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Article

Synthesis and Anti-Inflammatory Evaluation of Novel Hybrids of 7-Oxodehydroabietic Acid Bearing a 1,2,3-Triazole Moiety

by
Wen-Tao Fang
1,†,
Yong-Feng Lv
2,3,†,
Fu-Cai Ren
4,
Hong Zhang
1,
Dong-Mei Xie
1,
Xiao-Bo Zhang
5,
Cheng-Wu Fang
1,*,
Shou-Jin Liu
1,* and
Han Luo
1,*
1
College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230011, China
2
College of Science, Westlake University, Hangzhou 310024, China
3
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
4
College of Pharmacy, Anhui Medical University, Hefei 230032, China
5
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijng 100700, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2025, 30(3), 750; https://doi.org/10.3390/molecules30030750
Submission received: 31 December 2024 / Revised: 30 January 2025 / Accepted: 3 February 2025 / Published: 6 February 2025
(This article belongs to the Special Issue Heterocycles: Synthesis, Biological Activity, Pharmacokinetic Profiles, and Mechanism of Actions)
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Abstract

:
To discover novel, potent anti-inflammatory diterpenoids, a series of hybrids of 7-oxodehydroabietic acid bearing a 1,2,3-triazole moiety was designed and synthesized. The target compounds were characterized by means of 1H NMR, 13C NMR, and ESI-HRMS. All the compounds were evaluated for their anti-inflammatory activity towards BV2 cell lines using L-NMMA (IC50 = 42.36 ± 2.47 µM) as a positive control. Most showed good anti-inflammatory activities, especially compounds 10 (IC50 = 8.40 ± 0.98 µM), 15 (IC50 = 10.74 ± 2.67 µM), 16 (IC50 = 10.96 ± 1.85 µM), and 17 (IC50 = 9.76 ± 1.27 µM), which exhibited potent anti-inflammatory effects on BV2 cell lines.

1. Introduction

Natural products have played an important role in drug discovery, given their chemical structural diversity, good biological activities, and biocompatibility [1]. Abietanes are a family of natural tricyclic diterpenoids with interesting pharmacological activity, including antitumor, antimicrobial, antiviral, antiulcer, and anti-inflammatory activities [2,3,4,5,6,7]. In particular, dehydroabietic acid (DHA) and its derivatives have been reported in recent years to show a broad spectrum of biological activities [8,9,10]. However, 7-oxodehydroabietic acid (Figure 1), a highly oxidized derivative of benzyl oxidation of dehydroabietic acid (DHA), has rarely been considered. Given its potent biological activities and limited exploration, we set out to introduce new groups in order to develop new compounds bearing anti-inflammatory activity based on 7-oxodehydroabietic acid.
The 1,4-disubstituted triazole moiety is well-known in medicinal chemistry for its stability, with resistance to oxidation, reduction, and metabolic degradation [11]. Therefore, 1,2,3-triazole is often used as a pharmacophore, which warrants consideration in the process of drug design [12,13]. Click chemistry is considered the most efficient means of synthesis for preparing 1,2,3-triazoles derivatives under mild conditions. In order to search for potent agents bearing anti-inflammatory activity, we envisaged synthesizing new compounds containing the 1,4-disubstituted triazole moiety based on 7-oxodehydroabietic acid.
In this study, in order to enrich the structures of existing compounds and find highly active target molecules, a series of compounds containing the 1,4-disubstituted triazole unit derived from 7-oxodehydroabietic acid were prepared. The anti-inflammatory activities of all synthesized compounds were assessed in vitro towards BV2 cell lines (mouse small glioma cells), using NG-methyl-L-arginine acetate salt (L-NMMA) [14,15], a well-known nitric oxide synthase (NOS) inhibitor, as a positive control. BV2 cells can produce a series of inflammatory factors and cytokines after infection and inflammatory stimulation, so they are widely used in inflammation-related research [16]. To our delight, a better anti-inflammatory effect (nitric oxide (NO) inhibitory activities) was found in promising compounds 10, 15, 16, and 17.

2. Results

Chemistry

In this work, 7-oxodehydroabietic acid (2) was synthesized via benzyl oxidation of dehydroabietic acid (DHA), according to the reported literature [17]. In the presence of potassium carbonate, 7-oxodehydroabietic acid (2) was treated with 3-bromoprop-1-yne (3) or 5-iodopent-1-yne (5) in anhydrous DMF, yielding the corresponding desired products O-propargylated 7-oxodehydroabietic acid (4) and O-pentynylated 7-oxodehydroabietic acid (6) (Scheme 1).
In order to introduce a 1,2,3-triazole unit based on the key intermediates O-propargylated 7-oxodehydroabietic acid (4) and O-pentynylated 7-oxodehydroabietic acid (6), we adopted a copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of O-propargylated 7-oxodehydroabietic acid (4) and O-pentynylated 7-oxodehydroabietic acid (6) with different substituted aromatic azides (Scheme 2 and Scheme 3) [18,19]. To our delight, the click reaction exhibited excellent functional group compatibility, and a series of derivatives bearing the 1,2,3-triazole unit were synthesized. All aromatic azides were prepared from corresponding boronic acid with sodium azide in the presence of CuSO4 in methanol (MeOH) without further purification [20,21,22].
7-oxodehydroabietic acid–1,2,3-triazole hybrids (8–22) from O-propargylated 7-oxodehydroabietic acid (4) and 7-oxodehydroabietic acid–1,2,3-triazole hybrids (23–39) from O-pentynylated 7-oxodehydroabietic acid (6) were produced efficiently. Compounds 8–40 are described for the first time, all presenting different substituents at the triazole moiety. The structures of all the compounds were confirmed by spectroscopic and spectrometric means (see Supplementary Materials). Next, we applied these derivatives bearing the 1,2,3-triazole unit, to evaluate their influence on the anti-inflammatory effect (NO inhibitory activities).

3. Discussion

Using L-NMMA (IC50 = 42.36 ± 2.47 µM) as a positive control, all derivatives of 7-oxodehydroabietic acid were tested for an anti-inflammatory effect (NO inhibitory activities) on BV2 cell lines. It was found, as shown in Table 1, that some of the newly synthesized compounds from O-propargylated 7-oxodehydroabietic acid (4) had a significant anti-inflammatory effect (NO inhibitory activities) on BV2 cell lines. This suggests that the length of the CH2 linker has an importance influence on the anti-inflammatory activity. In particular, compounds 10–12, 14–17, and 22 exhibited a good anti-inflammatory effect (NO inhibitory activities) on BV2 cell lines with IC50 values from 8.40 ± 0.98 µM to 15.82 ± 1.40 µM. The results were much better than those for the positive control L-NMMA (IC50 = 42.36 ± 2.47 µM). These data allowed us to carry out a simple structure and activity relationship (SAR) analysis on the influence of the modifications of different groups. Derivatives containing electron donors, such as a methoxy group or methyl group, and electron acceptors, such as a fluorine atom or chlorine atom in the aromatic ring, especially when most of the group was in the ortho and para positions, tended to have better anti-inflammatory activity. A phenolic hydroxyl group in the para position was beneficial for anti-inflammatory activity, while trifluoromethoxy and ester groups showed relatively poor results.

