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In vitro and in silico studies on AChE inhibitory effects of a series of donepezil-like arylidene indanones

  • Belgin Sever ORCID logo EMAIL logo , Mehlika Dilek Altıntop ORCID logo und Halide Edip Temel
Veröffentlicht/Copyright: 27. Juli 2020
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Turkish Journal of Biochemistry
Aus der Zeitschrift Turkish Journal of Biochemistry Band 45 Heft 4

Abstract

Objective

Donepezil is the most potent acetylcholinesterase (AChE) inhibitor currently available on the market for the management of Alzheimer’s disease. In this study, it was aimed to identify potent donepezil analogues.

Materials and methods

The effects of arylidene indanones (1–10) on AChE inhibition were examined using modified Ellman’s assay. Compound 4, the most potent arylidene indanone in this series, was subjected to molecular docking to anticipate its binding mode in the AChE site (PDB code: 4EY7). The pharmacokinetic profiles of all derivatives were also predicted.

Results

Compound 4 was found as the most potent AChE inhibitor with an IC50 value of 5.93 ± 0.29 μg/mL. According to molecular docking studies, compound 4 presented favorable interactions such as π–π interactions with Trp286 and Tyr337. In silico studies revealed that the compound did not violate Lipinski’s rule of five and Jorgensen’s rule of three, making it a potential orally bioavailable agent.

Conclusion

Compound 4 is a feasible candidate for further experiments related to AChE inhibition.

Öz

Amaç

Donepezil, Alzheimer hastalığının tedavisi için piyasada var olan en etkili asetilkolinesteraz (AChE) inhibitörüdür. Bu çalışmada, etkili donepezil analoglarını tanımlamak amaçlanmıştır.

Gereç ve Yöntemler

Ariliden indanonların (1–10) AChE inhibisyonu üzerine etkileri Ellman yönteminin bir modifikasyonu kullanılarak araştırılmıştır. Bu serideki en etkili ariliden indanon olan 4 no’lu bileşik AChE enzimindeki (PDB kod: 4EY7) bağlanma biçimlerini öngörmek için moleküler docking çalışmalarına tabi tutulmuştur. Bütün bileşiklerin farmakokinetik profilleri de öngörülmüştür.

Bulgular

Bileşik 4, 5.93 ± 0.29 μg/mL IC50 değeriyle en etkili AChE inhibitörü olarak bulunmuştur. Moleküler docking çalışmalarına göre, 4 no’lu bileşik Trp286 ve Tyr337 ile π–π etkileşimleri gibi uygun etkileşimler göstermiştir. In silico çalışmalar, bileşiğin Lipinski’nin beş kuralını ve Jorgensen’in üç kuralını ihlal etmediğini ve potansiyel oral biyoyararlanımı olan bir ajan olduğunu ortaya koymuştur.

Sonuç

4 No’lu bileşik AChE inhibisyonuna dayalı ileriki deneyler için olası bir adaydır.

Keywords: Acetylcholinesterase; Alzheimer’s disease; arylidene indanone; donepezil analogs; molecular docking
Anahtar kelimeler: Asetilkolinesteraz; Alzheimer hastalığı; ariliden indanon; donepezil analogları; moleküler docking

Introduction

Alzheimer’s disease (AD) has become a prevalent and burdensome neurodegenerative disorder in elderly people across the globe [1]. The global burden of AD is increasing considerably due to the increased life expectancy. The incidence of AD is projected to more than triple by 2050 [2], and therefore the cost of long-term care for AD patients is predicted to be in the hundreds of billions of dollars [3]. Despite considerable research on AD over a century, there are only four currently available agents for the management of AD [4], [5]. Among them, donepezil, galantamine, rivastigmine decrease the breakdown of acetylcholine (ACh) in the synapse through the inhibition of cholinesterases (ChEs), whilst memantine is a N-methyl-d-aspartate (NMDA) receptor antagonist [6]. These agents only ameliorate symptoms but do not halt the progression of AD [1], [2], [3], [4].

