Anti-Neuroinflammatory Benzyl Benzoates from the Medicinal Plant Solidago decurrens

Abstract

Objectives

This study focused on the isolation, structural identification, and anti-neuroinflammatory effects of benzyl benzoates from the medicinal plant Solidago decurrens Lour.

Methods

A range of chromatographic techniques were employed to isolate compounds from the ethanol extract of S. decurrens. Their chemical structures were subsequently elucidated via comprehensive spectroscopic analyses, encompassing 1D/2D NMR and HR-ESI-MS data. The isolated compounds were then assessed for anti-neuroinflammatory potential, using lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cell model.

Results

A benzyl benzoate, namely benzyl 2-hydroxy-3-methoxybenzoate (1), was isolated as a naturally occurring compound for the first time from an EtOAc-soluble fraction of S. decurrens, together with seven known benzyl benzoate derivatives (2-8). A new product 3-deglucopyranosyloxy-3-hydroxyleiocarposide (9) was obtained by acid hydrolysis of the main component leiocarposide (8). Compounds 1, 2, 4, 6, 7, and 9 (20 μM) significantly suppressed lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production in BV-2 cells.

Conclusions

A benzyl benzoate was identified from S. decurrens as a natural product for the first time, and a new hydrolysate was prepared by acid hydrolysis of leiocarposide (8). Some of these benzyl benzoates showed promising anti-neuroinflammatory activities in vitro.

Keywords

medicinal plant benzyl benzoates structural identification anti-neuroinflammatory activity

Introduction

Solidago decurrens Lour. (family Asteraceae) is a herbaceous plant mainly distributed in South China. In traditional Chinese medicine, the whole plant of S. decurrens (known as “Yizhihuanghua”) is used for the treatments of sore throat and pyogenic infections by its effects of clearing heat, detoxifying, and dispelling wind-heat.¹ Rare phytochemical studies of S. decurrens have reported several benzyl benzoate aglycones and glycosides, such as benzyl 2,6-dimethoxybenzoate,² 2'-methoxybenzyl 23,6-trimethoxybenzoate,³ and leiocarposide.⁴ Some natural benzyl benzoates have shown to have pharmacological potentials including anti-scabies^5,6 and α-glucosidase inhibition activities,⁷ and contractility effects on human prostate smooth muscle.⁸ In addition, some natural benzyl benzoate glycosides showed neuroprotective effects against glutamate-induced oxidative stress damage.⁹ However, the anti-neuroinflammatory properties of these benzyl benzoates are still unknown.

Many studies have shown that imbalanced neuroinflammatory responses play a critical role in neurodegenerative diseases¹⁰ and neural damage caused by ischemic stroke.¹¹ A large number of natural products have been reported for their significant neuroinflammation-regulating effects, making natural compounds a promising source of neuroprotective drug candidates.^12–16 Our research group has been consistently engaged in the discovery of neuroprotective compounds from natural organisms.^17–23 Given the lipophilicity and favorable blood-brain barrier permeability of benzyl benzoate scaffold, it is hypothesized to have promising potential in neuroprotection. Therefore, we conducted a phytochemical study on the benzyl benzoate components of the medicinal plant S. decurrens. During this study, eight benzyl benzoate derivatives were isolated and identified, including a new compound benzyl 2-hydroxy-3-methoxybenzoate (1); additionally, acid hydrolysis was performed on the main component leiocarposide (8), providing a new hydrolysate 3-deglucopyranosyloxy-3-hydroxyleiocarposide (9) (Figure 1); all compounds were evaluated for their inhibitory effects on lipopolysaccharide (LPS)-induced inflammatory responses in BV-2 microglia cells. This paper reports the details of isolation, structure elucidation, and biological assay of these benzyl benzoates.

Figure 1.

Chemical structures of the benzyl benzoates 1-9 from Solidago decurrens.

