Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities

doi:10.1016/j.ejmech.2018.05.031

European Journal of Medicinal Chemistry

Volume 155, 15 July 2018, Pages 49-60

https://doi.org/10.1016/j.ejmech.2018.05.031 Get rights and content

Highlights

•
Twenty tetrahydro carbazole-benzyl piperidine hybrids were designed and synthesized.
•
All of the designed compounds were selective and potent BuChE inhibitors.
•
Compound 6i depicted the most potent anti-BuChE, neuroprotective and β-secretase inhibition activities.
•
Molecular modeling and kinetic studies showed compound 6i bound simultaneously to the peripheral site and catalytic sites of the BuChE.

Abstract

Butyrylcholinesterase (BuChE) inhibitors have become interesting target for treatment of Alzheimer's disease (AD). A series of dual binding site BuChE inhibitors were designed and synthesized based on 2,3,4,9-tetrahydro-1H-carbazole attached benzyl pyridine moieties. In-vitro assay revealed that all of the designed compounds were selective and potent BuChE inhibitors. The most potent BuChE inhibitor was compound 6i (IC₅₀ = 0.088 ± 0.0009 μM) with the mixed-type inhibition. Docking study revealed that 6i is a dual binding site BuChE inhibitor. Also, Pharmacokinetic properties for 6i were accurate to Lipinski's rule. In addition, compound 6i demonstrated neuroprotective and β-secretase (BACE1) inhibition activities. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100 μM and 10 μM respectively. Generally, the results are presented as new potent selective BuChE inhibitors with a therapeutic potential for the treatment of AD.

Graphical abstract

A series of dual binding site BuChE inhibitors were designed and synthesized based on 2,3,4,9-tetrahydro-1H-carbazole attached benzyl pyridine moieties. The most potent BuChE inhibitor was compound 6i (IC₅₀ = 0.088 μM). In addition, compound 6i demonstrated neuroprotective and β-secretase inhibition activities.

Introduction

Alzheimer's disease (AD) is the most common form of dementia leading to psychiatric and behavioral disturbances, cognitive dysfunction and difficulties in performing daily activities [1]. Correspondingly, it has shown surge in the overall mortality rate by over 66% [2]. Decreasing Acetylcholine (Ach) in the cortex and hippocampus regions of brain is the most simulated neurotransmitter deficiency in AD [3]. Thus, the most promising approach to alleviate the symptoms of AD is the inhibition of cholinestrase (ChE) [4]. Though in the normal healthy brain, AChE has the main role in the regulation of ACh, It seems that there is a significant increase in BuChE activity in the most affected areas of the brain during the progression of AD [5,6]. According to a recent study, selective BuChE inhibitors increase brain ACh and enhance learning in rodents [7]. Moreover, selective BuChE inhibitors might not have common side-effects as AChE inhibitors such as classical cholinergic toxicity [8].

Thus, in recent years, BuChE inhibitors have become more interesting targets for the treatment of AD [3,6,7,9,10].

Although both ChE have almost similar anionic site and oxyanion hole in their active sites, spatial capacity of the Acyl pocket is the most prominent difference between the structures of AChE and BuChE. The replacement of Phe288 and Phe290 residues (in AChE) with Leu286 and Val288 (in BuChE) enables BuChE to hydrolyze bulkier substrates [6,11].

Selective BuChE inhibitors usually contain tri- or polycyclic structures (N1-phenetylnorcymserine and ethopropazine) [5,7,[11], [12], [13]]. Especially, indole containing tricycle derivatives based on Latrepirdine have recently shown selective BuChE inhibition [12,14,15]. All in all, to obtain more information on BuChE's selectivity of indole containing tricycle derivatives, we have designed and synthesized a novel series of 2,3,4,9-tetrahydro-1H-carbazole containing derivatives.

On the other hand, the design of dual binding site ChE inhibitors seems to be a promising strategy to increase inhibitory activity through the enhancement of many drug-targeted interactions [[16], [17], [18], [19], [20]].