4. Materials and Methods

4.1. General Experimental Procedures

All reagents and solvents were purchased from Energy. All synthesized derivatives were purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 10:1 to 1:1, and petroleum ether/acetone, 10:1 to 1:1) and their structures were elucidated by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HR-ESIMS). Mass spectra were investigated on a UPLC-IT-TOF (Shimadzu, Kyoto, Japan) spectrometer. NMR spectra were recorded on Avance III 600 MHz (Bruker, Bremerhaven, Germany) instruments using CDCl3, CD3OD, or acetone-d6 as the solvent, with TMS as the internal standard. Chemical shifts (δ) were reported in parts per million (ppm), and the coupling constants (J) were given in Hertz. The abbreviations for the splitting of 1H NMR signals were as follows: s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Column chromatography was performed on silica gel (200–300 mesh, Qingdao Makall Group Co., Qingdao, China). All chemical reactions were monitored by TLC on silica gel 60 F254 plates, and spots were visualized by UV light and sprayed with 10% H3PO4·12MoO3 in EtOH, followed by heating. All compounds were named using the ACD40 Name-Pro program, which is based on IUPAC rules. Azides (7) were synthesized according to procedures previously described in the literature [20,21].
O-propargylated 7-oxodehydroabietic acid (4). To a solution of 7-oxodehydroabietic acid (2) (2.00 g, 6.37 mmol, 1.0 eq) in DMF (30 mL), were added K2CO3 (1.32 g, 9.55 mmol, 1.5 eq) slowly. The reaction mixture was stirred at rt for 30 min, and 3-bromoprop-1-yne (3) (0.67 mL, 7.64 mmol, 1.2 eq) was added dropwise at rt. The reaction mixture was stirred at rt for 24 h, before it was quenched by saturated NaCl aqueous solution (30 mL), and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (2 × 40 mL, and dried over Na2SO4, then filtered. After removing the solvent under a vacuum, the residue was purified by flash column chromatography on silica gel (10:1 to 5:1 petroleum ether/EtOAc), which provided O-propargylated 7-oxodehydroabietic acid (4) (1.68 g, 75% yield) as a white solid [23].
O-pentynylated 7-oxodehydroabietic acid (6). To a solution of 7-oxodehydroabietic acid (2) (2.00 g, 6.37 mmol, 1.0 eq) in DMF (30 mL), we added K2CO3 (1.32 g, 9.55 mmol, 1.5 eq) slowly. The reaction mixture was stirred at rt for 30 min, and 5-iodopent-1-yne (5) (0.87 mL, 7.64 mmol, 1.2 eq) was added dropwise at rt. The reaction mixture was stirred at rt for 24 h before it was quenched by saturated NaCl aqueous solution (30 mL), and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (2 × 40 mL) and dried over Na2SO4, then filtered. After removing the solvent under a vacuum, the residue was purified by flash column chromatography on silica gel (10:1 to 5:1 petroleum ether/EtOAc), which provided O-pentynylated 7-oxodehydroabietic acid (6) (1.70 g, 70% yield) as a white solid.