Materials and Methods

General

Column chromatography (CC) were performed with silica gel (200-300 mesh, Qingdao Marine Chemistry Co. Ltd), Sephadex LH-20 (GE Healthcare Bio-sciences AB), and ODS (50 μm, YMC). Thin-layer chromatography (TLC) analysis was carried out on Merck silica gel 60 (40-63 μm) pre-coated plates. High-performance liquid chromatography (HPLC) was conducted on an Agilent 1100 series apparatus with a YMC-Pack C₁₈ column (10 μm, 250 × 10 mm) and recorded by a UV detector (at 210 and 254 nm). Optical rotations were determined with a PoLAAR 3005 digital spectropolarimeter (Na filter, λ = 589 nm). UV spectra were obtained on a TU 1901 spectrophotometer. IR spectra were measured with an FTIR-850 spectrometer with KBr disks. NMR spectra were obtained with a Quantum-I Plus NMR spectrometer and performed at 400 MHz for ¹H and 100 MHz for ¹³C, using CDCl₃ or methanol-d₄ as the solvent and tetramethylsilane (TMS) as an internal reference. Standard pulse sequences were employed for the 2D NMR experiments, including the ¹H–¹H COrrelated SpectroscopY (COSY), Heteronuclear Single Quantum Coherence (HSQC), and Heteronuclear Multiple Bond Correlation (HMBC) experiments. HR-ESI-MS spectra were acquired on a Waters ACQUITY UPLCⅠ-Class/XEVO G2-XS Qtof-MS mass spectrometer in positive-ion mode.

Plant Material

The whole plant S. decurrens was collected at Shenxianju, Taizhou (Zhejiang province, China) in October 2023, and identified by one of the authors (Prof. Jinzhang Cai). A voucher specimen of the plant (ZY202302) was deposited at the Laboratory of Natural Product Chemistry, Wenzhou Medical University, China.

Extraction and Isolation

The whole plant S. decurrens was air dried (dry weight: 1.0 kg) and chopped into small pieces, and then extracted with a mixture of organic solvent (CH₂Cl₂/MeOH, 1:1) for two times (2 × 4 L) at room temperature. Evaporation of solvent in vacuo afforded a dark residue of 41.0 g. A portion of the organic extract (40.0 g) was dispersed in distilled water (800 mL) and extracted with EtOAc (3 × 400 mL) and n-butanol (2 × 400 mL), respectively. Evaporation of EtOAc and n-butanol under vacuum yielded the EtOAc- and n-butanol-soluble extracts of 15.1 and 4.2 g, respectively. The EtOAc extract (15.1 g) was separated by silica gel vacuum CC (150 × 50 mm), eluting with a stepwise gradient of petroleum ether (PE)/EtOAc (20:1, 10:1, 5:1, 3:1, 2:1, and 1:1, v/v), and MeOH, to obtain seven fractions (A–G), respectively. Fraction B [900 mg, eluted by PE/EtOAc (10:1, v/v)] was fractionated on a Sephadex LH-20 column (1200 × 30 mm), eluting with PE/CH₂Cl₂/MeOH (5:5:1, v/v) to yield four fractions (B1–B4). Fraction B3 (245.2 mg) was purified by HPLC (MeOH/H₂O, 73:27, v/v) to yield 1 (3.5 mg), 5 (15.7 mg), and 6 (49.5 mg). Fraction C [1.8 g, eluted by PE/EtOAc (5:1, v/v)] was separated on a Sephadex LH-20 column (1200 × 30 mm) and eluted with PE/CH₂Cl₂/MeOH (5:5:1, v/v) to afford six fractions (C1-C6). Fraction C4 (35.4 mg) was purified using HPLC (MeOH/H₂O, 70:30, v/v) to obtain 4 (5.0 mg). Fraction D [2.0 g, eluted by PE/EtOAc (3:1, v/v)] was subjected to a Sephadex LH-20 column (1200 × 30 mm) and eluted with CH₂Cl₂/MeOH (1:1, v/v) to afford seven fractions (D1-D7). Fraction D3 (56.8 mg) was purified by HPLC (MeOH/H₂O, 70:30, v/v) to yield 2 (3.7 mg) and 3 (9.9 mg). Fraction F [910 mg, eluted by PE/EtOAc (1:1, v/v)] was separated on an a Sephadex LH-20 column (1200 × 30 mm), eluting with CH₂Cl₂/MeOH (1:1, v/v) to afford five fractions (F1-F5). Fraction F4 (58.1 mg) was purified by a silica gel column (200 × 15 mm), eluting with CH₂Cl₂/MeOH (20:1, v/v), to yield 7 (4.7 mg). A portion of the n-butanol-soluble extract (2.0 g) was separated on a Sephadex LH-20 column (1200 × 30 mm), eluting with CH₂Cl₂/MeOH (1:1, v/v) to yield five fractions (BuA–BuE). Fraction BuC (610.3 mg) was purified on an ODS column (300 × 20 mm) and eluted with stepwise gradient of MeOH/H₂O (30:70, 40:60, 50:50, 60:40, 70:30, v/v) to yield 8 [201.7 mg, eluted by MeOH/H₂O (40:60, v/v)].

