Design, synthesis and evaluation of 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for Alzheimer's disease treatment (2023)

Table of Contents
European Journal of Medicinal Chemistry Abstract Graphical abstract Introduction Section snippets Chemistry Inhibition of Aβ1−42 self-aggregation by derivatives Conclusions Synthesis and characterization Acknowledgments References (60) Discovery of novel N-substituted carbazoles as neuroprotective agents with potent anti-oxidative activity Eur. J. Med. Chem. How to study proteins by circular dichroism Biochim. Biophys. acta Effect of osmolytes on the conformation and aggregation of some amyloid peptides: CD spectroscopic data Data Brief. High throughput artificial membrane permeability assay for blood-brain barrier Eur. J. Med. Chem. Anew and rapid colorimetric determination of acetylcholinesterase activity Biochem. Pharmacol Facile syntheses of disubstitutedbis (vinylquinolinium)-benzene derivatives as G-quadruplex DNA binders Tetrahedron Search for dual function inhibitors for Alzheimer's disease: synthesis and biological activityof acetylcholinesterase inhibitors of pyridinium-type and their Abeta fibril formation inhibition capacity Bioorg. Med. Chem. Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer's disease Eur. J. Med. Chem. Methylene blue and Alzheimer's disease Biochem. Pharmacol. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme Neuron Treatment of Alzheimer's disease: current status and new perspectives Lancet Neurol. The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect Pharmacol. Ther. Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease Eur. J. Med. Chem. Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo [7,8] chromeno [2,3-b] quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease Eur. J. Med. Chem. New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer's disease Eur. J. Med. Chem. Development and evaluation of multifunctional agents for potential treatment of Alzheimer's disease: application to a pyrimidine-2,4-diamine template Bioorg. Med. Chem. Lett. Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents Eur. J. Med. Chem. Alzheimer disease is multifactorial and heterogeneous Neurobiol. Aging World Alzheimer Report 2015. The Global Impact of Dementia: Ananalysis of Prevalence, Incidence, Cost and Trends Acentury of Alzheimer's disease Science Alzheimer's disease: from pathology to therapeutic approaches Angew. Chem. Int. Ed. Engl. Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers J.Med. Chem. β-Amyloid: the key peptide in the pathogenesis of Alzheimer's disease Front. Pharmacol. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics Science Causes of oxidative stress in Alzheimer disease Cell. Mol. Life Sci. Catalytic antioxidants and neurodegeneration Antioxid. Redox Signal Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush J.Med. Chem. Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors Curr. Pharm. Des. Propidium-based polyamine ligands as potent inhibitors of acetylcholinesterase and acetylcholinesterase-induced amyloid-beta aggregation J.Med. Chem. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation J.Med. Chem. Cited by (20) SAR studies of quinoline and derivatives as potential treatments for Alzheimer's disease Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress Resveratrol-based compounds and neurodegeneration: Recent insight in multitarget therapy Heck reaction in the synthesis of D-π-A chromophores: The effect of donor and acceptor on the ratio of 1,2- trans- and 1,1-isomer olefins Amyloid-β and tau aggregation dual-inhibitors: A synthetic and structure-activity relationship focused review Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents Recommended articles (6) Synthesis and evaluation of 7-substituted-5,6-dihydrobenzo[c]acridine derivatives as new c-KIT promoter G-quadruplex binding ligands New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies Endoplasmic reticulum-targetable fluorescent probe for visualizing HClO in EC1 cells Dimeric aryl-substituted imidazoles may inhibit ALT cancer by targeting the multimeric G-quadruplex in telomere Synthesis and living cell imaging of a novel fluorescent sensor for selective cupric detection Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens

European Journal of Medicinal Chemistry

Volume 130,

21 April 2017

, Pages 139-153

Author links open overlay panel, , , , , , , , , ,

Abstract

A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349–361). The results of invitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12•HAc was well tolerated at doses up to 2000mg/kg and could traverse blood-brain barrier.

Graphical abstract

A series of compounds with an introduction of methyl group into N1-position to previous reported 2-arylethenylquinoline analogues were synthesized and evaluated. The optimal compound a12 showed good anti-AD potential.