4.2. General Procedures for the Preparation of 7-Oxodehydroabietic Acid–1,2,3-Triazole Hybrids

To a solution of the corresponding azide (0.2 mmol) in 4 mL mixed solution (t-BuOH/H2O = 1:1, v/v), we added O-propargylated 7-oxodehydroabietic acid (4) or O-pentynylated 7-oxodehydroabietic acid (6) (0.2 mmol), sodium ascorbate (0.02 mmol), and CuSO4·5H2O (0.02 mmol). The reaction mixture was stirred for 48 h at room temperature before it was quenched by saturated NH4Cl aqueous solution (5 mL), and the mixture was extracted with ethyl acetate (3 × 6 mL). The combined organic layer was washed with brine (2 × 15 mL) and dried over Na2SO4, then filtered [24]. After removing the solvent under a vacuum, the residue was purified by flash column chromatography on silica gel (8/1 to 1/1 petroleum ether/EtOAc), which provided compounds 8–39.
  • 18-O-(1-(2,3-Dimethylphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (8). Yield: 39%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J = 1.9 Hz, 1H), 7.73 (s, 1H), 7.40 (dd, J = 8.1, 1.9 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 5.31 (d, J = 2.3 Hz, 2H), 2.92 (hept, J = 6.9 Hz, 1H), 2.65–2.76 (m, 2H), 2.37 (s, 3H), 2.24–2.36 (m, 2H), 2.00 (s, 3H), 1.79 (t, J = 10.3 Hz, 3H), 1.73 (d, J = 6.1 Hz, 1H), 1.59–1.64 (m, 1H), 1.35 (s, 3H), 1.25 (s, 3H), 1.24 (d, J = 2.1 Hz, 3H), 1.23 (d, J = 2.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.2, 177.2, 152.8, 146.9, 142.5, 138.7, 136.3, 132.6, 132.5, 131.4, 130.6, 126.1, 125.6, 125.0, 124.0, 123.4, 58.0, 46.6, 43.6, 37.8, 37.2, 37.0, 36.3, 33.5, 23.8, 23.7, 23.6, 20.3,18.0, 16.3, 14.2; HRESIMS: calcd for C31H37N3O3 [M + H]+ 500.2913, found 500.2914 (mass error ∆m = −0.0001 ppm).
  • 18-O-(1-(3,4-Dimethylphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (9). Yield: 66%, white oil, 1H NMR (600 MHz, CDCl3) δ 7.96 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 8.1, 2.1 Hz, 1H), 7.39 (dd, J = 8.1, 2.0 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 5.28 (s, 2H), 2.91 (hept, J = 6.9 Hz, 1H), 2.66–2.76 (m, 2H), 2.34 (s, 2H), 2.31– 2.33 (m, 2H), 2.31 (s, 2H), 1.78 (t, J = 11.6 Hz, 3H), 1.68–1.74 (m, 1H), 1.58–1.65 (m, 1H), 1.35 (s, 3H), 1.25 (s, 3H), 1.24 (d, J = 2.2 Hz, 3H), 1.23 (d, J = 2.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.3, 177.1, 152.8, 146.8, 143.2, 138.3, 137.6, 134.7, 132.5, 130.5, 130.5, 124.9, 123.5, 121.8, 121.7, 117.9, 58.0, 46.6, 43.6, 37.8, 37.3, 36.9, 36.3, 33.5, 23.7, 23.7, 23.6, 19.8, 19.4, 18.0, 16.3; HRESIMS: calcd for C31H37N3O3 [M + H]+ 500.2913, found 500.2914 (mass error ∆m = −0.0001 ppm).
  • 18-O-(1-(2-Ethylphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (10). Yield: 43%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.40 (dd, J = 8.1, 2.0 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.19 (s, 1H), 5.31 (d, J = 2.2 Hz, 2H), 2.92 (hept, J = 6.9 Hz, 1H), 2.71 (d, J = 14.4 Hz, 2H), 2.39 (s, 3H), 2.32 (m, 2H), 2.15 (s, 3H), 1.80 (t, J = 10.2 Hz, 3H), 1.70–1.75 (m, 1H), 1.61–1.64 (m, 1H), 1.36 (s, 3H), 1.26 (s, 3H), 1.25 (d, J = 1.4 Hz, 3H), 1.24 (d, J = 1.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.2, 177.2, 152.8, 146.9, 142.5, 136.8, 136.0, 132.5, 131.2, 130.6, 130.2, 126.5, 125.2, 125.0, 123.4, 58.0, 46.6, 43.6, 37.8, 37.2, 37.0, 36.3, 33.5, 29.6, 23.7, 23.7, 23.6, 20.6, 18.0, 17.3, 16.3; HRESIMS: calcd for C31H37N3O3 [M + H]+ 500.2913, found 500.2918 (mass error ∆m = −0.0005 ppm).
  • 18-O-(1-(4-Methoxy-2-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (11). Yield: 40%, brown oil, 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J = 2.2 Hz, 1H), 7.71 (s, 1H), 7.40 (dd, J = 8.1, 2.2 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 6.83–6.87 (m, 2H), 5.30 (s, 2H), 3.86 (s, 3H), 2.92 (p, J = 6.9 Hz, 1H), 2.71 (d, J = 14.9 Hz, 2H), 2.32–2.37 (m, 1H), 2.27 (d, J = 14.5 Hz, 1H), 2.14 (s, 3H), 1.76–1.84 (m, 3H), 1.74–1.70 (m, 1H), 1.64 (dd, J = 12.6, 4.5 Hz, 1H), 1.36 (s, 3H), 1.24–1.26 (m, 6H), 1.24 (d, J = 1.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.3, 177.3, 160.4, 152.9, 147.0, 135.4, 132.6, 130.7, 129.5, 127.4, 125.6, 125.0, 123.5, 116.4, 111.9, 58.1, 55.6, 46.7, 43.7, 37.8, 37.3, 37.0, 36.4, 33.6, 29.7, 23.8, 23.8, 23.7, 18.1, 18.0, 16.4; HRESIMS: calcd for C31H37N3O4 [M + H]+ 516.2862, found 516.2867 (mass error ∆m = −0.0005 ppm).
  • 19-O-(1-(2,4-Dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (12). Yield: 48%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 8.00 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.65 (m, 1H), 7.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 7.4 Hz, 2H), 5.29 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.91 (hept, J = 6.8 Hz, 1H), 2.63–2.79 (m, 2H), 2.33 (m, 2H), 1.80 (d, J = 9.4 Hz, 4H), 1.65 (d, J = 4.4 Hz, 1H), 1.35 (s, 3H), 1.24–1.26 (m, 6H), 1.23 (d, J = 1.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.3, 177.2, 161.2, 152.8, 152.5, 146.9, 141.9, 132.5, 130.6, 126.5, 125.9, 125.0, 123.4, 119.7, 104.7, 99.5, 58.1, 55.9, 55.6, 46.5, 43.5, 37.7, 37.2, 36.9, 36.4, 33.5, 23.8, 23.7, 23.7, 18.1, 16.3; HRESIMS: calcd for C31H37N3O5 [M + H]+ 532.2811, found 532.2818 (mass error ∆m = −0.0007 ppm).
  • 18-O-(1-(2,3,4-Trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (13). Yield: 49%, brown oil, 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 5.31 (m, 2H), 3.93(s, 9H), 2.91 (hept, J = 6.9 Hz, 1H), 2.64–2.76 (m, 2H), 2.32 (m, 2H), 1.77 (s, 3H), 1.72 (d, J = 5.5 Hz, 1H), 1.62 (m, 1H), 1.35 (s, 3H), 1.25 (s, 3H), 1.24 (d, J = 1.7 Hz, 3H), 1.23 (d, J = 1.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.2, 177.1, 154.4, 152.8, 146.9, 146.6, 142.6, 142.4, 132.5, 130.6, 125.5, 125.0, 124.2, 123.4, 120.0, 107.2, 61.4, 61.1, 58.0, 56.2, 46.6, 43.6, 37.7, 37.2, 37.0, 36.4, 33.5, 23.7, 23.7, 23.6, 18.1, 16.3; HRESIMS: calcd for C32H39N3O6 [M + H]+ 562.2917, found 562.2918 (mass error ∆m = −0.0001 ppm).
  • 19-O-(1-(5-Chloro-2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (14). Yield: 36%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 8.16 (s, 1H), 7.87 (d, J = 2.6 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.38 (ddd, J = 11.4, 8.5, 2.6 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 5.20–5.34 (m, 2H), 3.89 (s, 3H), 2.91 (p, J = 6.9 Hz, 1H), 2.63–2.78 (m, 2H), 2.33 (m, 2H), 1.74–1.84 (m, 3H), 1.72 (q, J = 3.0 Hz, 1H), 1.62 (td, J = 12.5, 4.1 Hz, 1H), 1.35 (s, 3H), 1.24–1.25 (m, 6H), 1.23 (d, J = 1.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.4, 177.2, 152.9, 147.0, 142.4, 132.6, 130.7, 129.8, 126.7, 126.2, 125.8, 125.3, 125.0, 123.5, 113.3, 58.0, 56.4, 46.6, 43.6, 37.8, 37.3, 37.0, 36.5, 33.6, 23.8, 23.8, 23.7, 18.1, 16.4; HRESIMS: calcd for C30H34ClN3O4 [M + H]+ 536.2316, found 536.2319 (mass error ∆m = −0.0003 ppm).
  • 18-O-(1-(2-Chloro-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (15). Yield: 40%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.96 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.0, 2.1 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.24 (dd, J = 8.2, 1.7 Hz, 1H), 5.30 (s, 2H), 2.91 (p, J = 7.0 Hz, 1H), 2.61–2.75 (m, 2H), 2.42 (s, 3H), 2.32–2.36 (m, 1H), 2.27 (d, J = 15.7, 1.2 Hz, 1H), 1.71–1.81 (m, 4H), 1.63 (m, 1H), 1.35 (s, 3H), 1.24 (m, 6H), 1.23 (d, J = 1.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.3, 177.2, 152.9, 146.9, 141.6, 132.6, 132.2, 131.0, 130.7, 128.6, 128.3, 127.5, 125.9, 125.1, 123.5, 57.9, 46.6, 43.7, 37.8, 37.3, 37.0, 36.4, 33.6, 23.8, 23.8, 23.7, 21.1, 18.1, 16.4; HRESIMS: calcd for C30H34ClN3O3 [M + H]+ 520.2367, found 520.2369 (mass error ∆m = −0.0002 ppm).