Acid Hydrolysis of 8

Compound 8 (50.0 mg) was dissolved in 2% (wt) HCl (100 mL), and refluxed for 30 min. After cooling to room temperature, the solution was extracted with EtOAc (3 × 50 mL). Evaporation of the solvent EtOAc in vacuo afforded a light yellow residue of 25.2 mg. The EtOAc extract was purified by HPLC, eluting by MeOH/H₂O (58:42, v/v), to yield 9 (4.1 mg).

Benzyl 2-hydroxy-3-methoxybenzoate (1). Colorless oil; UV (MeOH) λ_max (log ε) 320 (3.50), 248 (3.87), 217 (4.34) nm; IR (KBr) ν_max 3646, 2963, 2932, 2836, 1671, 1546, 1473, 1460, 1249, 1059, 749, 697 cm⁻¹; HR-ESI-MS m/z 259.0970 [M + H]⁺ (Calcd. for C₁₅H₁₅O₄, 259.0970); ¹H- and ¹³C-NMR data (CDCl₃): see Table 1.

Table 1.

¹H and ¹³C NMR Data for 1 and 9.

Pos.	1 ^a		9 ^b
Pos.	δ_C, type	δ_H (J in Hz)	δ_C, type	δ_H (J in Hz)
1	112.6, C		113.2, C
2	152.2, C		147.8, C
3	148.6, C		144.4, C
4	116.7, CH	7.04, d (8.0)	122.4, CH	6.90, d (8.0)
5	118.6, CH	6.82, t (8.0)	113.2, CH	6.54, d (8.0)
6	121.2, CH	7.48, d (8.0)	153.1, C
7	170.3, C		170.0, C
1′	135.3, C		126.6, C
2′	128.3, CH	7.44, d (8.0)	157.0, C
3′	128.7, CH	7.39, m	116.6, CH	7.24, d (8.0)
4′	128.6, CH	7.40, m	130.8, CH	7.33, t (8.0)
5′	128.7, CH	7.39, m	123.5, CH	7.06, t (8.0)
6′	128.3, CH	7.44, d (8.0)	130.9, CH	7.51, d (8.0)
7′	67.1, CH₂	5.39, s	63.8, CH₂	5.56, d (13.2)
				5.51, d (13.2)
2-OH		10.98, s
2-OCH₃			61.9, CH₃	3.69, s
3-OCH₃	56.2, CH₃	3.91, s
Glucose
1′′			102.7, CH	4.96, d (8.0)
2′′			74.9, CH	3.52, m
3′′			78.1, CH	3.43, m
4′′			71.3, CH	3.39, m
5′′			78.2, CH	3.42, m
6′′			62.5, CH₂	3.89, dd (12.0, 2.0)
				3.70, dd (12.0, 6.0)

^a ¹H (400 MHz) and ¹³C (100 MHz) NMR data were obtained in CDCl₃; ^b ¹H (400 MHz) and ¹³C (100 MHz) NMR data were obtained in methanol-d₄; the assignments were based on HSQC, HMBC, and COSY spectra.