Recently, benzyl pyridine derivatives have been designed and synthesized, according to the donepezil structure, to have the cholinesterase inhibitory effect [[21], [22], [23], [24]].

Therefore, in this study, a series of dual binding site BuChE inhibitors were designed and synthesized according to 2,3,4,9-tetrahydro-1H-carbazole attached benzyl pyridine moieties. Moreover, in-vitro and MTT assay, study of β-secretase inhibition activity, pharmacokinetic and docking studies were performed (see Scheme 1).

Section snippets

Chemistry

According to Scheme 2, compound 1 was prepared as the literature reported [25]. Synthesis of 3a/b was carried out in a two phasic condition using TBAB as phase transfer catalyst agent. Purification of the product was carried out using column chromatography method. Condensation of 3a (or 3 b) with different benzyl halides (4a-j) gave the final compounds 5 (or 6)-a-j in reflux condition using dry acetone as solvent.

AChE and BuChE inhibitory activity

The in-vitro IC₅₀ values of the all derivatives 5a-j and 6a-j were determined

Conclusion

In summary, a new series of potent selective BuChE inhibitors were designed. All of the compounds have shown selective inhibition of BuChE. They might have a therapeutic advantage for the treatment of AD as during AD's progression the loss of AChE-activity is compensated by unaffected BuChE. Also, eight of them had lower BuChE IC₅₀ values than donepezil as the reference drug. In-vitro assay revealed that compound 6i indicated the most potent anti-BuChE activity (IC₅₀ = 0.088 ± 0.0009 μM).

General chemistry

All reagents were purchased from Sigma Aldrich, Merck and Fluka and were used as provided. For all the derivatives, ¹H and ¹³C nuclear magnetic resonance (NMR) spectra's were recorded on a Bruker FT-500, using TMS as an internal standard and the IR spectra's were recorded with KBr disks using the Nicolet Magna FTIR 550 spectrophotometer. Furthermore, all of melting points were taken on a Kofler hot stage apparatus.

Acknowledgments

This work was financially supported by Tehran University of Medical Sciences and Health Services (Grant Number: 9211302001). The authors thank the equipment supports from the Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. Also, we'd like to appreciate Miss Ronas Simaei for English language editing.

References (40)

R. Brookmeyer et al.
Forecasting the global burden of Alzheimer's disease
Alzheimer's Dementia
(2007)
B. Sameem et al.
A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer's disease
Eur. J. Med. Chem.
(2017)
G. Huang et al.
Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine
Eur. J. Med. Chem.
(2014)
X. Chen et al.
Probing the mid-gorge of cholinesterases with spacer-modified bivalent quinazolinimines leads to highly potent and selective butyrylcholinesterase inhibitors
Bioorg. Med. Chem.
(2011)
J. Takahashi et al.
Design, synthesis and evaluation of carbamate-modified (−)-N 1-phenethylnorphysostigmine derivatives as selective butyrylcholinesterase inhibitors
Bioorg. Med. Chem. Lett
(2010)
M. de Candia et al.
New azepino [4, 3-b] indole derivatives as nanomolar selective inhibitors of human butyrylcholinesterase showing protective effects against NMDA-induced neurotoxicity
Eur. J. Med. Chem.
(2017)
R. Otto et al.
Beta and gamma carboline derivatives as potential anti-Alzheimer agents: a comparison
Eur. J. Med. Chem.
(2014)
M. Mohammadi-Khanaposhtani et al.
Potent acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and docking study of acridone linked to 1, 2, 3-triazole derivatives
Eur. J. Med. Chem.
(2015)
S. Motavallizadeh et al.
Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl) benzenesulfonamides
Tetrahedron Lett.
(2014)
M. Khoobi et al.
Design, synthesis, biological evaluation and docking study of 5-oxo-4, 5-dihydropyrano [3, 2-c] chromene derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors
Eur. J. Med. Chem.
(2013)

Cited by (27)