Design, synthesis and evaluation of 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for Alzheimer's disease treatment (3)
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Introduction

Alzheimer's disease (AD) is a highly complex neurodegenerative disorder of aged people, and its multiple factors contribute to its etiology in terms of initiation and progression [1]. It was estimated that the number of dementia patients is over 46 million worldwide, and 131.5 million people will have this neurodegenerative disorder by 2050 [2]. Because of the sheer number of patients, AD is considered the most common neurodegenerative disorder and a major health concern to societies worldwide. AD is characterized by progressive memory loss, language skill decline, and other cognitive impairments [3]. The etiology of AD is not completely known, but many factors, such as β-amyloid (Aβ) deposits, tau-protein (τ) aggregation, oxidative stress, decreased level of acetylcholine (ACh), neuroinflammation, and dyshomeostasis of biometal, are thought to play significant roles in the pathogenesis of the disease [4], [5], [6], [7]. Because of its complexity, AD has been described as a multifactorial disease, and the development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of today's research of AD treatment drugs [8], [9], [10], [11].

Amyloid cascade hypothesis plays a key role in the pathogenesis of AD. Many studies have demonstrated that the formation and toxicity of aggregative Aβ are closely related to several factors of the AD etiology [12], [13]. For example, Aβ plaque in the brain promotes the generation of free radicals via an inflammatory response, which causes oxidative stress and consequently leads to neuronal cell death [14], [15]. In addition, during aging, the cholinergic function is deficit in the central nervous system, which contributes to cognitive decline in AD [16]. Meanwhile, the peripheral anionic site (PAS) of acetylcholinesterase (AChE) can bind to Aβ and promote the formation of amyloid fibrils in the physiological condition [17], [18], which indicates that inhibiting the cholinesterases (ChEs) activity is a promising approach to inhibit Aβ aggregation [19], [20], [21]. Thus, inhibition of the formation and aggregation of Aβ is an important indicator to discover multifunctional candidates for AD treatment, which with the features of Aβ aggregation inhibition, cholinesterase inhibition, and antioxidant activity.

In recent years, although a few noteworthy advances in the area of multifunctional agents have been achieved, the design of multifunctional drugs to treat AD remains an urgent work [22], [23]. It has been reported that curcumin [24], resveratrol [25] and its derivative 5d [26], which have a styrene group (Fig.1), have a broad spectrum of AD-related biological activities such as antioxidant activity, Aβ aggregation inhibition, and neuroprotection invitro or improved cognitive invivo of mouse models. Moreover, the quinoline moiety acts as the pharmacophore of many drug candidates for AD treatment such as tacrine [27], clioquinol (CQ) [28], methylene blue [29], and tacrine-8-hydroxyquinoline hybrids [30] (Fig.1) with various biological activities of ChEs inhibition, Aβ aggregation inhibition, and neuroprotection.

Inspired by the aforementioned statement, in our research group, Wang [31] designed and synthesized a class of 2-arylethenylquinoline analogues (Fig.2) as multifunctional agents for the treatment of Alzheimer's disease, which contained the quinoline scaffold and vinylbenzene scaffold. However, these compounds had unsatisfactory inhibitory activities of Aβ aggregation and ChEs. On the other hand, it has been reported that the introduction of a positive charge may increase the inhibitory activity of Aβ aggregation and ChEs by enhancing the electrostatic interaction of the compound with the target [32]. In this study, we first evaluated the activities of ten 2-arylethenyl-N-methylquinolinium derivatives (a1a10) from our compound library [33], which have a positive charge at the N atom of the quinoline ring (Fig.2, Fig.3). The results showed that the N-methylquinolinium derivatives had a significantly improved inhibitory activity of Aβ self-aggregation and ChEs. For example, compound a1 had a 93.1% (20μM) inhibition ratio on the Aβ self-aggregation and 0.3μM of IC50 on hAChE, whereas Wang's compound 4e6 with the identical substituents compared to a1, showed only the activities of 42.0% (20μM) and 0.2% (5μM) inhibition ratios on the Aβ self-aggregation and hAChE, respectively (Table1). The results indicate the importance of a positive-charge introduction. Therefore, to find more effective lead compounds as multifunctional agents (Aβ aggregation inhibition, cholinesterase inhibition, antioxidant activity, and neuroprotection) for AD treatment, twenty-seven new 2-arylethenyl-N-methylquinolinium derivatives (a11a22, b1b15, Fig.3) were synthesized based on the structures of the initial derivatives (a1a10). Their biological activities were evaluated, which included the Aβ aggregation inhibition, ChEs inhibition, and antioxidant activity invitro. Some target compounds were also evaluated for the blood-brain barrier (BBB) permeability. Furthermore, an optimal compound, a12, was further assessed regarding the possible inhibitory mechanisms of AChE and Aβ aggregation, and the protective capacity for glutamate-induced HT22cell death.