3-Deglucopyranosyloxy-3-hydroxyleiocarposide (9). Colorless powder; [α]25 D －47.0 (c 0.1, MeOH); HR-ESI-MS m/z 475.1208 [M + Na]⁺ (Calcd. for C₂₁H₂₄O₁₁Na, 475.1216); ¹H- and ¹³C-NMR data (CD₃OD): see Table 1.

Cell Culture

Murine BV-2 microglia cells, obtained from the Cell Culture Center of the Institute of Basic Medical Sciences (Chinese Academy of Medical Sciences), were incubated in Dulbecco's modified Eagle's medium (DMEM, Gibco) supplemented with 10% (v/v) fetal bovine serum and 1% penicillin (both sourced from Gibco), and maintained at 37 °C in a humidified 5% CO₂ incubator.

MTT Assay

Cell viability was assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, using a 0.5 mg/mL MTT solution (Sigma). First, BV-2 cells in the logarithmic growth phase were seeded into 96-well plates and treated with various compounds for 24 h. The original culture medium was then replaced with the MTT solution, followed by incubation at 37 °C for 4 h. After removing the MTT solution, dimethyl sulfoxide (DMSO; Sigma) was added to solubilize the formazan crystals formed. Absorbance at 490 nm was detected using a microplate reader (Thermo Fisher Scientific), and cell viability was calculated with the formula: cell viability (%) = [OD₄₉₀ (experimental group)/OD₄₉₀ (control group)] × 100%.

Assay for Inhibition of LPS-Induced Nitric Oxide Production

A previously established protocol²⁰ was employed. BV-2 cells were seeded in 96-well plates at a density of 1 × 10⁴cells per well. The cells were then treated with varying doses of the test compounds (or left untreated as a control) for 4 h, after which 1 μg/mL lipopolysaccharide (LPS) was added to induce stimulation for an additional 24 h. The nitric oxide (NO) concentration in the cell supernatant was measured via the Griess reaction, following the protocol provided by the kit manufacturer (Nanjing Jiancheng Bioengineering Institute). Absorbance at 540 nm was measured with a microplate reader (Thermo Fisher Scientific).

Statistical Analysis

All bioassays were performed in triplicate to ensure reproducibility. Statistical analyses were conducted using SPSS 20.0 software, with significance determined via Student's t-test for pairwise comparisons or one-way analysis of variance (ANOVA) for multiple group comparisons. A P value < 0.05 was defined as statistically significant.