Synthesis, biological evaluation and molecular modeling studies of novel carbazole-benzylpiperazine hybrids as acetylcholinesterase and butyrylcholinesterase inhibitors
2023, Journal of Molecular Structure
A novel series of carbazole-benzylpiperazine hybrids (7a–n) were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated. The biological results indicated that the nature of linker between carbazole and benzylpiperazine moieties as well as the type of substitutions on the phenyl ring of benzylpiperazine moiety greatly affected the inhibitory activity and selectivity of the synthesized compounds towards eelAChE and eqBuChE enzymes. Among all the synthesized compounds, compounds 7a (IC₅₀ = 8.9 µM) and 7e (IC₅₀ = 5.7 µM) with fluorine substitution at meta and para positions of the phenyl ring showed the highest inhibitory activity against eelAChE and maximum inhibitory activity against eqBuChE were generated by compounds 7h (IC₅₀ = 5.4 µM) and 7k (IC₅₀ = 4.5 µM) with fluorine and methyl substitutions at meta position of the phenyl ring, respectively. Furthermore, kinetic analysis and molecular modeling studies revealed that the most active compound 7e acts as a mixed-type inhibitor against AChE, which suggested this compound interacted with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE enzyme.
Alzheimer's disease therapeutics: current strategies and future directions
2023, Privileged Scaffolds in Drug Discovery
Alzheimer's disease (AD) is a chronic and progressive brain neurodegenerative disease affecting over 30 million people globally. Currently, no effective treatment is available owing to multiple factors involved in the progression of AD. Based on numerous AD-related targets in the disease network, a single-target strategy, multiple-medication therapy and/or multiple-compound medication, and multiple target–directed ligands strategy have been employed to treat AD. Approved drug candidates are in clinical trials, and the promising preclinical compounds are summarized in this chapter. Sodium oligomannate GV-971, which is approved in China, opens the door for the discovery of novel anti-AD drugs. This review also suggests that cell-penetrating peptides, autophagy inducers, and protectors of brain pericytes provide an approach to treating early stage AD, and that obligate multispecific drugs with cell-penetrating peptides may be the most promising strategy for therapy at different stages of AD.
Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress
2022, European Journal of Medicinal Chemistry
Citation Excerpt :
Moreover, 69 does not display any hepatoxicity and neurotoxicity in cell models up to 10 μM, showing also moderate protective effects against NMDA-induced neurotoxicity in an SH-SY5Y cell model at concentrations in the low micromolar range. Then, Ghobadian et al. [110] develop tetrahydrocarbazole benzyl pyridine hybrids as potent and selective BuChE inhibitors with neuroprotective and BACE inhibition activities. In vitro assays reveal that 70 shows the most potent BuChE inhibitory activity (IC50 = 0.088 μM) with mixed-type inhibition.
Alzheimer's disease is a chronic and progressive brain neurodegenerative disease affecting over 30 million people globally. Currently, no effective treatment is available due to multiple factors involved in the progression of AD. Given that the numerous AD-related targets in the disease network, the multi-target-directed ligands (MTDLs) strategy are considered as the promising strategy to treat AD. Herein, the multi-target compounds with/without ChEs are in clinical and in progress are reviewed. To further characterize the drug-likeness, and ADME properties are calculated using the Qikprop. This review will provide highlights for the treatment of AD.
Construction of carbazole-based unnatural amino acid scaffolds via Pd(ii)-catalyzed C(sp<sup>3</sup>)-H functionalization
2022, Organic and Biomolecular Chemistry
