Quinoline containing chalcone derivatives as cholinesterase inhibitors and their in silico modeling studies

doi:10.1016/j.compbiolchem.2018.08.003

Computational Biology and Chemistry

Volume 76, October 2018, Pages 310-317

https://doi.org/10.1016/j.compbiolchem.2018.08.003 Get rights and content

Highlights

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Quinoline chalcone derivatives were screened for cholinesterase inhibition profile.
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Compounds exhibited inhibition against BChE to a considerable extent.
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Molecular docking studies were also carried out for potent and selective inhibitors of AChE and BChE.
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Drug likeness of tested molecules were carried out by in-silico ADME evaluation.

Abstract

Cholinesterases (ChEs) play a vital role in regulating cholinergic transmission. Inhibition of ChEs is thought to be an emerging and useful therapeutic target for neurodegenerative disorders through restoration of acetylcholine (ACh) levels in the brain (e.g. Alzheimer’s disease). To increase the chemical diversity of cholinesterase inhibitors, a series of quinoline chalcones derivatives were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) isoenzymes. All tested compounds (4a-1; 5a-s) exhibited inhibitory activities against AChE and BChE to a considerable extent. Molecular docking studies were performed by using homology models on both AChE and BChE isoenzymes with the aim of exploring probable binding modes of the most potent inhibitor. In order to evaluate drug likeness of newly tested molecules, we carried out in-silico ADME evaluation. All compounds displayed favourable ADME findings which predict good oral bioavailability of these derivatives. Due to an excellent ADME profile the tested compounds were predicted to be safer which can be considered as novel cholinesterase inhibitors.

Graphical abstract

Introduction

Cholinesterases (ChEs) belong to a superfamily of serine hydrolases which play a vital role through participating in termination of acetylcholine based signal transmission in neurosynaptic cleft (Ballard et al., 2005; Khaled et al., 2010). On the basis of substrate and inhibitor specificity, two types of ChEs are found in vertebrates; Acetylcholinesterase (AChE, EC 3.1.1.7) and Butyrylcholinesterase (BChE, EC 3.1.1.8). These enzymes are identical (>65%) in their structure with similar catalytic site and contain three amino acids (i.e. serine, glutamate and histidine) which are essential for enzymatic activity (Giacobini, 2001). AChE is present in conducting tissues (motor neurons) of higher organisms and hydrolyzes acetylcholine (ACh) quickly than other ChEs. BChE is actually pseudocholinesterase enzyme which is mainly found in liver and preferentially hydrolyzes butyrylthiocholine chloride (Sturm et al., 1999; Huang et al., 2010). Moreover, BChE is involved in hydrolysis of carboxylic or phosphoric acid ester in detoxification of many compounds like succinylcholine, cocaine etc. it acts as endogenous scavenger of anticholinesterase compounds thus protect AChE function (Çokuğraş, 2003).

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder of the brain which is considered a leading cause of dementia and affects 20–30 million people worldwide. Presently, a suitable treatment and prevention strategy against AD is hardly available. Various studies have been carried out so far without satisfactory results. However, etiology of AD is now partially understood at molecular level which describes the role of hyper phosphorylated tau protein, β-amyloid aggregation, and deficiency of cholinergic neurotransmitter in the pathogenesis of AD (Leoutsakos et al., 2012). The cholinergic hypothesis postulates that the main cause of memory deterioration in patients with AD is the deficiency in cholinergic functions of the brain (Rouleau et al., 2011). This provides a fresh incentive to the scientific research in this field.

In recent years, many treatment strategies are planned to interfere with the mechanisms which involve the progression of AD, but the most common one that has gained an outstanding importance is the reduction or blockade of global cognitive decline. Therefore, currently prescribed drugs for AD aim to increase neurotransmitter (i.e ACh) level in the brain by stopping AChE and BChE activity. However, the clinical use of FDA approved ChE inhibitors (Donepezil, Rivastigmine etc.) are sometimes limited due to their more adverse effects and prudent benefits to AD patients. Therefore, the novel and more effective ChE inhibitors are necessary to be developed.

Chalcones are synthetic molecules which exhibit a number of biological properties including antiviral, anti-HIV (Trivedi et al., 2007), antimalarial (Wu et al., 2003), anti-leishmanial (Wu et al., 2002), antioxidant (Mukherjee et al., 2001), anti-tuberculosis (Sivakumar et al., 2007), analgesic (Viana et al., 2003), antifungal (Nowakowska, 2007), etc. Furthermore, these are considered as therapeutic agents with anti-amoebic (Budakoti et al., 2006), molluscicidal, anti-inflammatory (Barsoum et al., 2006) and monoamine oxidase (MAO) inhibitory (Zaib et al., 2015) potential. Keeping in view the above mentioned biological importance of chalcone derivatives, we investigated SAR of quinolinyl chalcones derivatives against ChEs. Moreover, molecular docking studies were also performed with homology model by utilizing both ChEs and discovered probable binding mode of the most potent inhibitor of ChEs.

Section snippets

Materials and methods

All chemicals and reagents including Acetylcholinesterase (E.C.3.1.1.7, from electric eel), Butyrylcholinesterase (E.C. 3.1.1.8, from horse serum), acetylthiocholine chloride, butyrylthiocholine chloride and 5,5′-dithiobis [2-nitrobenzoic acid] were purchased from Sigma Aldrich (St. Louis, MO, USA) & Merck (Darmstadt, Germany). All chemicals used were of analytical grade. Neostigmine was used as a standard drug. A microplate reader (BioTek ELx800, Instruments, Inc. USA) was used to measure the

Synthesis of chalcone derivatives

The synthetic route adopted for the preparation of chalcone derivatives (4a-1; 5a-s) as well as their physicochemical properties and spectroscopic data were reported in our previous publications (Rizvi et al., 2012, 2010). The variations in aromatic moieties and position of substituents are described in Table 1.

In vitro cholinesterase inhibition studies

A series of synthetic quinolinyl chalcone derivatives were investigated on ChEs. Inhibition studies were carried out and experimental results are reported in Table 1. All compounds were

Conclusions

In this study, two series of quinolinyl chalcones derivatives, 2,6-dimethylquinoline derivatives (4a-l) and 2-methyl-6-methoxyquinoline (5a-s) were screened for ChEs inhibition. All synthesized derivatives emerged as highly effectual inhibitors of BChE. Most of the compounds displayed significant inhibition for AChE. The structural activity relationship of most potent compounds is drawn by using enzyme kinetic studies. The presence of methyl group (−CH₃) in basic structure and dioxane in side

Acknowledgements

Jamshed Iqbal is thankful to the Organization for the Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands and the Higher Education Commission of Pakistan for the financial support through Project No. 20-3733/NRPU/R&D/14/520.

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Research ArticleQuinoline containing chalcone derivatives as cholinesterase inhibitors and their in silico modeling studies

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials and methods

Synthesis of chalcone derivatives

In vitro cholinesterase inhibition studies

Conclusions

Acknowledgements

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Biochem. Pharmacol.

Bioorg. Med. Chem.

Int. J. Electrochem. Sci.

Structure

Drug Discov. Today Technol.

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Biochem. Biophys. Res. Comm.

Mar. Environ. Res.

Tetrahedron Lett.

Phytomedicine

Bioorg. Med. Chem. Lett.

Research Article
Quinoline containing chalcone derivatives as cholinesterase inhibitors and their in silico modeling studies