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PHARMASPIRE - Volume 15, Issue 02, 2023, April- June

Pages: 61-69

Date of Publication: 06-Sep-2023

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Molecular docking analysis of substituted 2-(1-benzylpiperidin-4-yl)-5-phenoxy-1H-benzo[d] imidazole derivatives as acetylcholinesterase inhibitors for the management of Alzheimer’s disease

Author: Abhimannu Shome, Pooja A. Chawla

Category: P'Ceutical Chemistry


The loss of cholinergic neurons in the brain and hippocampus is the hallmark of Alzheimer’s disease (AD). The hydrolyzing enzyme acetylcholinesterase (AChE) has been identified as a potential treatment for AD. One of the most significant scaffolds for AChE binding is benzyl piperidine, which is included in the medication donepezil. Along with benzimidazole, early investigations have also shown to significantly inhibit AChE. This study includes in designing of a hybrid of benzyl piperidine and benzimidazole as AChE inhibitors. The study revealed that B24, A24, and B8 showed the highest blood–brain barrier (BBB) permeability and binding affinities (?11.4 kcal/mol, 11.0 kcal/mol, and 11.1 kcal/mol, respectively). All the chemicals behaved similarly in the binding pocket of AChE. These important interactions between residues include those between Trp86, Tyr341, Ser293, and others. To stop the BBB from penetrating, polar substitutions on more than two locations were also identified. However, compound B24 is an exception. The series’ most potent ligands may be further evaluated biologically.

Keywords: Acetylcholinesterase, Alzheimer’s disease, Benzimidazole, Benzyl piperidine, Molecular docking

DOI: 10.56933/Pharmaspire.2023.15111



1. Bello-Lepe S, Alonso-Sánchez MF, Ortega A, Gaete M, Veliz M, Lira J, et al. Montreal cognitive assessment as screening measure for mild and major neurocognitive disorder in a Chilean population. Dement Geriatr Cogn Disord Extra 2020;10:105-14.
2. Prince MJ, Wimo A, Guerchet MM, Ali GC, Wu YT, Prina M. World Alzheimer Report 2015-The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends; 2015.
3. Sauer J, Ffytche DH, Ballard C, Brown RG, Howard R. Differences between Alzheimer’s disease and dementia with Lewy bodies: An fMRI study of task-related brain activity. Brain 2006;129(Pt 7):1780-8.
4. Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA. Identification of cDNA clones for the human microtubuleassociated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res 1986;387:271-80.
5. Tapia-Rojas C, Cabezas-Opazo F, Deaton CA, Vergara EH, Johnson GV, Quintanilla RA. It’s all about tau. Prog Neurobiol 2019;175:54-76.
6. Regan P, Piers T, Yi JH, Kim DH, Huh S, Park SJ, et al. Tau phosphorylation at serine 396 residue is required for hippocampal LTD. J Neurosci Res 2015;35:4804-12.
7. Yuzwa SA, Yadav AK, Skorobogatko Y, Clark T, Vosseller K, Vocadlo DJ. Mapping O-GlcNAc modification sites on tau and generation of a site-specific O-GlcNAc tau antibody. Amino Acids 2011;40:857-68.
8. Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke- Iqbal I, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 2009;132:1820-32.
9. Costanzo P, Cariati L, Desiderio D, Sgammato R, Lamberti A, Arcone R, et al. Design, synthesis, and evaluation of donepezil-like compounds as AChE and BACE-1 inhibitors. ACS Med Chem Lett 2016;7:470-5.
10. Asadi M, Ebrahimi M, Mohammadi-Khanaposhtani M, Azizian H, Sepehri S, Nadri H, et al. Design, synthesis, molecular docking, and cholinesterase inhibitory potential of phthalimidedithiocarbamate hybrids as new agents for treatment of Alzheimer’s disease. Chem Biodivers 2019;16:e1900370.
11. van Greunen DG, van der Westhuizen CJ, Cordier W, Nell M, Stander A, Steenkamp V, et al. Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease. Eur J Med Chem 2019;179:680-93.
12. Hussain R, Ullah H, Rahim F, Sarfraz M, Taha M, Iqbal R, et al. Multipotent cholinesterase inhibitors for the treatment of Alzheimer’s disease: Synthesis, biological analysis and molecular docking study of benzimidazolebased thiazole derivatives. Molecules 2022;27:6087.
13. Adalat B, Rahim F, Taha M, Alshamrani FJ, Anouar EH, Uddin N, et al. Synthesis of benzimidazole–based analogs as anti Alzheimer’s disease compounds and their molecular docking studies. Molecules 2020;25:4828.
14. Ultra C. 6.0 and Chem3d Ultra. Cambridge, USA: Cambridge Soft Corporation; 2001.
15. Tool AD. 1.5.6 (ADT)/MGL Tools 1.5.6.California, USA: The Scripps Research Institute; 2016.
16. Huey R, Morris GM, Forli S. Using AutoDock 4 and AutoDock Vina with AutoDock Tools: A Tutorial. California, USA: The Scripps Research Institute Molecular Graphics Laboratory; 2012. p. 1000.
17. Li H, Leung KS, Wong MH, Ballester PJ. Improving AutoDock Vina using random forest: the growing accuracy of binding affinity prediction by the effective exploitation of larger data sets. Mol Inform 2015;34:115-26.
18. Studio D. Discovery Studio. Accelrys [21]; 2008.
19. Jejurikar BL, Rohane SH. Drug designing in discovery studio. Asian J Res Chem 2021;14:135-8.
20. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017;7:42717.