Several enzymes, such as acetylcholinesterase (AChE), secretases, lipoxygenases, glycogen synthase kinase-3, sirtuins, caspases have been reported to participate in the pathogenesis of AD [7], [8]. Among them, AChE stands out as a promising target for anti-AD agents due to its pivotal role in the termination of signal transmission in the cholinergic system through the hydrolysis of ACh [7], [8], [9], [10]. According to cholinergic hypothesis, the decreased level of ACh results in impairment of the cholinergic neurotransmission leading to the loss of intellectual abilities [11]. As a result, the design of AChE inhibitors on the basis of the cholinergic hypothesis is still the most popular strategy to identify potent anti-AD drug candidates [4].

Chalcones have come into prominence as promising pharmacophores for the management of AD targeting a plethora of receptors and enzymes associated with the pathogenesis of AD ranging from AChE to β-secretase owing to their structural features allowing these ligands to interact with key residues of biological targets [12], [13], [14], [15], [16]. In particular, arylidene indanones identified as the rigid cousins or homologs of chalcones have emerged as potent weapons in the battle against AD due to their inhibitory potential against ChEs [17], [18], [19], [20].

Donepezil is one of the most commonly prescribed anti-AD agents used in the first-line treatment of patients with mild to severe AD due to its potent AChE inhibitory activity and favorable therapeutic profile [21], [22], [23], [24]. N-benzylpiperidine and indanone serve as crucial moieties in donepezil for the interactions with AChE [25] and therefore tremendous efforts have been devoted to the discovery of potent indanone-based donepezil analogs for the management of AD [25], [26], [27], [28], [29], [30].

In an effort to identify potent indanone-based donepezil analogs, herein arylidene indanones (1–10) [31] were evaluated as AChE inhibitors (Figure 1).

Figure 1: The similarity between the structures of donepezil and the arylidene indanones.
Figure 1:

The similarity between the structures of donepezil and the arylidene indanones.

Materials and methods

Chemistry

The synthetic method and the spectral data of 5-chloro-6-methoxy-2-arylidene-2,3-dihydro-1H-inden-1-ones (1–10) were reported previously by our research team [31].

Biochemistry

The AChE inhibitory effects of the compounds were determined by Ellman’s method [32] with minor modifications [33]. The compounds were dissolved in DMSO and tested at final concentrations ranging from 5 to 80 μg/mL. 20 μL of AChE (1 U/mL), 10 μL sample were added to 2.4 mL buffer, and the mixture was incubated at 37 °C for 15 min. After 15 min incubation, 50 μL of 0.01 M 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) and 20 μL of 75 mM acetylthiocholine iodide (ATCI) were added, and the final mixture was incubated at room temperature for 30 min. Blank was prepared using 10 μL of DMSO instead of the test sample, with all other procedures similar to those used in the sample mixture. Absorbances were measured at 412 nm and 37 °C using polystyrene cuvettes with spectrophotometer (UV-1700, Shimadzu, Japan). All experiments were performed in triplicate. Donepezil was used as a positive control. Data are expressed as mean ± standard deviation (SD).

Molecular modeling

Compound 4 was docked to the active site of AChE (PDB code: 4EY7) [34] as indicated formerly [35] using Schrodinger’s Maestro molecular modeling package.

In silico absorption, distribution, excretion, metabolism (ADME) studies

The pharmacokinetic profiles of compounds 1–10 were envisaged by QikProp module of Schrödinger’s Molecular modeling package.

Results and discussion

Arylidene indanones (1–10) were investigated for their AChE inhibitory effects (Table 1). Compound 4 was identified as a notable AChE inhibitor with an IC50 value of 5.93 ± 0.29 μg/mL. This outcome revealed that p-acetamidobenzylidene moiety significantly enhanced AChE inhibitory activity.