Section snippets

Chemistry

Our initial results show that 2-arylethenyl-N-methylquinolinium derivatives a1a10 [33] have better inhibitory activity of Aβ self-aggregation and cholinesterase than the corresponding 2-arylethenylquinoline derivatives (Table1). Based on these results, to obtain more potent compounds as multifunctional agents for AD treatment, we developed twenty-seven new 2-arylethenyl-N-methylquinolinium derivatives by extending the type of the aromatic group (Ar) at the 2-position (a11a22) or introducing

Inhibition of Aβ1−42 self-aggregation by derivatives

To evaluate the inhibitory potency of derivatives on Aβ1−42 self-aggregation, the Thioflavin T (ThT) fluorescence assay was used [35], where resveratrol, curcumin, and denepezil were the reference compounds, as shown in Table1. We found that most of compounds exhibited moderate or strong inhibitory activity (41.1–104.2% at 20μM) compared to resveratrol (80.1% at 20μM), curcumin (51.3% at 20μM), and donepezil (33.7% at 20μM). The structure-activity relationship was explored.

First, the

Conclusions

In summary, a series of new 2-arylethenyl-N-methylquinolinium derivatives were developed as multifunctional agents for the treatment of AD based on our previous study. Among the synthesized compounds, some compounds exhibited significant inhibition on the Aβ aggregation and ChEs, antioxidant activity, and a good BBB penetration. The structure-activity relationship was summarized, which confirms the importance of the positive charge on the quinolone ring for the activities of compounds,

Synthesis and characterization

All commercial chemicals used as starting materials were analytical grade and utilized without further purification. 1H and 13C NMR spectra were recorded using TMS as the internal standard in DMSO-d6 or CDCl3 with a Bruker BioSpin GmbH spectrometer at 400MHz and 100MHz, respectively; Chemical shifts are reported in parts per million (ppm) relative to residual CHCl3 (δ=7.26, 1H; δ=77.0, 13C). Mass spectra (MS) were recorded on a Shimadzu LCMS-2010A instrument with an ESI or ACPI mass

Acknowledgments

We thank the Natural Science Foundation of China (81273433 and 81330077), Specialized Research Fund for the Doctoral Program of Higher Education of China (20110171110051), Guangdong Provincial International Cooperation Project of Science & Technology (2013B051000038), and Guangdong Provincial Key Laboratory of Construction Foundation (Grant 2011A060901014) for financial support of this study.

References (60)

  • D. Zhu et al.

    Discovery of novel N-substituted carbazoles as neuroprotective agents with potent anti-oxidative activity

    Eur. J. Med. Chem.

    (2013)

  • S.M. Kelly et al.

    How to study proteins by circular dichroism

    Biochim. Biophys. acta

    (2005)

  • M. Inayathullah et al.

    Effect of osmolytes on the conformation and aggregation of some amyloid peptides: CD spectroscopic data

    Data Brief.

    (2016)

  • L. Di et al.

    High throughput artificial membrane permeability assay for blood-brain barrier

    Eur. J. Med. Chem.

    (2003)

  • G.L. Ellman et al.

    Anew and rapid colorimetric determination of acetylcholinesterase activity

    Biochem. Pharmacol

    (1961)

  • Z.Q. Liu et al.

    Facile syntheses of disubstitutedbis (vinylquinolinium)-benzene derivatives as G-quadruplex DNA binders

    Tetrahedron

    (2013)

  • P. Kapkova et al.

    Search for dual function inhibitors for Alzheimer's disease: synthesis and biological activityof acetylcholinesterase inhibitors of pyridinium-type and their Abeta fibril formation inhibition capacity

    Bioorg. Med. Chem.

    (2006)

  • X.Q. Wang et al.

    Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer's disease

    Eur. J. Med. Chem.

    (2015)

  • M. Oz et al.

    Methylene blue and Alzheimer's disease

    Biochem. Pharmacol.