  • 18-O-(1-(2-Fluoro-4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (16). Yield: 53%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.79 (t, J = 8.7 Hz, 1H), 7.39 (dd, J = 8.1, 2.0 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.85 (m, 1H), 6.81 (dd, J = 12.4, 2.6 Hz, 1H), 5.31 (d, J = 12.8 Hz, 1H), 5.27 (d, J = 12.8 Hz, 1H), 3.87 (s, 3H), 2.92 (hept, J = 6.9 Hz, 1H), 2.66–2.76 (m, 2H), 2.31 (t, J = 13.9 Hz, 2H), 1.79 (d, J = 9.7 Hz, 3H), 1.70–1.75 (m, 1H), 1.61–1.65 (m, 1H), 1.35 (s, 3H), 1.25 (s, 3H), 1.25 (s, 3H), 1.23–1.24 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 198.3, 177.1, 161.0 (d, JCF = 10.2 Hz), 154.4 (d, JCF = 250.8 Hz), 152.8, 146.9, 132.5, 130.6, 125.9, 125.0, 123.4, 118.3 (d, JCF = 10.9 Hz), 110.7 (d, JCF = 3.2 Hz), 102.5 (d, JCF = 23.2 Hz), 57.9, 55.9, 46.6, 43.6, 37.7, 37.2, 36.9, 36.3, 33.5, 23.8, 23.7, 23.6, 18.0, 16.3; HRESIMS: calcd for C30H34FN3O4 [M + H]+ 520.2612, found 520.2616 (mass error ∆m = −0.0004 ppm).
  • 18-O-(1-(3-Fluoro-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (17). Yield: 53%, brown oil, 1H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 9.9, 1.9 Hz, 1H), 7.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.34 (t, J = 8.2 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 5.30 (d, J = 12.8 Hz, 1H), 5.26 (d, J = 12.8 Hz, 1H), 2.92 (hept, J = 6.9 Hz, 1H), 2.66–2.79 (m, 2H), 2.33–2.35 (m, 3H), 2.10–2.32 (m, 2H), 1.75–1.81 (m, 3H), 1.72 (d, J = 6.2 Hz, 1H), 1.61 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.4 Hz, 3H), 1.23 (d, J = 2.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.4, 177.2, 161.2 (d, JCF = 247.3 Hz), 152.8, 146.9, 135.6 (d, JCF = 9.9 Hz), 132.6, 132.3 (d, JCF = 6.3 Hz), 130.5, 125.8 (d, JCF = 17.4 Hz), 125.0, 123.5, 121.9, 115.7 (d, JCF = 3.6 Hz), 108.1(d, JCF = 27.2 Hz), 57.9, 46.6, 43.7, 37.9, 37.3, 37.0, 36.3, 33.5, 23.7, 23.7, 23.5, 18.0, 16.3, 14.3; HRESIMS: calcd for C30H34FN3O3 [M + H]+ 504.2662, found 504.2664 (mass error ∆m = −0.0002 ppm).
  • 18-O-(1-(2,6-Difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (18). Yield: 64%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.86 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.49 (tt, J = 8.6, 6.0 Hz, 1H), 7.39 (dd, J = 8.1, 2.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 8.1, 2H), 5.34 (d, J = 12.8 Hz, 1H), 5.29 (d, J = 12.8 Hz, 1H), 2.92 (hept, J = 7.0 Hz, 1H), 2.71 (d, J = 13.6 Hz, 2H), 2.31–2.38 (m, 2H), 1.74–1.81 (m, 3H), 1.70–1.74 (m, 1H), 1.63 (dd, J = 14.3, 10.3 Hz, 1H), 1.35 (s, 3H), 1.25 (s, 3H), 1.24 (d, J = 1.2 Hz, 3H), 1.23 (d, J = 1.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.3, 177.2, 156.7 (d, JCF = 257.1 Hz), 156.7 (d, JCF = 257.1 Hz), 152.8, 142.7, 132.5, 131.4 (t, JCF = 9.5 Hz), 130.6, 126.4, 125.0, 123.4, 115.0(t, JCF = 15.3 Hz), 112.5 (dd, JCF = 19.7 Hz), 112.5 (dd, JCF = 19.7 Hz), 57.7, 46.5, 43.5, 37.2, 37.2, 36.9, 36.4, 33.5, 23.8, 23.7, 23.6, 18.0, 16.3; HRESIMS: calcd for C29H31F2N3O3 [M + H]+ 508.2412, found 508.2413 (mass error ∆m = −0.0001 ppm).
  • 18-O-(1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (19). Yield: 53%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.97 (s, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.75 (m, 2H), 7.40 (dd, J = 8.1, 1.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 5.32 (d, J = 12.8 Hz, 1H), 5.27 (d, J = 12.8 Hz, 1H), 2.91 (hept, J = 6.9 Hz, 1H), 2.67–2.76 (m, 2H), 2.24–2.38 (m, 2H), 1.75–1.82 (m, 3H), 1.72 (d, J = 6.1 Hz, 1H), 1.58–1.65 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.1 Hz, 3H), 1.23 (d, J = 2.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.4, 177.2, 162.5 (d, JCF = 249.5 Hz), 152.8, 146.9, 143.6, 133.1, 132.6, 130.5, 124.9, 123.5, 122.7 (d, JCF = 8.7 Hz), 122.7 (d, JCF = 8.7 Hz), 122.0, 116.6 (d, JCF = 23.0 Hz), 116.6 (d, JCF = 23.0 Hz), 57.9, 46.6, 43.7, 37.9, 37.3, 37.0, 36.3, 33.5, 23.7, 23.7, 23.5, 18.0, 16.3; HRESIMS: calcd for C29H32FN3O3 [M + H]+ 490.2506, found 490.2512 (mass error ∆m = −0.0006 ppm).
  • 18-O-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (20). Yield: 62%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.84 (m, 3H), 7.41 (m, 3H), 7.28 (d, J = 8.2 Hz, 1H), 5.34 (d, J = 12.8 Hz, 1H), 5.27 (d, J = 12.8 Hz, 1H), 2.91 (h, J = 6.9 Hz, 1H), 2.68–2.76 (m, 2H), 2.24–2.39 (m, 2H), 1.79 (t, J = 11.3 Hz, 3H), 1.72 (d, J = 6.1 Hz, 1H), 1.57–1.65 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.3 Hz, 3H), 1.23 (d, J = 2.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.4, 177.1, 152.8, 149.1, 146.9, 143.8, 135.2, 132.7, 130.5, 124.9, 123.6, 122.2, 122.1, 121.9, 120.3 (q, JCF = 258.4 Hz), 57.9, 46.6, 43.8, 38.0, 37.4, 37.0, 36.3, 33.5, 23.7, 23.7, 23.5, 18.0, 16.3; HRESIMS: calcd for C30H32F3N3O4 [M + H]+ 556.2423, found 556.2417 (mass error ∆m = 0.0006 ppm).
  • 18-O-(1-(4-(Ethoxycarbonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (21). Yield: 61%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 8.23 (d, J = 8.7 Hz, 2H), 8.08 (s, 1H), 7.88 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.1, 2.0 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 5.33 (d, J = 12.8 Hz, 1H), 5.28 (d, J = 12.8 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.91 (hept, J = 6.9 Hz, 1H), 2.68–2.77 (m, 2H), 2.26–2.39 (m, 2H), 1.75–1.82 (m, 3H), 1.72 (m, 1H), 1.61 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.5 Hz, 3H), 1.23 (d, J = 2.5 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.4, 177.1, 165.3, 152.8, 146.9, 143.9, 139.8, 132.6, 131.2, 130.6, 130.5, 124.9, 123.5, 121.7, 120.0, 61.3, 57.9, 46.6, 43.7, 38.0, 37.3, 37.0, 36.3, 33.5, 23.7, 23.7, 23.5, 18.0, 16.3, 14.3; HRESIMS: calcd for C32H37N3O5 [M + H]+ 544.2811, found 544.2814 (mass error ∆m = −0.0003 ppm).
  • 18-O-(1-(4-Hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl-7-oxo-dehydroabietic acid (22). Yield: 54%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.94 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 5.29 (d, J = 12.8 Hz, 1H), 5.26 (d, J = 12.8 Hz, 1H), 4.12 (q, J = 7.1 Hz, 1H), 2.89 (p, J = 6.9 Hz, 1H), 2.72 (dd, J = 7.2, 3.6 Hz, 2H), 2.20–2.41 (m, 2H), 1.71–1.82 (m, 4H), 1.59 (m, 1H), 1.34 (s, 3H), 1.24 (s, 3H), 1.22 (d, J = 1.5 Hz, 3H), 1.21 (d, J = 1.5 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 199.3, 177.3, 157.6, 153.1, 147.0, 133.0, 130.4, 129.5, 125.1, 123.7, 122.6, 122.3, 116.5, 57.9, 46.7, 43.8, 37.9, 37.4, 37.0, 36.4, 33.6, 23.8, 23.7, 23.6, 18.1, 16.4; HRESIMS: calcd for C29H33N3O4 [M + H]+ 488.2549, found 488.2555 (mass error ∆m = −0.0006 ppm).
