Synthesis, Evaluation of New Chalcone Derivatives as Potential Anticholinesterase
Agents and Docking Studies
Belgin Sever1, Mehlika Dilek Altıntop1, Halide Edip Temel2, Ahmet Özdemir1
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470
Eskişehir, Turkey
2
Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey
Cholinesterase inhibitors (ChEIs) increase the available acetylcholine for improved cholinergic
transmission at the neuronal synapse. ChEIs are mainly used for the treatment of cognitive
impairment in Alzheimer's disease (AD) which is one of the most complex neurodegenerative
disorders in the world [1].
Tacrine is the first ChEI drug approved for AD treatment in 1993, followed by other ChEIs:
Donepezil, rivastigmine, and galantamine. The last three agents represent similar efficacy on
cognition, global status and managing daily life activities, whereas they differ from their
adverse effect profiles and pharmacokinetic characteristics. Among them, donepezil is mostly
chosen as first ChEI upon diagnosis for AD treatment. It exerts its therapeutic effect by binding
to acetylcholinesterase enzyme (AChE) and being hydrolyzed instead of acetylcholine [1,2].
In the present study, 5-chloro-6-methoxy-2-[4-(substituted)benzylidene]-2,3-dihydro-1Hinden-1-one derivatives (1-10) were synthesized via the base-catalyzed Claisen-Schmidt
condensation of 5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-one with p-substituted
benzaldehydes [3]. Each derivative was evaluated for its ability to inhibit AChE using a
modification of Ellman’s spectrophotometric method. Generally, the tested compounds showed
reasonable activity when compared with donepezil. The most potent AChE inhibitor was found
as 5-chloro-6-methoxy-2-[4-(1H-1,2,4-triazol-4-yl)benzylidene]-2,3-dihydro-1H-inden-1-one
(9) (95.17± 0.74%).
Molecular docking studies were also performed for the potent AChE inhibitors in the binding
site of the human AChE (PDB code: 4EY7) where Tyr337 and 341, Trp86 and 286, Phe295
and 338 residues were located in [4]. Donepezil, the potent AChE inhibitor, was chosen as a
reference ligand for docking studies due to its structural resemblance to the compounds. The
compounds showed good affinity to the active site of the enzyme. Generally the indenone
moiety of the compounds formed pi-pi stacking contacts with Trp86 and Trp286 residues and
H-bonds with Phe295 residue on AChE similar to that of donepezil.
Keywords: Acetylcholinesterase, Chalcone, Donepezil analogues, Docking studies
Figure 1. Docking positions of compound 9 and donepezil on AChE (Ligand custom carbons
are colored in plum for compound 9 and in black for donepezil; green and blue lines: pi-pi
cation and stacking, yellow line: H-bonds ).
References
[1] Finn, L.A., Drug Discovery Approaches for the Treatment of Neurodegenerative
Disorders: Alzheimer's Disease, 4, Academic Press, London, 2016.
[2] Martinez, A., Emerging Drugs and Targets for Alzheimer’s Disease : Volume 1: BetaAmyloid, Tau Protein and Glucose Metabolism, 69-70, RSC Publishing, Cambridge, 2010.
[3] Özdemir A., Altintop M.D., Turan-Zitouni G., Akalın Çiftçi G., Ertorun İ., Alataş Ö.,
Kaplancikli Z.A., Eur J Med Chem. 89, 304-309, 2015.
[4] Khosravan A., Marani S., Sadeghi Googheri M.S., J Mol Graph Model 71, 124-134, 2017.