Table 1:

The inhibitory effects of compounds 1-10 on AChE.

CompoundRInhibition% (80 µg/mL)IC50 (µg/mL)
1Pyrrolidinyl30.68 ± 0.74nt
2Dimethylamino---nt
3Diethylamino---nt
4Acetamido87.27 ± 2.325.93 ± 0.29
5Piperidinyl23.34 ± 3.71nt
6Morpholinyl38.87 ± 2.85nt
74-Methyl-1-piperazinyl73.97 ± 1.3830.67 ± 0.51
81H-Imidazol-1-yl59.96 ± 1.1573.67 ± 1.15
91H-1,2,4-Triazol-1-yl95.17 ± 0.7410.00 ± 0.17
102-Morpholinoethoxy80.77 ± 3.0820.70 ± 1.13
Donepezil–nt0.0065 ± 0.001

  1. nt: not tested. ---: no inhibition.

Triazole-based compound 9 (IC50 = 10.00 ± 0.17 μg/mL) showed more potent AChE inhibitory activity than imidazole-based compound 8 (IC50 = 73.67 ± 1.15 μg/mL). 1,2,4-Triazole ring significantly increased AChE inhibitory activity.

The results demonstrated that compound 10 (IC50 = 20.70 ± 1.13 μg/mL) was found to be more effective on AChE than compound 6 (38.87 ± 2.85%). It can be concluded that the introduction of an ethoxy linker between the morpholine ring and the benzylidene moiety leads to a significant increase in anticholinesterase activity. On the other hand, the effects of the nitrogen heterocycles on AChE inhibitory activity were found to be in the following order: Piperazine > Morpholine > Pyrrolidine > Piperidine. Compound 7 exhibited AChE inhibitory activity with an IC50 value of 30.67 ± 0.51 μg/mL, whereas compounds 1, 5 and 6 caused less than 50% AChE inhibition at 80 μg/mL. The replacement of the nitrogen heterocycles with the dialkylamino groups resulted in the loss of AChE inhibitory activity.

Molecular docking studies were carried out to explore the possible binding mode of compound 4 in the active site of AChE (PDB code: 4EY7). Compound 4 showed good affinity to the active site of AChE (Figure 2A and 2B). Compound 4 was found to be capable of forming π–π stacking interactions with Trp286 and Tyr337 residues. The carbonyl group of the indanone scaffold formed a hydrogen bond with Phe295 residue. The docking score, glide gscore and glide emodel were found as −10.21 kcal/mol, −10.21 kcal/mol and −80.44 kcal/mol, respectively.

Figure 2: Docking pose (A) and interactions (B) of compound 4 in the active site of AChE (PDB code: 4EY7) (Hydrogen bonds are depicted as yellow dashes (A) and purple line (B), whereas π–π stacking interactions were presented as blue dashes (A) and green lines (B).
Figure 2:

Docking pose (A) and interactions (B) of compound 4 in the active site of AChE (PDB code: 4EY7) (Hydrogen bonds are depicted as yellow dashes (A) and purple line (B), whereas π–π stacking interactions were presented as blue dashes (A) and green lines (B).

The QikProp module of Schrödinger’s Molecular modeling package was used to predict the ADME profiles of compounds 1–10 (Table 2). Compounds 3 and 5 only violated one parameter of Lipinski’s rule of five, whilst other compounds did not violate Lipinski’s rule. Based on Lipinski’s rule, these compounds can be considered as drug-like molecules. On the other hand, compounds 1, 3 and 5 only violated one parameter of Jorgensen’s rule of three, whereas other derivatives did not violate Jorgensen’s rule of three. The percentage of human oral absorption for all derivatives was also predicted to be 100.00. On the basis of these findings, all compounds are predicted to possess good oral bioavailability. Their predicted QPlogBB, SASA, PSA and QPlogKhsa values were found to be within optimum range. According to in silico ADME studies, all compounds are also able to pass through the blood-brain barrier (BBB).