  • 18-O-(1-(2,3-Dimethylphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (23). Yield: 61.5%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.41 (dt, J = 8.1, 2.0 Hz, 1H), 7.30 (dd, J = 7.7, 4.3 Hz, 2H), 7.21 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 2.92 (p, J = 7.0, Hz, 1H), 2.84 (t, J = 7.7 Hz, 2H), 2.74 (m, 2H), 2.38 (m, 1H), 2.37 (s, 3H), 2.10 (m, 2H), 2.02 (s, 3H), 1.72–1.83 (m, 4H), 1.65 (m, 1H), 1.35 (s, 3H), 1.27 (s, 3H), 1.24 (d, J = 2.1 Hz, 3H), 1.23 (d, J = 2.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.6, 177.4, 153.2, 147.1, 146.6, 138.8, 136.9, 132.9, 132.8, 131.3, 130.8, 126.2, 125.2, 124.1, 123.7, 123.2, 64.2, 46.9, 44.0, 38.1, 37.5, 37.2, 36.7, 33.7, 28.4, 23.9, 23.9, 23.8, 22.3, 20.5, 18.3, 16.5, 14.4; HRESIMS: calcd for C33H42N3O3 [M + H]+ 528.3226, found 528.3228 (mass error ∆m = −0.0002 ppm).
  • 18-O-(1-(3,4-Dimethylphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (24). Yield: 51.5%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 1.7 Hz, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.41 (dd, J = 8.2, 1.7 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.15 (t, J = 6.2 Hz, 2H), 2.92 (p, J = 6.9 Hz, 1H), 2.82 (t, J = 7.3 Hz, 2H), 2.74 (d, J = 10.9 Hz, 2H), 2.37 (m, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 2.08 (m, 2H), 1.72–1.85 (m, 4H), 1.63 (m, 1H), 1.35 (s, 3H), 1.27 (s, 3H), 1.25 (d, J = 2.2 Hz, 3H), 1.24 (d, J = 2.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.5, 153.2, 147.1, 138.4, 137.3, 135.3, 132.8, 130.8, 130.7, 125.2, 123.7, 121.8, 119.5, 117.9, 64.2, 46.9, 44.1, 38.1, 37.6, 37.3, 36.7, 33.7, 28.4, 23.9, 23.9, 23.8, 22.4, 20.0, 19.6, 18.4, 16.5; HRESIMS: calcd for C33H42N3O3 [M + H]+ 528.3226, found 528.3228 (mass error ∆m = −0.0002 ppm).
  • 18-O-(1-(2-Ethylphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (25). Yield: 54.3%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 2.2 Hz, 1H), 7.56 (s, 1H), 7.44–7.46 (m, 1H), 7.40–7.42 (m, 2H), 7.29–7.34 (m, 3H), 4.17 (t, J = 6.4 Hz, 2H), 2.92 (p, J = 6.9 Hz, 1H), 2.85 (t, J = 7.6 Hz, 2H), 2.72–2.77 (m, 2H), 2.51 (q, J = 7.6 Hz, 2H), 2.37 (m, 2H), 2.11 (m, 2H), 1.73–1.87 (m, 4H), 1.66 (m, 1H), 1.36 (s, 3H), 1.27 (s, 3H), 1.25 (d, J = 2.5 Hz, 3H), 1.24 (d, J = 2.5 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.5, 153.2, 146.7, 147.1, 140.1, 136.3, 132.8, 130.8, 130.1, 129.9, 126.8, 126.5, 125.2, 123.7, 123.1, 64.2, 46.9, 44.0, 38.1, 37.5, 37.3, 36.8, 33.7, 29.8, 28.4, 24.4, 23.9, 23.9, 23.8, 22.3, 18.3, 16.6, 15.1; HRESIMS: calcd for C33H42N3O3 [M + H]+ 528.3226, found 528.3228 (mass error ∆m = −0.0002 ppm).
  • 19-O-(1-(4-Ethylphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (26). Yield: 63.3%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 2.1 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.41 (dd, J = 8.1, 2.1 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 1H), 4.15 (t, J = 6.3 Hz, 2H), 2.92 (p, J = 6.9 Hz, 1H), 2.83 (t, J = 8.2 Hz, 2H), 2.75 (d, J = 13.4 Hz, 2H), 2.68–2.73 (m, 2H), 2.37 (m, 2H), 2.08 (m, 2H), 1.72–1.82 (m, 4H), 1.62–1.68 (m, 1H), 1.35 (s, 3H), 1.27 (s, 3H), 1.27 (t, J = 6.2 Hz, 3H), 1.25 (d, J = 2.3 Hz, 3H), 1.23 (d, J = 2.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.4, 153.2, 147.4, 147.1, 145.0, 135.2, 132.8, 130.8, 129.1, 125.2, 123.7, 120.6, 120.6, 119.5, 64.2, 46.9, 44.1, 38.1, 37.5, 37.3, 36.7, 33.7, 28.6, 28.4, 23.9, 23.9, 23.8, 22.3, 18.3, 16.5, 15.6; HRESIMS: calcd for C33H42N3O3 [M + H]+ 528.3226, found 528.3228 (mass error ∆m = −0.0002 ppm).
  • 19-O-(1-(4-Isopropylphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (27). Yield: 43.3%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 2.1 Hz, 1H), 7.80 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.2 Hz, 1H), 4.15 (t, J = 6.3 Hz, 2H), 2.98 (p, J = 6.9 Hz, 1H), 2.92 (p, J = 6.9 Hz, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.75 (d, J = 13.3 Hz, 2H), 2.37 (m, 2H), 2.09 (m, 2H), 1.72–1.83 (m, 4H), 1.63 (m, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 1.28 (s, 3H), 1.27 (s, 3H), 1.25 (d, J = 2.7 Hz, 3H), 1.24 (d, J = 2.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.5, 153.2, 149.7, 147.4, 147.1, 135.2, 132.8, 130.8, 127.8, 125.2, 123.8, 120.6, 120.6, 119.5, 64.2, 46.9, 44.1, 38.2, 37.5, 37.3, 36.7, 34.0, 33.7, 28.4, 24.1, 24.1, 23.9, 23.9, 23.8, 22.3, 18.3, 16.5; HRESIMS: calcd for C34H44N3O3 [M + H]+ 542.3383, found 542.3387 (mass error ∆m = −0.0004 ppm).
  • 18-O-(1-(3,5-Dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (28). Yield: 60.9%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 2.2 Hz, 1H), 7.84 (s, 1H), 7.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.2 Hz, 2H), 6.49 (t, J = 2.2 Hz, 1H), 4.14 (t, J = 6.3 Hz, 2H), 3.86 (s, 6H), 2.92 (p, J = 6.9 Hz, 1H), 2.82 (td, J = 7.3, 2.2 Hz, 2H), 2.74 (d, J = 13.1 Hz, 2H), 2.36 (m, 2H), 2.09 (m, 2H), 1.74–1.82 (m, 4H), 1.64 (m, 1H), 1.35 (s, 3H), 1.27 (s, 3H), 1.24 (d, J = 2.7 Hz, 3H), 1.23 (d, J = 2.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.5, 177.2, 161.4, 153.0, 147.2, 146.9, 138.6, 132.6, 130.5, 124.9, 123.5, 119.4, 100.4, 98.7, 63.9, 55.6, 46.7, 43.9, 37.9, 37.3, 37.0, 36.4, 33.5, 28.2, 23.7, 23.7, 23.6, 22.1, 18.1, 16.3; HRESIMS: calcd for C33H41N3O5 [M + H]+ 560.3124, found 560.3127 (mass error ∆m = −0.0003 ppm).
  • 19-O-(1-(3,4,5-Trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (29). Yield: 67.3%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.88 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.02 (s, 2H), 4.13 (t, J = 6.2 Hz, 2H), 3.94 (s, 6H), 3.88 (s, 3H), 2.91 (p, J = 6.9 Hz, 1H), 2.82 (td, J = 7.3, 4.7 Hz, 2H), 2.70–2.77 (m, 2H), 2.36 (m, 2H), 2.08 (m, 2H), 1.78–1.87 (m, 4H), 1.59–1.68 (m, 1H), 1.34 (s, 3H), 1.27 (s, 3H), 1.23 (d, J = 3.0 Hz, 3H), 1.22 (d, J = 3.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.4, 154.0, 153.2, 147.4, 147.1, 138.1, 133.2, 132.9, 130.6, 125.0, 123.8, 119.9, 98.4, 98.4, 64.1, 61.2, 56.5, 46.9, 44.2, 38.1, 37.6, 37.2, 36.6, 33.7, 28.4, 23.9, 23.8, 22.2, 18.3, 16.5; HRESIMS: calcd for C34H43N3O6 [M + H]+ 590.3230, found 590.3233 (mass error ∆m = −0.0003 ppm).
  • 18-O-(1-(2,3,4-Trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (30). Yield: 67.0%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 2.1 Hz, 1H), 7.79 (s, 1H), 7.41 (dd, J = 8.1, 2.1 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.15 (h, J = 4.8 Hz, 2H), 3.92 (s, 3H), 3.92 (s, 3H), 3.76 (s, 3H), 2.92 (hept, J = 7.0 Hz, 1H), 2.83 (t, J = 7.6 Hz, 2H), 2.68–2.77 (m, 2H), 2.37 (m, 2H), 2.09 (m, 2H), 1.72–1.85 (m, 4H), 1.65 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.0 Hz, 3H), 1.23 (d, J = 2.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.6, 177.4, 154.4, 153.2, 147.1, 146.8, 146.5, 142.8, 132.8, 130.8, 125.2, 124.8, 123.7, 123.1, 120.1, 107.3, 64.2, 61.7, 61.3, 56.4, 46.9, 44.0, 38.1, 37.5, 37.2, 36.8, 33.7, 28.4, 23.9, 23.9, 23.9, 22.3, 18.3, 16.5; HRESIMS: calcd for C34H43N3O6 [M + H]+ 590.3230, found 590.3232 (mass error ∆m = −0.0002 ppm).
  • 19-O-(1-(5-Chloro-2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (31). Yield: 68.8%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.95 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.41 (dd, J = 8.1, 2.2 Hz, 1H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.15 (q, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.92 (hept, J = 7.0 Hz, 1H), 2.83 (t, J = 7.6 Hz, 2H), 2.68–2.77 (m, 2H), 2.36 (m, 2H), 2.09 (m, 2H), 1.69–1.85 (m, 4H), 1.60–1.68 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.0 Hz, 3H), 1.23 (d, J = 2.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.5, 153.2, 149.7, 147.1, 146.6, 132.8, 130.8, 129.6, 127.2, 126.3, 125.3, 125.2, 123.7, 123.3, 113.5, 64.2, 56.5, 46.9, 44.0, 38.0, 37.5, 37.2, 36.7, 33.7, 28.3, 23.9, 23.9, 23.9, 22.3, 18.3, 16.5; HRESIMS: calcd for C32H38ClN3O4 [M + H]+ 564.2629, found 564.2631 (mass error ∆m = −0.0002 ppm).
