Design, synthesis and bioactivity study of N-salicyloyl tryptamine derivatives as multifunctional agents for the treatment of neuroinflammation

doi:10.1016/j.ejmech.2020.112217

European Journal of Medicinal Chemistry

Volume 193, 1 May 2020, 112217

https://doi.org/10.1016/j.ejmech.2020.112217 Get rights and content

Highlights

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N-salicyloyl tryptamine derivatives were firstly applicated for neuroinflammation.
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Some were multifunction with inhibiting COX, glia cell activation and neuron damage.
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Improved efficacy, PK profiles and multifunction supported combination principle.

Abstract

Because of the complex etiology in neuroinflammatory process, the design of multifunctional agents is a potent strategy to cure neuroinflammatory diseases including AD and PD. Herein, based on the combination principles, 23 of N-salicyloyl tryptamine derivatives as multifunctional agents were designed and their new application for anti-neuroinflammation was disclosed. In cyclooxygenase assay, two compounds 3 and 16 displayed extremely preferable COX-2 inhibition than N-salicyloyl tryptamine. In LPS-induced C6 and BV2 cell models, some compounds decreased the production of proinflammatory mediators NO, PGE₂, TNF-α, iNOS, COX-2 and ROS, while increased the production of IL-10. Among them, compound 3 and 16 showed approximately six-fold better inhibition on nitric oxide production than N-salicyloyl tryptamine in C6. Besides, compounds 3, 13 and 16 attenuated the activation of BV2 and C6 cells. More importantly, in vivo, compounds 3 and 16 reduced GFAP and Iba-1 levels in the hippocampus, and displayed neuroprotection in Nissl staining. Besides, both compounds 3 and 16 had high safety (LD₅₀ > 1000 mg/kg). Longer plasma half-life of compounds 3 and 16 than melatonin supported combination strategy. All these results demonstrated that N-salicyloyl tryptamine derivatives are potential anti-neuroinflammation agents for the treatment of neurodegenerative disorder.

Graphical abstract

Based on the combination principles, N-salicyloyl tryptamine derivatives were equipped with multifunctional profiles covering inhibiting COX, attenuating activation of glial cells in vitro and in vivo and alleviating neuronal damage in vivo.

Introduction

Neuroinflammation is an important defense mechanism against injury toxins, but persistent neuroinflammation can result in neuronal death and ultimately contribute to neurodegeneration, such as Alzheimer’s (AD) or Parkinson’s (PD) diseases [1]. It is characterized by activation of resident immune cells (microglia and astrocytes), which cause production of proinflammatory cytokines and neuronal damage [[2], [3], [4], [5], [6], [7]]. Recently, an approved drug for the treatment of Alzheimer’s diseases, GV-971, does takes effect partially due to inhibition of neuroinflammation [8]. This indicates that development of anti-neuroinflammatory drugs for the treatment of neurodegenerative diseases is promising [9]. However, due to extremely complex and dynamic process which resembles a well-orchestrated symphony of neuroinflammation, many agents modulating at one process could only enable a palliative treatment instead of definitively curing [10]. Therefore, seeking the multi-functional candidates is an imperative strategy of designing anti-neuroinflammation agents.

Melatonin, a versatile endogenous hormone, has been proved to prevent neuroinflammation by inhibiting activation of microglia and astrocyte [[11], [12], [13], [14]]. Furthermore, high drug-able profiles (high lipophilicity and easy permeability through the blood-brain barrier), exalt its application for neuroinflammatory treatment [[15], [16], [17]]. However, it exerts poor pharmacokinetic properties, such as a short plasma half-life (∼30 min), which limits its use for neuroinflammation [18]. Thus, rational modifications based on the template of melatonin were conducted (Scheme 1) [19]. Besides, salicylic acid derivatives have been reported to alleviate neuroinflammation [[20], [21], [22], [23], [24], [25], [26], [27]]. The mechanism may involve targeting COX, a therapeutic target for treating neuroinflammation [[28], [29], [30], [31], [32], [33], [34], [35]]. Nevertheless, the lack of repair capacity on damaged neuron, limited exposure to brains and varying degrees of side effects narrow their application on long-term clinical use [29,36,37]. Thus, it is worth to combine salicylic acid derivatives with melatonin to develop multifunctional molecules as anti-neuroinflammatory agents.

