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Communication

Synthesis of Imine Congeners of Resveratrol and Evaluation of Their Anti-Platelet Activity

by
Mohammad Bigdeli
1,
Maryam Sabbaghan
2,
Marjan Esfahanizadeh
3,
Farzad Kobarfard
3,4,*,
Sara Vitalini
5,*,
Marcello Iriti
5,* and
Javad Sharifi-Rad
6,*
1
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Islamic Azad University-Pharmaceutical Sciences Branch (IAUPS), Tehran 11369, Iran
2
Chemistry Department, Faculty of Sciences, Shahid Rajaee Teacher Training University, Lavizan 16785-163, Tehran, Iran
3
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran 14155-6153, Iran
4
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran 11369, Iran
5
Department of Agricultural and Environmental Sciences, Milan State University Via G. Celoria 2, 20133 Milan, Italy
6
Zabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol 61615585, Iran
*
Authors to whom correspondence should be addressed.
Molbank 2019, 2019(1), M1039; https://doi.org/10.3390/M1039
Submission received: 27 November 2018 / Revised: 19 December 2018 / Accepted: 20 December 2018 / Published: 22 December 2018
(This article belongs to the Section Natural Products)
Browse Figures
Versions Notes

Abstract

:
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a cardioprotective phytochemical occurring in many plant products. In this study, a new series of imine congeners of resveratrol has been synthesized in which the imine moiety replaced the double bond in the structure of resveratrol. In addition, the in vitro antiplatelet activity of these resveratrol derivatives has been evaluated against adenosine diphosphate (ADP), arachidonic acid (AA), and collagen as platelet aggregation inducers. In general, the synthesized compounds were active as antiplatelet agents, and, therefore, the imine functional group may be considered as an effective replacement for a double bond in resveratrol for developing new and promising antiplatelet drugs.

1. Introduction

Cardiovascular diseases (CVDs) are recognized as the first global cause of death. It has been reported by the World Health Organization (WHO) that 17.7 million people died from CVDs in 2015 [1,2]. Platelet aggregation plays an essential role in the process of blood clotting and CVDs. However, many antiplatelet drugs such as aspirin and clopidogrel, which are available in clinics, are associated with some side effects such as bleeding and drug resistance that limit their usage [3,4]. Therefore, the search for new antiplatelet agents with fewer side effects and higher efficacy is among the priorities of medicinal chemists.
Natural products with various chemical structures have an important role in drug discovery and development [5,6,7,8,9]. Although chemical diversity of the natural products is pivotal in finding useful lead compounds, usually chemical modifications are needed to improve their potency and physicochemical properties [10,11,12]. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) (1) (Figure 1) is one of these lead compounds. This stilbene is found in many natural sources such as grapes, apples, and berries [13,14,15]. Various biological activities of resveratrol have been reported such as anticancer, anti-inflammatory, antioxidant, and antiplatelet [13,16,17]. Orsini et al. synthesized and evaluated the antiplatelet aggregation activity of resveratrol 3-O-β-d-glucopyranoside and related hyroxystilbenes [18]. Dutra et al. synthesized new resveratrol and resveratrol-furoxan hybrids as antiplatelet and antithrombotic agents [19].
A literature review revealed that C=N moiety is present in many structures with antiplatelet activity. Tehrani et al. synthesized a series of Schiff bases derived from 2-hydrazinyl-1,3,4-thiadiazole with high antiplatelet activity [20]. Akhlaghi et al. reported 3-(arylimino)indolin-2-one and 1-(aryl)-3-(phenylimino)indolin-2-one derivatives as antiplatelet agents [21]. Among their synthesized derivatives, compound (2) exhibited high antiplatelet activity against arachidonic acid (AA) as a platelet aggregation inducer (IC50 = 3.4 µM) [21]. Furthermore, antiplatelet activity of N′-benzylidene-carbohydrazide-1H-pyrazolo[3,4-b]pyridine derivatives have been reported [22]. A variety of indole hydrazone derivatives such as indole N-acylhydrazones [23,24], indole-3-carboxaldehyde phenylhydrazones [25], N-1 substituted indolehydrazones [26], indole-3-carbaldehyde, and indole-2-carbaldehayde hydrazones [27] have been previously synthesized in our research group. Some of these reported derivatives exhibited remarkable antiplatelet activity.
Therefore, the present research was aimed at the synthesis of a new series of imine congeners of resveratrol in which the imine moiety replaced the double bond in the structure of resveratrol (Figure 1) [28], and the evaluation of their in vitro antiplatelet activity against adenosine diphosphate (ADP), arachidonic acid (AA), and collagen as platelet aggregation inducers.