  • 18-O-(1-(2-Chloro-4-methylphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (32). Yield: 64.8%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 2.1 Hz, 1H), 7.75 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 8.1, 2.2 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 4.16 (t, J = 6.2 Hz, 2H), 2.92 (hept, J = 6.8 Hz, 1H), 2.84 (t, J = 7.6 Hz, 2H), 2.71–2.75 (m, 2H), 2.42 (s, 3H), 2.37 (m, 2H), 2.09 (m, 2H), 1.71–1.83 (m, 4H), 1.65 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.2 Hz, 3H), 1.23 (d, J = 2.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.5,177.2, 152.9, 146.9, 146.3, 141.2, 132.6, 132.5, 130.9, 130.6, 128.4, 128.1, 127.3, 125.0, 123.5, 123.1, 64.0, 46.7, 43.8, 37.9, 37.3, 37.0, 36.5, 33.5, 28.1, 23.7, 23.7, 23.6, 22.1, 20.9, 18.1, 16.3; HRESIMS: calcd for C32H38ClN3O3 [M + H]+ 548.2680, found 548.2686 (mass error ∆m = −0.0006 ppm).
  • 18-O-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabi etic acid (33). Yield: 53.7%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.90 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.42 (dd, J = 8.1, 2.0 Hz, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.14 (q, J = 5.9 Hz, 2H), 2.92 (p, J = 6.9 Hz, 1H), 2.83 (q, J = 6.8 Hz, 2H), 2.76 (d, J = 13.4 Hz, 2H), 2.36 (m, 2H), 2.10 (m, 2H), 1.72–1.86 (m, 4H), 1.62–1.67 (m, 1H), 1.35 (s, 3H), 1.28 (s, 3H), 1.25 (d, J = 2.7 Hz, 3H), 1.24 (d, J = 2.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.8, 177.5, 153.2, 149.0, 147.9, 147.2, 135.7, 132.9, 130.7, 125.2, 123.8, 122.4, 121.9, 120.5 (q, JCF = 258.4 Hz), 119.7, 64.0, 47.0, 44.1, 38.2, 37.6, 37.2, 36.7, 33.7, 29.8, 28.3, 23.9, 23.9, 23.8, 22.2, 18.3, 16.5; HRESIMS: calcd for C32H36F3N3O4 [M + H]+ 584.2736, found 584.2738 (mass error ∆m = −0.0002 ppm).
  • 18-O-(1-(3-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabi etic acid (34). Yield: 54.7%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.56 (t, J = 8.3 Hz, 1H), 7.42 (dd, J = 8.1, 1.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 4.15 (t, J = 6.3 Hz, 2H), 2.92 (p, J = 6.9 Hz, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.76 (d, J = 15.1 Hz, 2H), 2.37 (m, 2H), 2.10 (m, 2H), 1.72–1.85 (m, 4H), 1.63–1.65 (m, 1H), 1.35 (s, 3H), 1.28 (s, 3H), 1.25 (d, J = 2.4 Hz, 3H), 1.24 (d, J = 2.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.5, 153.2, 150.1, 148.0, 147.2, 138.4, 132.9, 131.2, 130.7, 125.2, 123.8, 120.7, 120.5 (q, JCF = 258.6 Hz), 119.5, 118.4, 113.5, 64.1, 47.0, 44.2, 38.2, 37.6, 37.3, 36.7, 33.7, 28.3, 23.9, 23.9, 23.8, 22.3, 18.3, 16.5; HRESIMS: calcd for C32H36F3N3O4 [M + H]+ 584.2736, found 584.2735 (mass error ∆m = 0.0001 ppm).
  • 18-O-(1-(4-(Ethoxycarbonyl)phenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (35). Yield: 65.5%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz, 2H), 7.96 (s, 1H), 7.87 (d, J = 8.2 Hz, 3H), 7.41 (dd, J = 8.1, 2.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.14 (h, J = 4.8 Hz, 2H), 2.92 (hept, J = 6.9 Hz, 1H), 2.83 (td, J = 7.4, 3.8 Hz, 2H), 2.75 (d, J = 13.3 Hz, 2H), 2.36 (m, 2H), 2.09 (m, 2H), 1.70–1.86 (m, 4H), 1.60–1.66 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.34 (s, 3H), 1.27 (s, 3H), 1.24 (d, J = 2.4 Hz, 3H), 1.23 (d, J = 2.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7, 177.4, 165.6, 153.2, 147.9, 147.1, 140.3, 132.9, 131.4, 130.7, 130.4, 125.1, 123.8, 119.8, 119.4, 64.0, 61.5, 46.9, 44.1, 38.2, 37.6, 37.3, 36.6, 33.7, 28.3, 23.9, 23.9, 23.8, 22.2, 18.3, 16.5, 14.4; HRESIMS: calcd for C34H41N3O5 [M + H]+ 572.3124, found 572.3128 (mass error ∆m = −0.0004 ppm).
  • 18-O-(1-(3-Chloro-4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (36). Yield: 45.0%, red oil, 1H NMR (600 MHz, CDCl3) δ 7.87 (s, 1H), 7.80 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 4.15 (t, J = 6.0 Hz, 2H), 2.93 (p, J = 6.9 Hz, 1H), 2.82 (m, 2H), 2.75 (m, 2H), 2.37 (dd, J = 13.5, 6.5 Hz, 2H), 2.09 (m, 2H), 1.80–1.83 (m, 3H), 1.74 (m, 1H), 1.67 (m, 1H), 1.35 (s, 3H), 1.28 (s, 3H), 1.25 (d, J = 1.9 Hz, 3H), 1.24 (d, J = 1.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.8, 177.5, 153.2, 151.9, 147.2, 133.8, 132.9, 130.7, 127.8, 125.2, 123.8, 121.8, 121.0, 120.9, 119.7, 117.1, 64.1, 56.2, 47.0, 44.1, 38.2, 37.6, 37.3, 36.7, 33.7, 28.3, 23.9, 23.8, 22.2, 18.3, 16.5; HRESIMS: calcd for C32H38ClN3O3 [M + H]+ 548.2680, found 548.2686 (mass error ∆m = −0.0006 ppm).
  • 18-O-(1-(4-Hydroxyphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (37). Yield: 60.6%, brown oil, 1H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 4.14 (t, J = 6.3 Hz, 2H), 2.91 (p, J = 6.9 Hz, 1H), 2.82 (t, J = 7.6 Hz, 2H), 2.75 (d, J = 13.7 Hz, 2H), 2.36 (m, 2H), 2.08 (m, 2H), 1.71–1.83 (m, 4H), 1.57–1.63 (m, 1H), 1.34 (s, 3H), 1.26 (s, 3H), 1.23 (d, J = 2.1 Hz, 3H), 1.22 (d, J = 2.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 199.3, 177.6, 157.6, 153.3, 147.1, 133.0, 130.6, 129.9, 125.2, 123.8, 122.4, 120.0, 116.6, 64.2, 60.6, 46.9, 44.0, 38.1, 37.5, 37.2, 36.7, 33.7, 28.3, 23.9, 23.9, 23.8, 22.2, 21.2, 18.3, 16.5; HRESIMS: calcd for C31H37N3O4 [M + H]+ 516.2862, found 516.2863 (mass error ∆m = −0.0001 ppm).
  • 18-O-(1-(3-Hydroxyphenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (38). Yield: 64.5%, white oil, 1H NMR (600 MHz, CDCl3) δ 8.47 (s, 1H), 7.94 (s, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.41 (dd, J = 8.1, 2.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 4.15 (t, J = 6.0 Hz, 2H), 2.91 (p, J = 6.9 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.75 (d, J = 15.0 Hz, 2H), 2.37 (m, 2H), 2.11 (m, 2H), 1.72–1.84 (m, 4H), 1.62 (m, 1H), 1.34 (s, 3H), 1.26 (s, 3H), 1.24 (d, J = 2.4 Hz, 3H), 1.23 (d, J = 2.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 199.0, 177.4, 171.4, 158.8, 153.2, 147.1, 137.8, 132.9, 130.7, 130.6, 125.2, 123.8, 119.6, 116.6, 109.8, 108.8, 64.0, 60.5, 46.9, 44.1, 38.2, 37.5, 37.2, 36.6, 33.7, 28.1, 23.9, 22.1, 18.3, 16.5; HRESIMS: calcd for C31H37N3O4 [M + H]+ 516.2862, found 516.2863 (mass error ∆m = −0.0001 ppm).
  • 18-O-(1-(3-(Dimethylamino)phenyl)-1H-1,2,3-triazol-4-yl)propyl-7-oxo-dehydroabietic acid (39). Yield: 52.0%, white oil, 1H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 1.9 Hz, 1H), 7.81 (s, 1H), 7.41 (dd, J = 8.1, 1.9 Hz, 1H), 7.31 (d, J = 3.7 Hz, 1H), 7.30 (d, J = 3.8 Hz, 1H), 7.11 (d, J = 11.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 4.15 (t, J = 6.3 Hz, 2H), 3.02 (s, 6H), 2.92 (p, J = 7.0 Hz, 1H), 2.82 (t, J = 7.6 Hz, 2H), 2.75 (d, J = 13.4 Hz, 2H), 2.37 (m, 2H), 2.08 (m, 2H), 1.73–1.84 (m, 4H), 1.64 (m, 1H), 1.34 (s, 3H), 1.27 (s, 3H), 1.24 (d, J = 2.3 Hz, 3H), 1.23 (d, J = 2.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.5, 177.3, 153.1, 151.4, 147.2, 147.0, 138.2, 132.7, 130.6, 130.1, 125.1, 123.6, 119.6, 112.5, 108.3, 104.6, 64.1, 46.8, 43.9, 40.6, 38.0, 37.4, 37.1, 36.6, 33.6, 28.3, 23.8, 23.8, 23.7, 22.2, 18.2, 16.4; HRESIMS: calcd for C33H42N4O3 [M + H]+ 542.3335, found 543.3333 (mass error ∆m = 0.0002 ppm).