Based on above findings, we reported a series of N-salicyloyl tryptamine derivatives with multifunctional properties including radicals scavenging, COX inhibition, attenuating activation of glial cells, and attenuating neuronal damage (Scheme 1). Although N-salicyloyl tryptamine was applied as anticonvulsant agents or anti-inflammatory agents in RAW264.7 model, its new application as anti-neuroinflammatory agents has not been reported [[38], [39], [40], [41], [42], [43], [44]]. To develop more potent anti-neuroinflammatory activities than the parent compound N-salicyloyl tryptamine, two kinds of derivatives which had different substituents (hydroxyl, amine) in C2’ were synthesized. After the introduction of different substituents with various electronic and steric properties in C5, C4’, C5’ position, the structure-activity relationship study on cyclooxygenase inhibition assay was conducted, followed by LPS-induced glial cells model and LPS-induced neuroinflammatory model of mice. Taken together, all data suggest that the strategy of combining tryptamine derivatives and salicylic acid derivatives provides a new sight of designing multi-functional candidates for neuroinflammation related neurodegenerative diseases.

Section snippets

Synthesis

Well-established methodology was utilized in the synthesis of N-salicyloyl tryptamine derivatives as indicated in Scheme 2. In detail, target compounds were obtained by condensation reaction using salicylic acid derivatives and tryptamine derivatives in the presence of EDCI, HOBt and triethylamine [45]. All the compounds were synthesized in near quantitative yields (70%–90%), characterized by NMR and mass spectrometry, and analyzed by HPLC suggesting a minimum purity of 95.0%.

^aCompounds 1 [46],

Conclusion

In summary, a new series of N-salicyloyl tryptamine derivatives were synthesized based on the combination of melatonin and salicylic acid for the treatment of neuroinflammation with multi-functional profiles. Several biological assays in vitro and in vivo were conducted and proved N-salicyloyl tryptamine derivatives as multifunctional agents to treat neuroinflammation. In COX inhibitor screening assay, synthesized compounds exhibited diversely inhibitory effects with IC₅₀ values ranging from

Chemistry

All chemicals used were of reagent grade. Proton (¹H) and carbon (¹³C) NMR spectra (400 or 300 MHz for ¹HNMR; 101 MHz for ¹³CNMR) were recorded on a Bruker spectrometer (Bruker Company, Germany). NMR spectra used DMSO‑d₆, CDCl₃ or CH₃OD as solvent (TMS as the internal standard). Proton chemical shifts are reported relative to a residual solvent peak (CDCl₃ at 7.26 ppm, DMSO‑d₆ at 2.50 ppm). Carbon chemical shifts are reported relative to a residual solvent peak (CDCl₃ at 77.00 ppm, DMSO‑d₆ at

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work is dedicated to Lanzhou University on the occasion of its 110th birthday. It was financially supported by the Recruitment Program of Global Experts (1000 Talents Plan), and the Fundamental Research Funds for the Central Universities (lzujbky-2019-ct08).

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¹: These authors contributed equally to the work.

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Research paperDesign, synthesis and bioactivity study of N-salicyloyl tryptamine derivatives as multifunctional agents for the treatment of neuroinflammation

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis

Conclusion

Chemistry

Declaration of competing interest

Acknowledgements

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Brain Behav. Immun.

Eur. J. Pharmacol.

Neurobiol. Aging

J. Neuroimmunol.

Life Sci.

Brain Res.

Biochimie

Eur. J. Med. Chem.

Mol. Genet. Metabol.

J. Neuroinflammation

Int. Immunopharm.

Pharmacol. Res.

Pharmacol., Biochem. Behav.

Bioorg. Med. Chem. Lett

Phytochemistry

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J. Immunol. Methods

Free Radical Biol. Med.

Free Radical Biol. Med.

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Role of neuroinflammation in neurodegenerative diseases

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The immunology of neurodegeneration

J. Clin. Invest.

Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease

Inflammopharmacology

Microglia-mediated inflammation and neurodegenerative disease

Mol. Neurobiol.

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Glia

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Cell Res.

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Research paper
Design, synthesis and bioactivity study of N-salicyloyl tryptamine derivatives as multifunctional agents for the treatment of neuroinflammation