0223-5234(03)00012-6] [PMID: 12667689]
[24]
Guzior, N.; Bajda, M.; Rakoczy, J.; Brus, B.; Gobec, S.; Malawska, B. Isoindoline-1,3-dione derivatives targeting cholinesterases: Design, synthesis and biological evaluation of potential anti-Alzheimer’s agents. Bioorg. Med. Chem., 2015, 23(7), 1629-1637.
[http://dx.doi.org/10.1016/j.bmc.2015.01.045] [PMID: 25707322]
[25]
Guzior, N.; Bajda, M.; Skrok, M.; Kurpiewska, K.; Lewiński, K.; Brus, B.; Pišlar, A.; Kos, J.; Gobec, S.; Malawska, B. Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective properties. Eur. J. Med. Chem., 2015, 92, 738-749.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.027] [PMID: 25621991]
[26]
Więckowska, A.; Więckowski, K.; Bajda, M.; Brus, B.; Sałat, K.; Czerwińska, P.; Gobec, S.; Filipek, B.; Malawska, B. Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with β-amyloid anti-aggregation properties and beneficial effects on memory in vivo. Bioorg. Med. Chem., 2015, 23(10), 2445-2457.
[http://dx.doi.org/10.1016/j.bmc.2015.03.051] [PMID: 25868744]
[27]
Saeedi, M.; Golipoor, M.; Mahdavi, M.; Moradi, A.; Nadri, H.; Emami, S.; Foroumadi, A.; Shafiee, A. Phthalimide-derived n-benzylpyridinium halides targeting cholinesterases: Synthesis and bioactivity of new potential Anti-Alzheimer’s disease agents. Arch. Pharm. (Weinheim), 2016, 349(4), 293-301.
[http://dx.doi.org/10.1002/ardp.201500425] [PMID: 26898241]
[28]
Ignasik, M.; Bajda, M.; Guzior, N.; Prinz, M.; Holzgrabe, U.; Malawska, B. Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors. Arch. Pharm. (Weinheim), 2012, 345(7), 509-516.
[http://dx.doi.org/10.1002/ardp.201100423] [PMID: 22467516]
[29]
Greenblatt, H.M.; Guillou, C.; Guénard, D.; Argaman, A.; Botti, S.; Badet, B.; Thal, C.; Silman, I.; Sussman, J.L. The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: Implications for structure-based drug design. J. Am. Chem. Soc., 2004, 126(47), 15405-15411.
[http://dx.doi.org/10.1021/ja0466154] [PMID: 15563167]


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Article Details

VOLUME: 17
ISSUE: 9
Year: 2020
Published on: 11 September, 2020
Page: [1155 - 1163]
Pages: 9
DOI: 10.2174/1570180817999200420120519
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