4.3. NO Inhibitory Assay

Mouse small glioma cells and the BV2 cell line (Cat #20220326) were sourced from Saibai Kang (Shanghai) Biotechnology Co., Ltd. BV2 cells were seeded in 96-well cell culture plates (1.5 × 105 cells/well) and treated with serial dilutions of the compounds, with a maximum concentration of 50 μM in triplicate, followed by stimulation with 1 μg·mL−1 LPS (Sigma, St. Louis, MO, USA) for 18 h. NO production in the supernatant was assessed by Griess reagents (Reagent A and Reagent B, respectively, Sigma). The absorbance at 570 nm was measured with a microplate reader (Thermo, Waltham, MA, USA). NG-Methyl-L-arginine acetate salt (L-NMMA, Sigma), a well-known nitric oxide synthase (NOS) inhibitor, was used as a positive control [14]. The viability of BV2 cells was evaluated by the MTS assay simultaneously, to exclude the interference of the cytotoxicity of the test compounds. All tests were performed in triplicate, and the results are expressed as IC50 values.

5. Conclusions

In summary, 33 7-oxodehydroabietic acid–1,2,3-triazole derivatives (8–39) were synthesized via a click reaction between O-propargylated 7-oxodehydroabietic acid (4), O-pentynylated 7-oxodehydroabietic acid (6), and different substituted aromatic azides. All compounds were further evaluated for their anti-inflammatory effect (NO inhibitory activities) on BV2 cell lines. Compounds 10–12, 14–17, and 22 exhibited a good anti-inflammatory effect (NO inhibitory activities) on BV2 cell lines with IC50 values from 8.40 ± 0.98 µM to 15.82 ± 1.40 µM. In particular, compounds 10 (IC50 = 8.40 ± 0.98 µM), 15 (IC50 = 10.74 ± 2.67 µM), 16 (IC50 = 10.96 ± 1.85 µM), and 17 (IC50 = 9.76 ± 1.27 µM) were the most promising derivatives. Based on the SAR studies, we propose that derivatives containing electron donors, such as a methoxy group or methyl group, and electron acceptors, such as a fluorine atom or chlorine atom in the aromatic ring, especially when most of the group are in the ortho and para positions, tend to have a better anti-inflammatory activity.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30030750/s1, Figures S1–S34: 1H NMR spectrum and 13C NMR spectrum of compound 4, 6, 8-39; Tables S1–S4: 13C chemical shifts for Compounds 4, 6, 8–39.

