2-(2-(4-Benzoylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives: Synthesis, docking and acetylcholinesterase inhibitory evaluation as anti-alzheimer agents

Document Type : Original Article


1 Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Department of Pharmacology, Toxicology and Medical Services, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

3 Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran

4 Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

5 Neurobiomedical Research Center, Yazd Shahid Sadoughi University of Medical Sciences, Yazd, Iran


Objective(s): Alzheimer’s disease (AD) as progressive cognitive decline and the most common form of dementia is due to degeneration of the cholinergic neurons in the brain. Therefore, administration of the acetylcholinesterase (AChE) inhibitors such as donepezil is the first choice for treatment of the AD. In the present study, we focused on the synthesis and anti-cholinesterase evaluation of new donepezil like analogs.
Materials and Methods: A new series of phthalimide derivatives (compounds 4a-4j) were synthesized via Gabriel protocol and subsequently amidation reaction was performed using various benzoic acid derivatives. Then, the corresponding anti-acetylcholinesterase activity of the prepared derivatives (4a-4j) was assessed by utilization of the Ellman's test and obtained results were compared to donepezil. Besides, docking study was also carried out to explore the likely in silico binding interactions. 
Results: According to the obtained results, electron withdrawing groups (Cl, F) at position 3 and an electron donating group (methoxy) at position 4 of the phenyl ring enhanced the acetylcholinesterase inhibitory activity. Compound 4e (m-Fluoro, IC50 = 7.1 nM) and 4i (p-Methoxy, IC50 = 20.3 nM) were the most active compounds in this series and exerted superior potency than donepezil (410 nM). Moreover, a similar binding mode was observed in silico for all ligands in superimposition state with donepezil into the active site of acetylcholinesterase.
Conclusion: Studied compounds could be potential leads for discovery of novel anti-Alzheimer agents in the future.


1. Sugimoto H, Yamanishi Y, Iimura Y, Kawakami Y. Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr Med Chem 2000; 7:303-339.
2. Zhang J, Zhu D, Sheng R, Wu H, Hu Y, Wang F, et al. BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide. Eur J Pharmacol 2009; 613:1-9.
3. Ucar G, Gokhan N, Yesilada A, Bilgin AA.1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: A novel cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson’s and Alzheimer’s diseases. Neurosci Lett 2005; 382:327-331.
4. Liston DR, Nielsen JA, Villalobos A, Chapin D, Jones SB, Hubbard ST, et al. Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer’s disease. Eur J Pharmacol 2004; 486:9-17.
5. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol 2003; 2:539-547.
6. Vitorović-Todorović MD, Juranić IO, Mandić LM, Drakulic BJ. 4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields. Bioorg Med Chem 2010; 18:1181-1193.
7. Kapková P, Alptüzün V, Frey P, Erciyasb E, Holzgrabe U. 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 2006; 14:472-478.
8. Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K. Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-l-oxoindan-2yl)methyl]piperidine Hydrochloride and Related Compounds. J Med Chem 1995; 24:4821-4829.
9. Foroumadi A, Mohammadi-Farani A, Garmsiri Mahvar M, Aliabadi A. Synthesis and evaluation of anti-acetylcholinesterase activity of 2-(2-(4-(2-Oxo-2-phenylethyl)piperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives with potential anti-Alzheimer effects. Iran J Basic Med Sci 2013; 10:1049-1054.
10. Mohammadi-Farani A, Ahmadi A, Nadri H, Aliabadi A. Synthesis, docking and acetylcholinesterase inhibitory assessment of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione with potential anti-alzheimer effects. Daru 2013; 21:47-55.
11. Zhao Q, Yang G, Mei X, Yuan H, Ning J. Novel acetylcholinesterase inhibitors: Synthesis and structure-activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives. Pestic Biochem Physiol 2009; 95:131-134.
12. Kryger G, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with E2020 (Aricept®): implications for the design of new anti-Alzheimer drugs. Structure 1999; 3:297-307.
13. Alonso D, Dorronsoro I, Rubio L, Munoz P, García-Palomero E, Del Monte M, et al. Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorg Med Chem 2005; 13:6588-6597.
14. Mary A, Zafiarisoa Renko D, Guillou C, Thal C. Potent acetylcholinesterase inhibitors: design, synthesis, and structure-activity relationships of bis-interacting ligands in the galanthamine series. Bioorg Med Chem 1998; 6:1835-1850.
15. Ragavendran JV, Sriram D, Patel SK, Reddy IV, Bharathwajan N, Stables J. Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore.Eur J Med Chem 2007; 42:146-151.
16. Mohammadi-Farani A, Foroumadi A, Rezvani Kashani M, Aliabadi A. N-Phenyl-2-p-tolylthiazole-4-carboxamide derivatives: Synthesis and cytotoxicity evaluation as anticancer agents. Iran J Basic Med Sci 2014; 17:502-508.
17. Mohammadi-Farani A, Heidarian N, AliabadiA. N-(5-Mercapto-1,3,4-thiadiazol-2-yl)-2-phenylacetamide derivatives: Synthesis and in vitro cytotoxcity evaluation as potential anticancer agents. Iran J Pharm Res 2014; 12:487-492.
18. Aliabadi A, Foroumadi A, Safavi M, Kaboudian Ardestani S. Synthesis, molecular docking and cytotoxicity evaluation of 2-(4-substituted-benzyl)isoindoline-1,3-dione derivatives as anticancer agents. J Rep Pharm Sci 2012; 1:19-22.
19. Aliabadi A, Shamsa F, Ostad SN, Emami S, Shafiee A, Davoodi J, et al Synthesis and biological evaluation of 2-Phenylthiazole-4-carboxamide derivatives as anticancer agents. Eur J Med Chem 2010; 11:5384-5389.
20. ArgusLab 4.0 Mark A. Thompson Planaria Software LLC, Seattle, WA.  http://www.arguslab.com.
21. http://RCSB.org.
22. Fernandez D, Aviles FX, Vendrell J. A new type of five-membered heterocyclic inhibitors of basic metallocarboxypeptidases. Eur J Med Chem 2009; 44:3266-3271.
23. http://www.molegro.com.
24. Ellman GL, Courtney KD, Andres V, Feather-Stone RM.  A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7:88-95.
25. Nadri H, Pirali-Hamedani M, Shekarchi M, Abdollahi M, Sheibani V, Amanlou M, et al. Design, synthesis and anticholinesterase activity of a novel series of 1-benzyl-4-((6-alkoxy-3-oxobenzofuran-2(3H)-ylidin)methyl) pyridinium derivatives. Bioorg Med Chem 2010; 18:6360-6366.