Results

Compound 1 had a molecular formula of C₁₅H₁₄O₄ according to the high resolution-electrospray ionization-mass spectrum (HR-ESI-MS) data (m/z 259.0970 [M + H]⁺) (Figure S1), which required nine degrees of molecular unsaturation. The IR spectrum indicated the presence of hydroxy (3646 cm⁻¹) and carbonyl (1671 cm⁻¹) functionalities. The ¹H-NMR spectrum (Figure S2) showed signals for a methoxy group at δ_H 3.91 (s, 3-OCH₃), an oxygenated methylene at δ_H 5.39 (s, H₂-7′), eight aromatic protons, and a hydroxy proton at δ_H 10.98 (s, 2-OH) (Table 1). The ¹³C-NMR data (Figure S3) exhibited a total of 15 carbon signals, including an ester carbonyl at δ_C 170.3 (C, C-7); 12 sp² carbons attributed to two benzene rings, an oxygenated methylene carbon at δ_C 67.1 (CH₂, C-7′), and a methoxy carbon at δ_C 56.2 (CH₃, 3-OCH₃) (Table 1). Heteronuclear single quantum coherence (HSQC) spectrum (Figure S4) was employed for the assignment of protonated carbons and protons. These NMR data are characteristic of a benzyl benzoate, closely related to those of the co-occurring analogue benzyl 2-hydroxy-6-methoxybenzoate (5).²³ Detailed analysis of 2D NMR data [heteronuclear multiple bond correlations (HMBC, Figure S5) and ¹H–¹H correlation spectroscopy (COSY, Figure S6)] revealed that 1 is an isomer of 5 with respect to the substitution of benzoic acid unit. The COSY relationships between H-4 (δ_H 7.04, d, J = 8.0 Hz)/H-5 (δ_H 6.82, t, J = 8.0 Hz) and H-5/H-6 (δ_H 7.48, d, J = 8.0 Hz) defined a 12,3-trisubstituted benzene ring. HMBC correlations from the hydroxy proton (δ_H 10.98, s, 2-OH) to C-2 (δ_C 152.2, C), C-3 (δ_C 148.6, C), and C-1 (δ_C 112.6, C), from the methoxy (δ_H 3.91, s, 3-OCH₃) to C-3, and from H-6 to the carbonyl carbon C-7 (δ_C 170.3, C) revealed a 2-hydroxy-3-methoxybenzoate unit in 1 (Figure 2), instead of a 2-hydroxy-6-methoxybenzoate unit in 5. In addition, the benzyl moiety of 1 was found to be identical to that of 5 by the same NMR data including key HMBC correlations from the oxygenated methylene H₂-7′ (δ_H 5.39, s) to the carbonyl carbon C-7 and three aromatic carbons C-1′ (δ_C 135.3, C) and C-2′/C-6′ (δ_C 128.3, CH). Therefore, compound 1 was established as benzyl 2-hydroxy-3-methoxybenzoate (Figure 1). Previously, 1 was synthesized by the reaction of 3-methoxysalicylic acid and benzyl alcohol.^24,25 Herein, it is reported as a naturally occurring compound for the first time.

Figure 2.

HMBC and COSY correlations for compounds 1 and 9.

Compound 9 was an acid hydrolysis product of 2′-β-D-glucopyranosyloxybenzyl 3-β-D-glucopyranosyloxy-2-methoxy-6-hydroxybenzoate (leiocarposide, 8).⁴ Its molecular formula was determined as C₂₁H₂₄O₁₁ based on the HR-ESI-MS data (m/z 475.1208 [M + H]⁺) (Figure S7). The NMR data (Figure S8-S13) of 9 showed signals for the 2′-β-D-glucopyranosyloxybenzyl (Table 1), while loss of signals for the 3-O-β-D-glucopyranosyl, indicating that 9 was a 3-deglucopyranosyl derivative of 8. HMBC correlations (Figure S11) from H-4 (δ_H 6.90, d, J = 8.0 Hz) and H-5 (δ_H 6.54, d, J = 8.0 Hz) to two nonprotonated aromatic carbons C-3 (δ_C 144.4, C) and C-6 (δ_C 153.1, C), from the methoxy (δ_H 3.69, s, 2-OCH₃) and H-4 to a nonprotonated aromatic carbon C-2 (δ_C 147.8, C), and from H-5 to C-1 (δ_C 113.2, C) supported the existence of 2-methoxy-3,6-dihydroxybenzoate moiety (Figure 2). In addition, HMBC correlations from the glucosyl anomeric proton H-1′′ (δ_H 4.96, d, J = 8.0 Hz) and oxygenated methylene H₂-7′ (δ_H 5.56, d, J = 13.2 Hz; 5.51, d, J = 13.2 Hz) to C-2′ (δ_C 157.0, C) confirmed the 2′-β-D-glucopyranosyloxybenzyl unit. Thus, compound 9 was established to be 3-deglucopyranosyloxy-3-hydroxyleiocarposide (Figure 1).

In addition, seven known compounds were co-isolated from the ethanol extract of S. decurrens and determined to be benzyl 2-hydroxy-3,6-dimethoxybenzoate (2),²⁶ 2'-methoxybenzyl 2, 6-dimethoxybenzoate (3),³ benzyl 2,6-dimethoxybenzoate (4),² benzyl 2-hydroxy-6-methoxybenzoate (5),²³ 2'-methoxybenzyl 2-hydroxy-6-methoxybenzoate (6),²³ 2-hydroxy-6-methoxybenzoic acid (7),²⁷ and leiocarposide (8),⁴ respectively, by comparison of their spectroscopic data (Figure S14-S26) with those reported in the literature.

