European Journal of Medicinal Chemistry
21 April 2017
, Pages 139-153
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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.
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.
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 . 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 . 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 . 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 , , , . 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 , , , .
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 , . 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 , . In addition, during aging, the cholinergic function is deficit in the central nervous system, which contributes to cognitive decline in AD . Meanwhile, the peripheral anionic site (PAS) of acetylcholinesterase (AChE) can bind to Aβ and promote the formation of amyloid fibrils in the physiological condition , , which indicates that inhibiting the cholinesterases (ChEs) activity is a promising approach to inhibit Aβ aggregation , , . 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 , . It has been reported that curcumin , resveratrol  and its derivative 5d , 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 , clioquinol (CQ) , methylene blue , and tacrine-8-hydroxyquinoline hybrids  (Fig.1) with various biological activities of ChEs inhibition, Aβ aggregation inhibition, and neuroprotection.
Inspired by the aforementioned statement, in our research group, Wang  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 . In this study, we first evaluated the activities of ten 2-arylethenyl-N-methylquinolinium derivatives (a1∼a10) from our compound library , 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.
Our initial results show that 2-arylethenyl-N-methylquinolinium derivatives a1∼a10  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 , 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.
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
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.
- D. Zhu et al.
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- M. Inayathullah et al.
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- L. Di et al.
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Eur. J. Med. Chem.
- G.L. Ellman et al.
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- Z.Q. Liu et al.
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- P. Kapkova et al.
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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 Aβ1–42 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 Aβ1-42 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.
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