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, , , , , , , , , ,

https://doi.org/10.1016/j.ejmech.2017.02.042 Get rights and content

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)

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 (a1∼a10) 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 (a11∼a22, b1∼b15, Fig.3) were synthesized based on the structures of the initial derivatives (a1∼a10). 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 a1∼a10 [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 (a11∼a22) 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)
See Also
(S)-3-(Methoxymethyl)morpholine 98%Morpholine CAS 110-91-8 - Buy Morpholine, CAS 110-91-8, C4H9NO Product on BOSS CHEMICAL Sociedad Americana de Fitopatología Morfolina | Fórmula molecular: C4H9NO - Tratamiento de agua IRO
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)

Cited by (20)

SAR studies of quinoline and derivatives as potential treatments for Alzheimer's disease
2023, Arabian Journal of Chemistry
Quinoline analogs are an important class of N-based heterocyclic compounds, which have received extensive attention because of their use in medicinal chemistry and organic synthesis. Over the past few decades, several new scaffold-based functionalization synthesis strategies have been reported for quinolines. Quinoline derivatives have a wide range of biological activities, including anti-Alzheimer’s disease activity. Herein, we review research on quinoline and related analogs as anti-Alzheimer’s disease agents from 2001 to 2022 and particularly highlight the structure–activity relationships and molecular binding modes. This review provides information for the rational design of more effective and target-specific drugs for Alzheimer's disease.
Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress
2022, European Journal of Medicinal Chemistry
Citation Excerpt :
Quinoline/quinazoline-based multi-target compounds Quinoline and quinazoline ring scaffold represent privileged structures that have been utilized to design therapeutic agents for a wide number of diseases including, but not limited to, cancer, anti-microbial therapy, and neurodegeneration disease. Herein, Xia et al. [119] design and synthesize novel 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for AD treatment. The results of in vitro biological activities show that 78 (Fig. 12) indicates good dual AChE/BuChE inhibitory activity (hAChE, IC50 = 1.5 μM; hBuChE, IC50 = 1.1 μM), both kinetic study and molecular docking provide a rational explanation for the ChEs inhibitory potency.
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.
Resveratrol-based compounds and neurodegeneration: Recent insight in multitarget therapy
2022, European Journal of Medicinal Chemistry
Citation Excerpt :
Among all tested compounds, 10 (Fig. 12, Table 1) showed the best and specific inhibition of PAS of AChE, and the AChE-induced Aβ aggregation. It has a significant effect on the protection of neuronal cells against the glutamate-induced cytotoxicity in HT22 cells by preventing the ROS production and increasing the GSH level [117]. Sulfonamide-based compounds have demonstrated biological properties as antimicrobial agents and useful against different diseases such as diabetes, psychosis, various cancers [118,119], anti-inflammatory, anticonvulsant, antidepressant activities, as well as carbonic anhydrase inhibitors [120] and other CNS disorders [121].
Neurodegenerative diseases (NDs) are characterized by gradual and progressive loss of selectively vulnerable populations of neurons, including death of neurons in different regions, leading to nervous system dysfunction. However, pharmacological treatments are only symptomatic, because the exact causes of the disease are not yet known. For this reason, in recent years, the research has been focused on the discovery of new molecules able to target neuropathological pathways involved in NDs. A great deal of attention has been paid to natural polyphenols due to their many biological effects and resveratrol has attracted special interest since its ability to interact simultaneously with the multiple targets implicated in NDs. Moreover, the structural simplicity of the stilbene core, the broad spectrum of possible modifications, and the improved synthetic strategies, made resveratrol an attractive chemical starting point for the search of new entities with extended therapeutic uses in NDs. In this review, a systematic update of the resveratrol-based compounds, and Structure-Activity Relationship analysis were provided as promising drug candidates for the treatment of NDs.
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
2022, Synthetic Communications
The effect of substituents in the aniline donor and the type of heterocyclic acceptor/donor moieties on the yields of 1,2-trans- and 1,1-isomer ethylene D-π-A chromophores in Pd-catalyzed Heck reaction has been studied. Various D-π-A chromophores – derivatives of quinoline, quinoxaline, benzothiazole, carbazole and indolizine – were synthesized.
Amyloid-β and tau aggregation dual-inhibitors: A synthetic and structure-activity relationship focused review
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
In 2018, Lv et al. designed and synthesized a novel class of 1,2,3,4-tetrahydro-1-acridone analogues and evaluated their potential as dual inhibitors of Aβ and tau aggregations [56]. Several studies have already reported that the quinoline moiety is a very important pharmacophore of many anti-AD agents, as well as α,β-unsaturated carbonyl compounds (such as cinnamaldehyde) acting as tau anti-aggregating inhibitors (Fig. 15) [57–61]. Following these evidences, Lv et al. pursued a fusion strategy of the structural motifs of tacrine and cinnamaldehyde into a single molecular entity, to obtain the basic core structure 55 (Fig. 15) [56].
Alzheimer’s disease (AD) is one of the most common types of dementia, especially in elderly, with an increasing number of people suffering from this disease worldwide. There are no available disease-modifying therapies and only four drugs are approved for the relief of symptoms. Currently, the therapeutic approach used for AD treatment is based on single target drugs, which are not capable to stop its progression. To address this issue, multi-target compounds, combining two or more pharmacophores in a single molecular entity, have gained increasing interest to deal with the multiple factors related to AD. The exact cause of AD is not yet completely disclosed, and several hallmarks have been associated to this neurodegenerative disease. Even though, the accumulation of both amyloid-β plaques (Aβ) and neurofibrillary tangles (NFTs) are fully accepted as the main AD hallmarks, being object of lots of research for early-stage diagnosis and pharmacological therapy. In this context, this review summarizes the state-of-the-art in the field of dual-target inhibitors of both Aβ and tau aggregation simultaneously, including the design and synthetic strategy of the dual-target compounds, as well as a brief structure-activity relationships (SAR) analysis.
Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents
2020, Bioorganic Chemistry
Citation Excerpt :
Several stilbene derivatives with encouraging Aβ binding abilities have been developed as Aβ imaging probes and Aβ aggregation inhibitors during the last two decades (Fig. 1) [32]. In combination with other bioactive moieties, these stilbene hybrids showed cholinesterase inhibitory, metal chelating, Aβ aggregation inhibitory, and free radical scavenging activities [33–35]. A central lipophilic scaffold with a terminal amine group is the salient feature of most of the reported stilbene derivatives which could have an impact on their anti-AD properties.
Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer’s disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aβ aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC₅₀ value of 2.64μM) and BuChE (IC₅₀ value of 1.29μM), and significant inhibition of self-mediated Aβ_1–42 aggregation (51.29% at 25μM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aβ_1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.

View all citing articles on Scopus