Extensive studies have shown that neuroinflammation participates in the progression of various neurological diseases, such as ischemic stroke-induced nerve injury,¹¹ Alzheimer's disease, and Parkinson's disease.¹⁰ Regulating the level of neuroinflammation may contribute to the improvement and treatment of neurological disorders. In this study, the anti-neuroinflammatory effects of compounds 1-9 were evaluated using the lipopolysaccharide (LPS)-stimulated BV-2 cell inflammation model. The results showed that compounds 1, 2, 4, 6, 7, and 9 significantly reduced LPS-induced NO production in BV-2 cells at a concentration of 20 μM, and compound 1 was the most potent one; while 3, 5, and 8 were inactive in this assay (Figure 3A). The anti-neuroinflammatory effect of 1 was further verified by investigation of dose-effect relationship. As shown in Figure 3B, 1 could suppress LPS-induced NO production in a dose-dependent manner within the concentration range of 2.5-40 μM. Additionally, to rule out the possibility that the NO inhibition effect of the compounds was caused by cytotoxicity, the MTT assay was employed to investigate the impact of compounds 1, 2, 4, 6, 7, and 9 on cell viability. It was found that none of them showed obvious toxicity to BV-2 microglia cells at a high concentration of 40 μM (Figure S27). This bioassay revealed the promising neuroprotective properties of benzyl benzoates (1, 2, 4, 6, and 9) and benzoic acid (7) against neuroinflammation.

Figure 3.

The inhibitory effects of 1-9 against LPS-induced NO production in BV-2 microglia cells. (A) Inhibitory activities of 1-9 at a concentration of 20 μM. (B) Compound 1 suppressed LPS-induced NO level in a dose-dependent manner. Dexamethasone (DXM, 1 μM) was employed as a positive control. Data are presented as the mean ± standard deviation (SD), n = 3. ***P < 0.001, **P < 0.01, *P < 0.05 versus LPS.

Discussion

Previous phytochemical studies of the medicinal plant S. decurrens have reported a limited number of benzyl benzoates including aglycones and glycosides.^2–4 The present study afforded benzyl 2-hydroxy-3-methoxybenzoate (1) as a natural product for the first time, and a new hydrolysis product 3-deglucopyranosyloxy-3-hydroxyleiocarposide (9), to enrich the structural diversity of benzyl benzoates. The chemical structure of 1 was established to be closely similar to that of benzyl 2-hydroxy-6-methoxybenzoate (5),²³ with difference in the position of hydroxy group in the benzoic acid unit. Acid hydrolysis of the diglycoside leiocarposide (8)⁴ only afforded 3-deglucopyranosyloxy-3-hydroxyleiocarposide (9) as a major product, suggesting that in 9, the glucosidic bond at C-3 is more easily hydrolyzed by acid than that at C-2′, this is probably because of the existence of electron-donating groups (2-methoxy and 6-hydroxy) in the benzoic acid unit.