Author Contributions

Y.-F.L. and H.L. were responsible for the experimental design; W.-T.F. and H.L. performed the experiments; F.-C.R. and H.Z. performed data analysis; W.-T.F. and Y.-F.L. wrote the manuscript; D.-M.X., H.Z. and S.-J.L. supervised and revised the manuscript; H.L. and X.-B.Z. carried out project administration; H.L., X.-B.Z. and C.-W.F. completed funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Natural Science Research Project of the Anhui Educational Committee (RZ2400001411), the Project of High-level Talent of Anhui University of Chinese Medicine (DT2300000267), and Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (2060302).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Gao, J.; Chen, M.; Ren, X.C.; Zhou, X.B.; Shang, Q.; Lu, W.Q.; Luo, P.; Jiang, Z.H. Synthesis and cardiomyocyte protection activity of crocetin diamide derivatives. Fitoterapia 2017, 121, 106–111. [Google Scholar] [CrossRef] [PubMed]
  2. González, M.A. Aromatic abietane diterpenoids: Their biological activity and synthesis. Nat. Prod. Rep. 2015, 32, 684–704. [Google Scholar] [CrossRef] [PubMed]
  3. González, M.A. Aromatic abietane diterpenoids: Total syntheses and synthetic studies. Tetrahedron 2015, 71, 1883–1908. [Google Scholar] [CrossRef]
  4. González, M.A. Synthetic derivatives of aromatic abietane diterpenoids and their biological activities. Eur. J. Med. Chem. 2014, 87, 834–842. [Google Scholar] [CrossRef]
  5. Fonseca, T.; Gigante, B.; Marques, M.M.; Gilchrist, T.L.; De Clercq, E. Synthesis and antiviral evaluation of benzimidazoles, quinoxalines and indoles from dehydroabietic acid. Bioorg. Med. Chem. 2004, 12, 103–112. [Google Scholar] [CrossRef] [PubMed]
  6. Kang, M.S.; Hirai, S.; Goto, T.; Kuroyanagi, K.; Lee, J.Y.; Uemura, T.; Ezaki, Y.; Takahashi, N.; Kawada, T. Dehydroabietic acid, a phytochemical, acts as ligand for PPARs inmacrophages and adipocytes to regulate inflammation. Biochem. Biophys. Res. Commun. 2008, 369, 333–338. [Google Scholar] [CrossRef]
  7. Li, F.Y.; Huang, L.; Li, Q.; Wang, X.; Ma, X.L.; Jiang, C.N.; Zhou, X.Q.; Duan, W.G.; Lei, F.H. Synthesis and antiproliferative evaluation of novel hybrids of dehydroabietic acid bearing 1,2,3-Triazole Moiety. Molecules 2019, 24, 4191. [Google Scholar] [CrossRef]
  8. Wada, H.; Kodato, S.; Kawamori, M.; Morikawa, T.; Nakai, H.; Takeda, M.; Saito, S.; Onoda, Y.; Tamaki, H. Antiulcer activity of dehydroabietic acid derivatives. Chem. Pharm. Bull. 1985, 33, 1472–1487. [Google Scholar] [CrossRef] [PubMed]
  9. Feio, S.S.; Roseiro, J.C.; Gigante, B.; Marcelo-Curto, M.J. Method on multiwell plates for the evaluation of the antimicrobial activity of resin acid derivatives. J. Microbiol. Methods 1997, 28, 201–206. [Google Scholar] [CrossRef]
  10. Gigante, B.; Silva, A.M.; Marcelo-Curto, M.J.; Feio, S.S.; Roseiro, J.; Reis, L.V. Structural effects on the bioactivity of dehydroabietic acid derivatives. Planta Med. 2002, 68, 680–684. [Google Scholar] [CrossRef]
  11. De las Heras, F.G.; Alonso, R.; Alonso, G. Synthesis and cytostatic activity of N-glycosyl(halomethyl)-1,2,3-triazoles. A new type of alkylating agent. J. Med. Chem. 1979, 22, 496–501. [Google Scholar] [CrossRef] [PubMed]
  12. Agalave, S.G.; Maujan, S.R.; Pore, V.S. Click Chemistry: 1,2,3-Triazoles as Pharmacophores. Chem. Asian J. 2011, 6, 2696–2718. [Google Scholar] [CrossRef]
  13. Pingaew, R.; Mandi, P.; Nantasenamat, C.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V. Design, synthesis and molecular docking studies of novel N-benzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-based triazoles with potential anticancer activity. Eur. J. Med. Chem. 2014, 81, 192–203. [Google Scholar] [CrossRef] [PubMed]
  14. Reif, D.W.; McCreedy, S.A. N-Nitro-L-arginine and N-monomethyl-L-arginine exhibit a different pattern of inactivation toward the three nitric oxide synthases. Arch. Biochem. Biophys. 1995, 320, 170–176. [Google Scholar] [CrossRef] [PubMed]
  15. Müller, E.; Kerschbaum, H.H. Progesterone and its metabolites 5-dihydroprogesterone and 5-3-tetrahydroprogesterone decrease LPS-induced NO release in the murine microglial cell line, BV-2. Neuroendocrinol. Lett. 2006, 27, 675–678. [Google Scholar]
  16. Wang, X.; Su, L.; Liu, S.; He, Z.; Li, J.; Zong, Y.; Chen, W.; Du, R. Paeoniflorin Inhibits the Activation of Microglia and Alleviates Depressive Behavior by Regulating SIRT1-NF-kB-NLRP3/Pyroptosis Pathway. Int. J. Mol. Sci. 2024, 25, 12543. [Google Scholar] [CrossRef] [PubMed]
  17. Lv, X.S.; Cui, Y.M.; Wang, H.Y.; Lin, H.X.; Ni, W.Y.; Ohwada, T.; Ido, K.; Sawada, K. Synthesis and BK channel-opening activity of novel N-acylhydrazone derivatives from dehydroabietic acid. Chin. Chem. Lett. 2013, 24, 1023–1026. [Google Scholar] [CrossRef]
  18. Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise Huisgen cycloaddition process: Copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596–2599. [Google Scholar] [CrossRef]
  19. Farooq, S.; Shakeel, U.R.; Hussain, A.; Hamid, A. Click chemistry inspired synthesis and bioevaluation of novel triazolyl derivatives of osthol as potent cytotoxic agents. Eur. J. Med. Chem. 2014, 84, 545–554. [Google Scholar] [CrossRef]
  20. Clerc, A.; Bénéteau, V.; Pale, P.; Chassaing, S. Chan-Lam-type azidation and one-pot CuAAC under CuI-Zeolite catalysis. ChemCatChem 2020, 12, 2060–2065. [Google Scholar] [CrossRef]
  21. Tao, C.Z.; Xin, C.; Li, J.; Liu, A.X.; Liu, L.; Guo, Q.X. Copper-catalyzed synthesis of aryl azides and 1-aryl-1,2,3-triazoles from boronic acids. Tetrahedron Lett. 2007, 48, 3525–3529. [Google Scholar] [CrossRef]
  22. Luo, H.; Lv, Y.F.; Zhang, H.; Hu, J.M.; Li, H.M.; Liu, S.J. Synthesis and antitumor activity of 1-substituted 1,2,3-triazole-mollugin derivatives. Molecules 2021, 26, 3249. [Google Scholar] [CrossRef]
  23. Lopez-Rojas, P.; Janeczko, M.; Kubinski, K.; Amesty, A.; Maslyk, M.; Estevez-Braun, A. Synthesis and antimicrobial activity of 4-substituted 1,2,3-triazole-coumarin derivatives. Molecules 2018, 23, 199. [Google Scholar] [CrossRef] [PubMed]
  24. Silva, V.; Faria, B.D.; Colombo, E.; Ascari, L.; Freitas, G.P.A.; Flores, L.S.; Cordeiro, Y.; Ramao, L.; Buarque, C.D. Design, synthesis, structural characterization and in vitro evaluation of new 1,4-disubstituted-1,2,3-triazole derivatives against glioblastoma cells. Bioorg. Chem. 2018, 83, 87–97. [Google Scholar] [CrossRef]
Molecules 30 00750 g001
Figure 1. The structures of dehydroabietic acid (1) and 7-oxodehydroabietic acid (2).
Figure 1. The structures of dehydroabietic acid (1) and 7-oxodehydroabietic acid (2).
Molecules 30 00750 g001
Molecules 30 00750 sch001
Scheme 1. Preparation of O-propargylated 7-oxodehydroabietic acid (4) and O-pentynylated 7-oxodehydroabietic acid (6).
Scheme 1. Preparation of O-propargylated 7-oxodehydroabietic acid (4) and O-pentynylated 7-oxodehydroabietic acid (6).
Molecules 30 00750 sch001
Molecules 30 00750 sch002
Scheme 2. Synthesis of 7-oxodehydroabietic acid–1,2,3-triazole hybrids from O-propargylated 7-oxodehydroabietic acid (4).
Scheme 2. Synthesis of 7-oxodehydroabietic acid–1,2,3-triazole hybrids from O-propargylated 7-oxodehydroabietic acid (4).
Molecules 30 00750 sch002
Molecules 30 00750 sch003
Scheme 3. Synthesis of 7-oxodehydroabietic acid–1,2,3-triazole hybrids from O-pentynylated 7-oxodehydroabietic acid (6).
Scheme 3. Synthesis of 7-oxodehydroabietic acid–1,2,3-triazole hybrids from O-pentynylated 7-oxodehydroabietic acid (6).
Molecules 30 00750 sch003
Table 1. IC50 values in µM of 7-oxodehydroabietic acid–1,2,3-triazole hybrids on the panel of BV2 cell lines.
Table 1. IC50 values in µM of 7-oxodehydroabietic acid–1,2,3-triazole hybrids on the panel of BV2 cell lines.
CompoundIC50 (µM)CompoundIC50 (µM)
844.64 ± 1.2825>50
9>5026>50
108.40 ± 0.9827>50
1115.11 ± 1.8928>50
1211.43 ± 1.2429>50
13>5030>50
1411.45 ± 2.0531>50
1510.74 ± 2.6732>50
1610.96 ± 1.8533>50
179.76 ± 1.2734>50
1834.33 ± 1.4135>50
19>5036>50
20>5037>50
21>5038>50
2215.82 ± 1.4039>50
23>50
24>50L-NMMA a42.36 ± 2.47
a L-NMMA: NG-methyl-L-arginine acetate salt.
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Fang, W.-T.; Lv, Y.-F.; Ren, F.-C.; Zhang, H.; Xie, D.-M.; Zhang, X.-B.; Fang, C.-W.; Liu, S.-J.; Luo, H. Synthesis and Anti-Inflammatory Evaluation of Novel Hybrids of 7-Oxodehydroabietic Acid Bearing a 1,2,3-Triazole Moiety. Molecules 2025, 30, 750. https://doi.org/10.3390/molecules30030750

AMA Style

Fang W-T, Lv Y-F, Ren F-C, Zhang H, Xie D-M, Zhang X-B, Fang C-W, Liu S-J, Luo H. Synthesis and Anti-Inflammatory Evaluation of Novel Hybrids of 7-Oxodehydroabietic Acid Bearing a 1,2,3-Triazole Moiety. Molecules. 2025; 30(3):750. https://doi.org/10.3390/molecules30030750

Chicago/Turabian Style

Fang, Wen-Tao, Yong-Feng Lv, Fu-Cai Ren, Hong Zhang, Dong-Mei Xie, Xiao-Bo Zhang, Cheng-Wu Fang, Shou-Jin Liu, and Han Luo. 2025. "Synthesis and Anti-Inflammatory Evaluation of Novel Hybrids of 7-Oxodehydroabietic Acid Bearing a 1,2,3-Triazole Moiety" Molecules 30, no. 3: 750. https://doi.org/10.3390/molecules30030750

APA Style

Fang, W.-T., Lv, Y.-F., Ren, F.-C., Zhang, H., Xie, D.-M., Zhang, X.-B., Fang, C.-W., Liu, S.-J., & Luo, H. (2025). Synthesis and Anti-Inflammatory Evaluation of Novel Hybrids of 7-Oxodehydroabietic Acid Bearing a 1,2,3-Triazole Moiety. Molecules, 30(3), 750. https://doi.org/10.3390/molecules30030750

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