    (2009)

  • N.C. Inestrosa et al.

    Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme

    Neuron

    (1996)

  • E. Scarpini et al.

    Treatment of Alzheimer's disease: current status and new perspectives

    Lancet Neurol.

    (2003)

  • S. Chu et al.

    The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect

    Pharmacol. Ther.

    (2016)

  • P. González-Naranjo et al.

    Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease

    Eur. J. Med. Chem.

    (2014)

  • E. Maalej et al.

    Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo [7,8] chromeno [2,3-b] quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease

    Eur. J. Med. Chem.

    (2012)

  • X.T. Luo et al.

    New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer's disease

    Eur. J. Med. Chem.

    (2015)

  • T. Mohamed et al.

    Development and evaluation of multifunctional agents for potential treatment of Alzheimer's disease: application to a pyrimidine-2,4-diamine template

    Bioorg. Med. Chem. Lett.

    (2012)

  • J.B. Shaik et al.

    Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents

    Eur. J. Med. Chem.

    (2016)

  • K. Iqbal et al.

    Alzheimer disease is multifactorial and heterogeneous

    Neurobiol. Aging

    (2000)

  • M. Prince et al.

    World Alzheimer Report 2015. The Global Impact of Dementia: Ananalysis of Prevalence, Incidence, Cost and Trends

    (2015)

  • M. Goedert et al.

    Acentury of Alzheimer's disease

    Science

    (2006)

  • R. Jakob-Roetne et al.

    Alzheimer's disease: from pathology to therapeutic approaches

    Angew. Chem. Int. Ed. Engl.

    (2009)

  • P.C. Trippier et al.

    Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers

    J.Med. Chem.

    (2013)

  • X. Sun et al.

    β-Amyloid: the key peptide in the pathogenesis of Alzheimer's disease

    Front. Pharmacol.

    (2015)

  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)

  • X. Zhu et al.

    Causes of oxidative stress in Alzheimer disease

    Cell. Mol. Life Sci.

    (2007)

  • T.R. Golden et al.

    Catalytic antioxidants and neurodegeneration

    Antioxid. Redox Signal

    (2009)

  • M. Rosini et al.

    Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer's disease: a promising direction for the multi-target-directed ligands gold rush

    J.Med. Chem.

    (2008)

  • A. Castro et al.

    Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors

    Curr. Pharm. Des.

    (2006)

  • M.L. Bolognesi et al.

    Propidium-based polyamine ligands as potent inhibitors of acetylcholinesterase and acetylcholinesterase-induced amyloid-beta aggregation

    J.Med. Chem.

    (2005)

  • P. Camps et al.

    Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation

    J.Med. Chem.

    (2008)

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      Copper is an important element indispensable for human life and health. Many copper-determining probes have been created for exploring its functional behavior in various cell types but few of them contains both fluorescent and colorimetric characters. In the present study, we developed a set of copper probes by synthesizing several novel thiophene-based Schiff bases in order to make a suitable sensor for quantifying and imaging copper in living cells. We find that the ligand FS-1 has a splendid selectivity and affinity toward Cu2+ among the common divalent metal ions. Living cell imaging show that FS-1 has a robust and repetitive fluorescence response in the presence of Cu2+ only in the cytosolic space of Hepg2 cell and not in the other cells examined. These data suggest that we have developed a new copper probe that can be used as a Cu2+ fluorescent and colorimetric sensor for in vivo and in vitro copper studies.

    • Research article

      Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens

      Bioorganic & Medicinal Chemistry Letters, Volume 30, Issue 8, 2020, Article 127037

      Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm infection, and it has been reported to have antiparasitic and antimicrobial activities. Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these compounds against malaria parasite P. falciparum 3D7 revealed analogs with better antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC50 of 23nM and 60nM against P. falciparum 3D7, respectively. These compounds were also effective against drug-resistant malaria parasite P. falciparum Dd2 with IC50 of 53nM and 97nM, respectively. The cytotoxicity against CHO-K1, HEK and NRK-49F cells revealed better selectivity index for these new analogs compared to pyrvinium. Additionally, this series of compounds showed activity against M. tuberculosis H37Rv; particularly compounds 10, 13, 14 and 16 showed equipotent antitubercular activity to that of pyrvinium pamoate. The compounds 14 and 16 should be taken forward as leads for further optimization.

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