2. Results and Discussion

2.1. Chemistry

The designed compounds were synthesized by the reaction of different aniline derivatives with appropriate aldehydes in water as a green solvent without any catalyst (Figure 2). The synthesized derivatives (3a–3r) were obtained with high yields (>89%). Structure of the synthesized compounds was characterized by LC-MS 1H-NMR and 13C-NMR. The 1H-NMR spectra of the synthesized compounds exhibited a singlet peak for the CH=N proton between 8.51 and 8.96 ppm.

2.2. Anti-Platelet Activity

The anti-platelet activity of the synthesized derivatives against ADP, AA, and collagen as platelet aggregation inducers were evaluated, according to the Born method [29,30]. The obtained data are presented in Table 1.

2.3. Structure Activity Relationship

The data reported in Table 1 show that all the compounds (3a–3r) at the concentration of 1 mM inhibited platelet aggregation induced by ADP, AA, and collagen. The inhibition range for ADP and collagen were 30%–84.6% and 15.9%–93.4%, respectively. When AA was used as a platelet aggregation inducer, the inhibition was increased and ranged from 74.7% to 100%.
Compound 3m with three-methoxy group on ring A inhibited platelet aggregation induced by all the three platelet inducers above 85%.
Since all compounds at concentration of 1 mM were able to completely inhibit platelet aggregation induced by AA, the IC50 values for these compounds were calculated (Table 1).
As shown in Table 1, all the compounds with hydroxyl substituent on the B ring show high activity (IC50 < 69.1 μM) except 3o. The results demonstrated that all the compounds with Schiff base and phenolic hydroxyl groups at the ortho position of ring A or B show IC50 values ranging between 19.8 μM and 30.7 μM except for 3c and 3p. Compounds 3i and 3q exhibited satisfactory activity with IC50 values of 29.9 μM and 30.7 μM, respectively. Compound 3r with IC50 value of 19.8 μM was the most active compound.

3. Materials and Methods

3.1. General Procedure for the Preparation of 3a–3r

The mixture of aromatic amine (1 mmol) and aldehyde (1 mmol) in water was stirred at room temperature. After completion of the reaction indicated by TLC (thin-layer chromatography), the obtained precipitate was filtered off and washed with water. The obtained precipitate was recrystallized from the appropriate solvent.
(E)-1-(4-Methoxyphenyl)-N-phenylmethanimine (3a). Yield 95%; m.p. 48–50 °C (m.p. 49–50 °C [31]). ESI-MS m/z: 212 [M + H]+. Anal. Calcd for C14H13NO: C 79.59, H 6.20, N 6.63, found C 79.57, H 6.21, N 6.64.
(E)-2-Methoxy-4-[(phenylimino)methyl]phenol (3b). Yield 89%. m.p. 159–162 °C (m.p. 158–160 °C [32]). ESI-MS m/z: 228 [M + H]+; Anal. Calcd for C14H13NO2: C 73.99, H 5.77, N 6.16, found C 73.97, H 5.76, N 6.15.
(E)-2-{[(4-Methoxyphenyl)imino]methyl}phenol (3c). Yield 94%. m.p. 76–77 °C; 1H-NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H, OH), 8.94 (s, 1H, HC=N), 7.61 (m, 1H, Ar-H), 7.42 (m, 3H, Ar-H), 6.96 (m, 4H, Ar-H), 3.79 (s, 3H, OCH3). 13C-NMR (100 MHz, DMSO-d6) δ 161.72, 160.62, 158.99, 141.19, 133.25, 132.80, 123.09, 119.85, 119.53, 116.97, 115.13, 55.86; ESI-MS m/z: 228 [M + H]+. Anal. Calcd for C14H13NO2: C 73.99, H 5.77, N 6.16, found C 73.95, H 5.76, N 6.17.
(E)-N,1-bis(4-Methoxyphenyl)methanimine (3d). Yield 89%. m.p. 154–155 °C (m.p. 154 °C [33]). ESI-MS m/z: 242 [M + H]+. Anal. Calcd for C15H15NO2: C 74.67, H 6.27, N 5.81, found C 74.68, H 6.28, N 5.79.
(E)-1-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenyl)methanimine (3e). Yield 85%. m.p. 126–128 °C. 1H-NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H, HC=N), 6.96–7.54 (m, 7H, Ar-H), 3.77–3.83 (m, 9H, OCH3); 13C-NMR (100 MHz, DMSO-d6) δ 158.46, 158.05, 151.97, 149.45, 144.89, 129.77, 124.08, 122.66, 115.46, 114.95, 114.85, 111.74, 109.68, 56.07, 55.88, 55.73. ESI-MS m/z: 272 [M + H]+. Anal. Calcd for C16H17NO3: C 70.83, H 6.32, N 5.16, found C 70.81, H 6.31, N 5.17.
(E)-N-(4-Methoxyphenyl)-1-(p-tolyl)methanimine (3f). Yield 96%. m.p. 87–88 °C. 1H-NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H, HC=N), 7.70-7.81 (m, 2H, Ar-H), 7.31-7.42 (m, 4H, Ar-H), 6.98 (m, 2H, Ar-H), 3.78 (s, 3H, OCH3), 2.38 (s, 3H, OCH3). 13C-NMR (100 MHz, DMSO-d6) δ 158.2, 157.8, 144.2, 141.0, 133.8, 129.85, 128.88, 122.79, 114.87, 55.76, 21.1. ESI-MS m/z: 226 [M + H]+. Anal. Calcd for C15H15NO: C 79.97, H 6.71, N 6.22, found C 79.95, H 6.70, N 6.23.
(E)-2-Methoxy-4-{[(4-methoxyphenyl)imino]methyl}phenol (3g). Yield 94%. m.p. 154–155 °C (m.p. 154 °C [34]). ESI-MS m/z: 258 [M + H]+. Anal. Calcd for C15H15NO3: C 70.02, H 5.88, N 5.44, found C 70.01, H 5.89, N 5.43.
(E)-4-[(3-Methoxybenzylidene)amino]phenol (3h). Yield 94%. m.p. 165–167 °C (m.p. 167 °C [35]). ESI-MS m/z: 228 [M + H]+. Anal. Calcd for C14H13NO2: C 73.99, H 5.77, N 6.16, found C 73.97, H 5.76, N 6.15.
(E)-2-{[(4-Hydroxyphenyl)imino]methyl}phenol (3i). Yield 98%. m.p. 140–143 °C. 1H-NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H, OH), 9.72 (s, 1H, OH), 8.94 (s, 1H, HC=N), 7.58 (m, 1H, Ar-H), 7.31–7.37 (m, 3H, Ar-H), 6.84–6.95 (m, 4H, Ar-H). 13C-NMR (100 MHz, DMSO-d6) δ 160.67, 160.60, 157.41, 139.65, 133.00, 132.67, 123.12, 119.89, 119.46, 116.92, 116.43, 116.01, 115.85. ESI-MS m/z: 214 [M + H]+. Anal. Calcd for C13H11NO2: C 73.23, H 5.20, N 6.57, found C 73.21, H 5.21, N 6.56.
(E)-4-[(4-Methoxybenzylidene)amino]phenol (3j). Yield 95%. m.p. 187–188 °C (m.p. 189 °C [36]). ESI-MS m/z: 228 [M + H]+. Anal. Calcd for C14H13NO2: C 73.99, H 5.77, N 6.16, found C 74.20, H 5.77, N 6.15.
(E)-4-[(4-Methylbenzylidene)amino]phenol (3k). Yield 94%. m.p. 152–153 °C; 1H-NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H, OH), 8.55 (s, 1H, HC=N), 7.78 (m, 2H, Ar-H), 7.18–7.30 (m, 4H, Ar-H), 6.80 (m, 2H, Ar-H), 2.36 (s, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6) δ 157.51, 156.57, 143.19, 141.24, 134.36, 129.82, 128.73, 122.86, 116.15, 21.59; ESI-MS m/z: 212 [M + H]+. Anal. Calcd for C14H13NO: C 79.59, H 6.20, N 6.63, found C 79.45, H 6.19, N 6.62.
(E)-4-[(3,4-Dimethoxybenzylidene)amino]phenol (3l). Yield 92%. m.p. 155–156 °C (m.p. 155 °C [37]). ESI-MS m/z: 258 [M + H]+. Anal. Calcd for C15H15NO3: C 70.02, H 5.88, N 5.44, found C 70.10, H 5.87, N 5.45.
(E)-4-[(3,4,5-Trimethoxybenzylidene)amino]phenol (3m). Yield 96%. m.p. 140–142 °C. 1H-NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H, OH), 8.51 (s, 1H, HC=N), 7.18–7.23 (m, 4H, Ar-H), 6.81 (m, 2H, Ar-H), 3.85 (s, 6H, OCH3), 3.73 (s, 3H, OCH3). 13C-NMR (100 MHz, DMSO-d6) δ 157.42, 156.60, 153.58, 143.06, 140.31, 132.44, 122.85, 116.19, 115.87, 107.19, 105.88, 60.61, 56.50, 56.36; ESI-MS m/z: 288 [M + H]+. Anal. Calcd for C16H17NO4: C 66.89, H 5.96, N 4.88, found C 66.84, H 5.95, N 4.88.
(E)-3-{[(4-Hydroxyphenyl)imino]methyl}phenol (3n). Yield 94%. m.p. 191–193 °C. 1H-NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H, OH), 9.55 (s, 1H, OH), 8.51 (s, 1H, HC=N), 7.19–7.37 (m, 5H, Ar-H), 6.83–6.91 (m, 3H, Ar-H). 13C-NMR (100 MHz, DMSO-d6) δ 158.10, 157.66, 156.70, 143.04, 138.29, 130.23, 122.95, 120.44, 118.64, 116.19, 115.90, 114.35; ESI-MS m/z: 214 [M + H]+. Anal. Calcd for C13H11NO2: C 73.23, H 5.20, N 6.57, found C 73.21, H 5.21, N 6.58.
(E)-4-[(2-Methoxybenzylidene)amino]phenol (3o). Yield 92%. m.p. 168–169 °C (m.p. 168 °C [35]). ESI-MS m/z: 228 [M + H]+. Anal. Calcd for C14H13NO2: C 73.99, H 5.77, N 6.16, found C 73.94, H 5.78, N 6.15.
(E)-2-[(2-Hydroxybenzylidene)amino]phenol (3p). Yield 98%. m.p. 141–143 °C. 1H-NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H, OH), 9.77 (s, 1H, OH), 8.96 (s, 1H, HC=N), 7.13–7.61 (m, 4H, Ar-H), 6.89–6.95 (m, 4H, Ar-H). 13C-NMR (100 MHz, DMSO-d6) δ 162.13, 161.20, 151.56, 135.40, 133.31, 132.78, 128.53, 120.09, 120.04, 119.96, 119.21, 117.16, 116.98. ESI-MS m/z: 214 [M + H]+. Anal. Calcd for C13H11NO2: C 73.23, H 5.20, N 6.57, found C 73.24, H 5.19, N 6.56.
(E)-2-[(3-Hydroxybenzylidene)amino]phenol (3q). Yield 99%. m.p. 122–124 °C (m.p. 122.5–123.5 °C [38]). ESI-MS m/z: 214 [M + H]+. Anal. Calcd for C13H11NO2: C 73.23, H 5.20, N 6.57, found C 73.24, H 5.19, N 6.55.
(E)-2-[(4-Methylbenzylidene)amino]phenol (3r). Yield 98%. m.p. 107–108 °C (m.p. 108.5 °C [39]). ESI-MS m/z: 212 [M + H]+. Anal. Calcd for C14H13NO: C 79.59, H 6.20, N 6.63, found C 79.58, H 6.19, N 6.64.

3.2. Anti-Platelet Assay

The anti-platelet aggregation activity of the synthesized compounds was evaluated on an APACT 4004 aggregometer (LABiTec, Ahrensburg, Germany), according to the method described before [29,40,41]. Compounds (3a–3r) were added to platelet-rich plasma (PRP) and were incubated for 5 min at 37 °C. Adenosine diphosphate (ADP), arachidonic acid, and collagen were added separately as platelet aggregation inducers at a final concentration of 5 µM, 1.35 µM, and 2.5 µg·mL−1, respectively. The aggregation procedure was monitored for 5 min. Compounds were screened at a concentration of 1 mM in DMSO. The IC50 values against AA were determined for the synthesized compounds. Each experiment was carried out in triplicate and the results are shown as a mean ± standard error of mean (SEM).

4. Conclusions

In the present study, a series of resveratrol derivatives was synthesized and their antiplatelet activity was evaluated against ADP, AA, and collagen as platelet aggregation inducers. Compound 3r was the most active agent against AA and, therefore, possesses the potential to be considered a lead compound for future studies and further investigations. Lastly, the imine functional group may be qualified as an effective replacement for the double bond in resveratrol for anti-platelet aggregation pharmacophore.

Supplementary Materials

The following are available online https://www.mdpi.com/1422-8599/2019/1/M1039/s1, Figure S1: Qualitative data analysis report.

Author Contributions

M.B., M.S., M.E., and F.K. carried out the experiments, analyzed the results, and wrote the manuscript. S.V., M.I., and J.S.-R. contributed to the discussion of results and critically reviewed the manuscript. All the authors read and approved the final manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Molbank 2019 m1039 g001 550
Figure 1. Design of imine resveratrol derivatives.
Figure 1. Design of imine resveratrol derivatives.
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Molbank 2019 m1039 g002 550
Figure 2. Synthesis of resveratrol derivatives.
Figure 2. Synthesis of resveratrol derivatives.
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Table
Table 1. Anti-platelet activity of the synthesized derivatives. Adenosine diphosphate (ADP), arachidonic acid (AA), and collagen were used as a platelet aggregation inducer at a final concentration of 5 µM, 1.35 µM, and 2.5 µg·mL−1, respectively. The results are expressed as the mean ± standard error of mean (SEM) from three independent experiments.
Table 1. Anti-platelet activity of the synthesized derivatives. Adenosine diphosphate (ADP), arachidonic acid (AA), and collagen were used as a platelet aggregation inducer at a final concentration of 5 µM, 1.35 µM, and 2.5 µg·mL−1, respectively. The results are expressed as the mean ± standard error of mean (SEM) from three independent experiments.
Molbank 2019 m1039 i001
CompoundRR′AA a
Inhibition (%)		AA
(IC50 µM)		ADP a
Inhibition (%)		Collagen a
Inhibition (%)
3a4-OCH3-74.7 ± 2.5301.0 ± 8.743.2 ± 3.315.9 ± 1.5
3b3-OCH3, 4-OH-100180.2 ± 5.452.1 ± 2.239.0 ± 8.8
3c2-OH4′-OCH310086.1 ± 6.630.2 ± 5.346.8 ± 4.3
3d4-OCH34′-OCH3100155.5 ± 4.341.4 ± 6.429.1 ± 1.9
3e3,4-dimethoxy4′-OCH310073.6 ± 3.463.2 ± 3.180.7 ± 1.4
3f4-CH34′-OCH3100143.3 ± 6.233.6 ± 1.460.0 ± 4.1
3g3-OCH3, 4-OH4′-OCH394.9 ± 0.7179.2 ± 7.134.4 ± 5.641.0 ± 6.6
3h3-OCH34′-OH10069.1 ± 5.477.4 ± 1.973.1 ± 2.1
3i2-OH4′-OH10029.9 ± 1.136.3 ± 3.970.8 ± 1.3
3j4-OCH34′-OH10068.3 ± 1.444.1 ± 3.667.2 ± 3.2
3k4-CH34′-OH10065.4 ± 3.445.8 ± 3.359.03 ± 6.2
3l3,4-dimethoxy4′-OH93.7 ± 5.665.3 ± 2.053.5 ± 2.767.8 ± 3.5
3m3,4,5-trimethoxy4′-OH88.0 ± 3.165.2 ± 3.484.6 ± 1.193.4 ± 0.9
3n3-OH4′-OH10062.3 ± 7.133.4 ± 3.580.5 ± 1.4
3o2-OCH34′-OH92.4 ± 2.1130.7 ± 5.143.8 ± 1.674.9 ± 3.4
3p2-OH2′-OH95.1 ± 3.065.5 ± 4.341.1 ± 3.770.2 ± 2.5
3q3-OH2′-OH10030.7 ± 1.238.4 ± 3.936.1 ± 3.5
3r4-CH32′-OH10019.8 ± 1.139.8 ± 3.263.5 ± 1.3
Indomethacin 1.67 ± 0.6742.0 ± 1.1
Acetyl salicylic acid (ASA) 0.24 ± 0.0521.0 ± 0.6
a Inhibition of platelet aggregation was assessed at 1 mM concentration.

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Bigdeli, M.; Sabbaghan, M.; Esfahanizadeh, M.; Kobarfard, F.; Vitalini, S.; Iriti, M.; Sharifi-Rad, J. Synthesis of Imine Congeners of Resveratrol and Evaluation of Their Anti-Platelet Activity. Molbank 2019, 2019, M1039. https://doi.org/10.3390/M1039

AMA Style

Bigdeli M, Sabbaghan M, Esfahanizadeh M, Kobarfard F, Vitalini S, Iriti M, Sharifi-Rad J. Synthesis of Imine Congeners of Resveratrol and Evaluation of Their Anti-Platelet Activity. Molbank. 2019; 2019(1):M1039. https://doi.org/10.3390/M1039

Chicago/Turabian Style

Bigdeli, Mohammad, Maryam Sabbaghan, Marjan Esfahanizadeh, Farzad Kobarfard, Sara Vitalini, Marcello Iriti, and Javad Sharifi-Rad. 2019. "Synthesis of Imine Congeners of Resveratrol and Evaluation of Their Anti-Platelet Activity" Molbank 2019, no. 1: M1039. https://doi.org/10.3390/M1039

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