Table 2:

In silico ADME profiles of compounds 1–10.

CompoundQPlogBBaSASAaPSAaQPlogKhsaaHuman oral absorption %aRule of fivebRule of threec
10.01647.3040.320.77100.0001
2−0.03610.6839.940.52100.0000
3−0.15662.3338.470.74100.0011
4−0.64668.8875.190.34100.0000
50.02667.2040.250.90100.0011
60.02626.3349.750.29100.0000
70.35689.2945.860.50100.0000
8−0.28624.0452.440.50100.0000
9−0.55617.7868.290.19100.0000
100.14720.5056.890.12100.0000

  1. aQPlogBB: Predicted brain/blood partition coefficient (Recommended range: −3.0–1.2). SASA: Total solvent accessible surface area in square angstroms using a probe with a 1.4 Å radius (recommended range: 300.0–1000.0). PSA: Van der Waals surface area of polar nitrogen and oxygen atoms (recommended range: 7.0–200.0). QPlogKhsa: Prediction of binding to human serum albumin (Recommended range: −1.5–1.5). Human oral absorption%: Predicted human oral absorption on 0 to 100% scale. Human oral absorption higher than 80% is considered to be high, whilst human oral absorption lower than 25% is considered to be poor.

  2. bRule of five: number of violations of Lipinski’s rule of five. The rules are: molecular weight <500, predicted octanol/water partition coefficient <5, hydrogen-bond donor atoms ≤5, hydrogen-bond acceptor atoms ≤10. Compounds that provide these rules are considered as drug-like molecules.

  3. cRule of three: number of violations of Jorgensen’s rule of three. The three rules are: predicted aqueous solubility (QPlogS) >−5.7, predicted apparent Caco-2 cell permeability (QPPCaco in nm/s) >22 nm/s, # Primary metabolites <7. Compounds with fewer (and preferably no) violations of these rules are more likely to be orally available agents (Schrödinger Release 2016-2: Schrödinger, LLC, New York, NY, USA).

Conclusion

In this paper, we focused on the assessment of a series of arylidene indanones as AChE inhibitors. The most active AChE inhibitor in this series was found as compound 4. According to docking studies, compound 4 was capable of forming proper interactions with Trp286, Tyr337 and Phe295 in the active site of AChE. Based on ADME studies, compound 4 is expected to possess a favorable ADME profile. The results highlight that compound 4 is a hit compound for the generation of AChE inhibitors with enhanced efficacy and selectivity through the molecular modification of compound 4.

Corresponding author: Belgin Sever, PhD, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir, 26470, Turkey, E-mail: , Phone: +90 222 3350580/3807; Fax: +90 222 3350750

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: The authors state no conflict of interest.

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Received: 2019-08-26
Accepted: 2020-01-21
Published Online: 2020-07-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/tjb-2019-0356
Schlagwörter für diesen Artikel
Acetylcholinesterase; Alzheimer’s disease; arylidene indanone; donepezil analogs; molecular docking

Artikel in diesem Heft

  1. Frontmatter
  2. Research Articles
  3. Development of new total RNA isolation method for tissues with rich phenolic compounds
  4. Myofibrillar degeneration with diphtheria toxin
  5. In vitro and in silico studies on AChE inhibitory effects of a series of donepezil-like arylidene indanones
  6. In vitro antioxidant, anti-inflammatory and anti-cancer activities of methanolic extract of Asparagus horridus grows in North Cyprus Kuzey Kıbrıs da yetişen Asparagus horridus metanolik ekstraktının in-vitro antioksidan, anti-enflamatuar ve anti-kanser aktivitesi
  7. Purification and characterization of glucose-6-phosphate dehydrogenase from Eisenia fetida and effects of some pesticides and metal ions
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Heruntergeladen am 31.12.2025 von https://www.degruyterbrill.com/document/doi/10.1515/tjb-2019-0356/html
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