A previous study had shown that a natural benzyl benzoate glycoside, 2′-β-D-glucopyranosyloxybenzyl 6-α-L-(4′-O-acetyl)-rhamnopyranosyloxy-3-hydroxy-2-methoxybenzoate from Disporum viridescens roots had neuroprotective property against glutamate-induced oxidative damage in HT22 hippocampal neuronal cells.⁹ Another study showed that two benzyl benzoate aglycones, 2'-methoxybenzyl 2,6-dimethoxybenzoate (3) and 2'-methoxybenzyl 2-hydroxy-6-methoxybenzoate (6) from S. virgaurea, had potent anti-inflammatory activities against LPS-induced production of inflammatory factors in RAW264.7 murine monocytes.²⁸ These two studies inspired us that benzyl benzoates may have suppressive effects against inflammatory responses in neuron cells. However, the anti-neuroinflammatory potential of these plant-derived benzyl benzoates have not been reported yet. In this study, all benzyl benzoates were evaluated for their inhibitory activities against LPS-induced NO production in BV-2 microglia cells. The preliminary structure-activity relationships (SARs) were analyzed for the benzyl benzoate aglycones (1-6) as follows: the substitutions of benzoic acid unit was important to the inhibitory action, and the 2-hydroxy-3-methoxy (1) had stronger activity than 2-hydroxy-6-methoxy (5 and 6) and 2,6-dimethoxy (3 and 4); in addition, the 2'-methoxy was not necessary for the activity. Therefore, this study provided new insights into the pharmacological values of benzyl benzoates from Solidago plants.

There are two major limitations in this study. First, the anti-neuroinflammatory activities of the active benzyl benzoates need to be evaluated by testing their effects on other inflammatory factors, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, and further confirmed by in vivo experiments. Second, the potential mechanisms of action remain to be clarified by investigating their regulatory effects on signaling pathways (eg, NF-κB and MAPK). However, in-depth study on the therapeutic effects of benzyl benzoates-containing extract (EtOAc-soluble fraction) from S. decurrens against sepsis-associated encephalopathy is currently conducted both in vitro and in vivo.

Conclusion

In summary, chemical investigation of the medicinal plant S. decurrens afforded benzyl 2-hydroxy-3-methoxybenzoate (1) as a naturally occurring compound for the first time, together with six known benzyl benzoates (2-6, and 8) and a benzoic acid (7). Hydrolysis of leiocarposide (8) yielded a new product 3-deglucopyranosyloxy-3-hydroxyleiocarposide (9). Compounds 1, 2, 4, 6, 7, and 9 significantly inhibited the LPS-stimulated NO production in murine BV-2 microglia cells, implying promising neuroprotective properties in combating neuroinflammation. In addition, preliminary SARs were analyzed for the benzyl benzoate aglycones. To the best of our knowledge, this is the first report of anti-neuroinflammatory property of natural benzyl benzoates. This research indicates that these plant-derived benzyl benzoates hold potential for further development as neuroprotective drug candidates. The detailed in vitro and in vivo neuroprotective effects of benzyl benzoates from S. decurrens, as well as their anti-neuroinflammatory mechanisms, remain to be investigated.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X251411175 - Supplemental material for Anti-Neuroinflammatory Benzyl Benzoates from the Medicinal Plant Solidago decurrens

Supplemental material, sj-docx-1-npx-10.1177_1934578X251411175 for Anti-Neuroinflammatory Benzyl Benzoates from the Medicinal Plant Solidago decurrens by Junzhi Pan, Ziqiang Zou, Huayuan Liu, Junpeng Xu, Yali Lv, Jingyang Du, Xiaohong Ma, Yu Qi, Jinzhang Cai, Pengcheng Yan and Yao Ding in Natural Product Communications

Footnotes

Acknowledgments

The authors wish to acknowledge the valuable support received from the Wenzhou Key Laboratory of Research and Transformation of Chinese Medicine during the course of this study.

ORCID iD

Pengcheng Yan

Author Contribution Statement

Junzhi Pan: Methodology, Investigation. Funding acquisition. Ziqiang Zou: Methodology, Investigation. Huayuan Liu: Investigation. Junpeng Xu: Investigation. Yali Lv: Funding acquisition. Jingyang Du: Investigation. Xiaohong Ma: Investigation. Yu Qi: Methodology, Data curation. Jinzhang Cai: Investigation, Resources. Pengcheng Yan: Writing–review & editing, Writing–original draft, Data curation, Conceptualization. Yao Ding: Writing–review & editing, Writing–original draft, Project administration, Conceptualization.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Jinhua City Science and Technology Project, Zhejiang Provincial Science and Technology Plan of Traditional Chinese Medicine, (grant number 2023-3-061, 2026ZL0991).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

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