We report the synthesis of carbazole-based unnatural α-amino acid and non-α-amino acid derivatives via a Pd(ii)-catalyzed bidentate directing group 8-aminoquinoline-aided β-C(sp³)–H activation/functionalization method. Various N-phthaloyl, dl-, l- and d-carboxamides derived from their corresponding α-amino acids, non-α-amino acids and aliphatic carboxamides were subjected to the β-C(sp³)–H functionalization with 3-iodocarbazoles in the presence of a Pd(ii) catalyst to afford the corresponding carbazole moiety installed unnatural amino acid derivatives and aliphatic carboxamides. Carbazole motif-containing racemic (dl) and enantiopure (l and d) amino acid derivatives including phenylalanine, norvaline, leucine, norleucine and 2-aminooctanoic acid with anti-stereochemistry and various non-α-amino acid derivatives including GABA have been synthesized. Removal of the 8-aminoquinoline directing group, deprotection of the phthalimide moiety and the preparation of carbazole amino acid derivatives containing free amino- and carboxylate groups are shown. The carbazole motif is prevalent in alkaloids and biologically active molecules and functional materials. Thus, this work on the synthesis of carbazole-based unnatural amino acid derivatives would enrich the libraries of unnatural amino acid derivatives and carbazoles.
Pyridine derivatives as anti-Alzheimer agents
2022, Recent Developments in the Synthesis and Applications of Pyridines
Alzheimer's disease (AD) is a neurodegenerative disorder and the leading reason for dementia. Morbidity and mortality are associated with AD and trouble mostly old-age people; however, in recent times, people with age groups lower than 50 are also getting affected. The etiology of AD has been an exciting area of research; still, an evidence-based conclusive pathway is a matter of research. Some of the targets exploited for the AD treatment include shortage of choline neurotransmitters, accumulation of β-amyloid, oxidative stress, MAO B inhibition, etc. Pyridine scaffold has been helping medicinal chemistry researchers for years in the development of different drugs. The synthesis of pyridine derivatives has been easily achieved by routine chemical reactions. This chapter will discuss the synthesis of pyridine derivatives and their biological evaluation toward different targets of AD.
Recent developments in the synthesis of pyridine analogues as a potent anti-Alzheimer's therapeutic leads
2022, Recent Developments in the Synthesis and Applications of Pyridines
Alzheimer's disease (AD) is currently the third most progressive neurodegenerative disorder people facing across globally. The brains of AD patients undergo significant changes because of damage in brain nerve cells in regions like learning, thinking, and cognitive functions (memory) and ensuing experiences memory loss and speech damage, etc. In this situation, they start to face difficulties in common activities such as trouble to recalling earlier conversations, names/events. Therefore, AD patients are become bed-bound and need help around the clock and can eventually lead to malignancy. The current therapeutic targets of AD include the amelioration of β-amyloid plaque, cholinesterase inhibitors, tau-protein hyper-phosphorylation, biometal dyshomeostasis, and oxidative stress. In this state, pyridine analogues have been accredited as a promising anti-Alzheimer therapeutic leads. Since donepezil and tacrine are two pyridine analogues in the FDA-approved five drugs for the preliminary treatment of AD. Further, pyridine is an important key template for the existence of several natural molecules such as Vitamin B3, β-picoline, quinoline, trigonelline, and coenzymes (e.g., NADP), etc. The Hantzsch synthesis, Emil Knoevenagel process, Aleksei Chichibabin, Bonnemann cyclization, Gattermann–Skita synthesis, and Ciamician–Dennstedt rearrangement are the well-known methods for the synthesis of pyridine analogues. The production of industrial-scale pyridine analogues became easier after the invention of Chichiban synthesis by Russian chemist “Aleksei Chichibabin” through inexpensive staring materials and a more efficient route that is still practiced. Thus, it expands the importance of pyridine analogues for the treatment of AD and hence further studies are recommended for the development of potent anti-Alzheimer drugs. Therefore, the present chapter describes the role of pyridine analogues and their recent developments in the management of multisyndrome AD.

View all citing articles on Scopus

View full text

Research paperNovel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

AChE and BuChE inhibitory activity

Conclusion

General chemistry

Acknowledgments

Alzheimer's Dementia

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Tetrahedron Lett.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Chem. Biol. Interact.

Bioorg. Med. Chem.

Bioorg. Chem.

Research paper
Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities