Design, Synthesis, and Anti-Tyrosinase, Anti-Melanogenic, and Antioxidant Activities of Novel (Z)-3-Benzyl-5-Benzylidene-2-Thioxothiazolidin-4-One Analogs
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Target Compounds (Z)-BBTT Analogs 1–12
2.2. Inhibitory Activity of (Z)-BBTT Analogs 1–12 Against Mushroom Tyrosinase
2.3. Kinetic Analysis of Mushroom Tyrosinase Using Lineweaver–Burk Plots
2.4. In Silico Docking Simulation of (Z)-BBTT Analogs and Mushroom Tyrosinase
2.5. Cell Viability of (Z)-BBTT Analogs on B16F10 Cells
2.6. Effect of (Z)-BBTT Analogs 1 and 3 on Melanin Production in B16F10 Cells
2.7. Effect of (Z)-BBTT Analogs 1 and 3 on Tyrosinase Activity in B16F10 Cells
2.8. In Situ B16F10 Cell Tyrosinase Inhibitory Activity of (Z)-BBTT Analogs 1 and 3
2.9. Antioxidant Capacity of (Z)-BBTT Analogs 1–12
2.9.1. ABTS+ Radical-Scavenging Capacity
2.9.2. DPPH Radical-Scavenging Capacity
2.9.3. ROS-Scavenging Capacity
2.10. Effects of Analogs 1–3 on HaCaT Cell Viability
3. Materials and Methods
3.1. Synthesis
3.1.1. General Methods
3.1.2. Synthesis of 3-Benzyl-2-Thioxothiazolidin-4-One (13) [34,35]
3.1.3. General Preparation of (Z)-BBTT Analogs 1–12
- (Z)-3-Benzyl-5-(4-hydroxybenzylidene)-2-thioxothiazolidin-4-one (1).1H NMR (dimethyl sulfoxide [DMSO]-d6, 500 MHz) δ 10.51 (s, 1H, OH), 7.76 (s, 1H, vinyl H), 7.52 (d, 2H, J = 8.5 Hz, 2′-H, 6′-H), 7.35–7.26 (m, 5H, Ph), 6.94 (d, 2H, J = 8.5 Hz, 3′-H, 5′-H), 5.23 (s, 2H, benzyl H2); 13C NMR (DMSO-d6, 125 MHz) δ 193.7, 167.5, 161.2, 135.5, 134.7, 133.9, 129.0, 128.1 (2 × C), 124.4, 117.9, 117.1, 47.5; LR-MS (ESI−) m/z 326 (M − H)−; yield, 76%; molecular formula, C17H13NO2S2; HR-MS (EDA) m/z C17H14NO2S2 (M + H)+ calcd. 328.0466, obsd. 328.0460; melting point, 199–201 °C; brown solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.38.
- (Z)-3-Benzyl-5-(3,4-dihydroxybenzylidene)-2-thioxothiazolidin-4-one (2).1H NMR (DMSO-d6, 500 MHz) δ 10.06 (s, 1H, OH), 9.59 (s, 1H, OH), 7.68 (s, 1H, vinyl H), 7.35–7.25 (m, 5H, Ph), 7.08–7.04 (m, 2H, 2′-H, 6′-H), 6.90 (d, 1H, J = 8.5 Hz, 5′-H), 5.23 (s, 2H, benzyl H2); 13C NMR (DMSO-d6, 125 MHz) δ 193.7, 167.5, 150.1, 146.6, 135.5, 135.1 (2 × C), 129.0, 128.1, 125.9, 124.8, 117.7, 117.2, 117.0, 47.5; LR-MS (ESI−) m/z 342 (M − H)−; yield, 84%; molecular formula, C17H13NO3S2; HR-MS (EDA) m/z C17H14NO3S2 (M + H)+ calcd. 344.0415, obsd. 344.0410; melting point, 140–142 °C; brown solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.10.
- (Z)-3-Benzyl-5-(2,4-dihydroxybenzylidene)-2-thioxothiazolidin-4-one (3).1H NMR (DMSO-d6, 500 MHz) δ 10.76 (s, 1H, OH), 10.42 (s, 1H, OH), 7.99 (s, 1H, vinyl H), 7.35–7.25 (m, 5H, Ph), 7.22 (d, 1H, J = 8.5 Hz, 6′-H), 6.45–6.43 (m, 2H, 3′-H, 5′-H), 5.22 (s, 2H, benzyl H2); 13C NMR (DMSO-d6, 125 MHz) δ 193.9, 167.7, 163.3, 160.5, 135.6, 132.1, 130.4, 128.9, 128.0 (2 × C), 115.6, 112.4, 109.5, 102.9, 47.3; LR-MS (ESI−) m/z 342 (M − H)−; yield, 74%; molecular formula, C17H13NO3S2; HR-MS (EDA) m/z C17H14NO3S2 (M + H)+ calcd. 344.0415, obsd. 344.0412; melting point, 191–193 °C; copper-colored solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.10.
- (Z)-3-Benzyl-5-(4-hydroxy-3-methoxybenzylidene)-2-thioxothiazolidin-4-one (4).1H NMR (CDCl3, 500 MHz) δ 7.67 (s, 1H, vinyl H), 7.47 (d, 2H, J = 7.0 Hz, 2-H, 6-H), 7.33–7.28 (m, 3H, 3-H, 4-H, 5-H), 7.08 (brd, 1H, J = 8.0 Hz, 6′-H), 7.00 (d, 1H, J = 8.0 Hz, 5′-H), 6.95 (s, 1H, 2′-H), 6.04 (s, 1H, OH), 5.32 (s, 2H, benzyl H2), 3.95 (s, 3H, OCH3); 13C NMR (CDCl3, 125 MHz) δ 193.0, 167.9, 148.6, 147.1, 134.9, 133.9, 129.0, 128.6, 128.1, 126.4, 126.0, 119.8, 115.4, 112.0, 56.1, 47.5; LR-MS (ESI−) m/z 356 (M − H)−; yield, 68%; molecular formula, C18H15NO3S2; melting point, 157–159 °C (lit. [19] 151–154 °C); brown solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.29.
- (Z)-3-Benzyl-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5).1H NMR (CDCl3, 500 MHz) δ 7.64 (s, 1H, vinyl H), 7.47 (d, 2H, J = 7.0 Hz, 2-H, 6-H), 7.33–7.27 (m, 3H, 3-H, 4-H, 5-H), 7.07–7.04 (m, 2H, 2′-H, 6′-H), 6.92 (d, 1H, J = 8.0 Hz, 5′-H), 5.72 (s, 1H, OH), 5.32 (s, 2H, benzyl H2), 3.95 (s, 3H, OCH3); 13C NMR (CDCl3, 125 MHz) δ 193.3, 168.0, 148.9, 146.2, 134.9, 133.6, 129.0, 128.6, 128.1, 126.9, 124.6, 120.7, 116.1, 111.0, 56.2, 47.5; LR-MS (ESI−) m/z 356 (M − H)−; yield, 54%; molecular formula, C18H15NO3S2; melting point, 173–175 °C; yellow solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.28.
- (Z)-3-Benzyl-5-(4-methoxybenzylidene)-2-thioxothiazolidin-4-one (6).1H NMR (CDCl3, 500 MHz) δ 7.70 (s, 1H, vinyl H), 7.47 (d, 2H, J = 7.0 Hz, 2-H, 6-H), 7.45 (d, 2H, J = 9.0 Hz, 2′-H, 6′-H), 7.33–7.27 (m, 3H, 3-H, 4-H, 5-H), 6.99 (d, 2H, J = 9.0 Hz, 3′-H, 5′-H), 5.32 (s, 2H, benzyl H2), 3.87 (s, 3H, OCH3); 13C NMR (CDCl3, 125 MHz) δ 193.2, 168.0, 161.8, 135.0, 133.5, 132.8, 129.0, 128.6, 128.1, 126.0, 119.9, 115.0, 55.6, 47.5; yield, 69%; molecular formula, C18H15NO2S2; HR-MS (EDA) m/z C18H16NO2S2 (M + H)+ calcd. 342.0622, obsd. 342.0619; melting point, 146–148 °C (lit. [19] 142–145 °C); copper-colored solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.63.
- (Z)-3-Benzyl-5-(3,4-dimethoxybenzylidene)-2-thioxothiazolidin-4-one (7).1H NMR (CDCl3, 500 MHz) δ 7.69 (s, 1H, vinyl H), 7.47 (d, 2H, J = 7.0 Hz, 2-H, 6-H), 7.33–7.27 (m, 3H, 3-H, 4-H, 5-H), 7.13 (d, 1H, J = 8.5 Hz, 6′-H), 6.97 (s, 1H, 2′-H), 6.95 (d, 1H, J = 8.5 Hz, 5′-H), 5.32 (s, 2H, benzyl H2), 3.94 (s, 6H, 2 × OCH3); 13C NMR (CDCl3, 125 MHz) δ 193.0, 167.9, 151.6, 149.5, 134.9, 133.7, 129.0, 128.6, 128.1, 126.3, 125.7, 120.1, 112.4, 111.5, 56.1, 56.0, 47.5; LR-MS (ESI+) m/z 372 (M + H)+, 394 (M + Na)+; yield, 52%; molecular formula, C19H17NO3S2; melting point, 166–168 °C; yellow solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.45.
- (Z)-3-Benzyl-5-(2,4-dimethoxybenzylidene)-2-thioxothiazolidin-4-one (8).1H NMR (CDCl3, 500 MHz) δ 8.07 (s, 1H, vinyl H), 7.48 (d, 2H, J = 7.5 Hz, 2-H, 6-H), 7.33–7.25 (m, 4H, 3-H, 4-H, 5-H, 6′-H), 6.57 (dd, 1H, J = 9.0, 2.0 Hz, 5′-H), 6.45 (d, 1H, J = 2.0 Hz, 3′-H), 5.32 (s, 2H, benzyl H2), 3.88 (s, 3H, OCH3), 3.86 (s, 3H, OCH3); 13C NMR (CDCl3, 125 MHz) δ 194.0, 168.1, 163.9, 160.4, 135.1, 132.1, 129.6, 129.0, 128.5, 128.0, 119.4, 115.7, 105.9, 98.5, 55.7, 55.6, 47.5; LR-MS (ESI+) m/z 372 (M + H)+, 394 (M + Na)+; yield, 81%; molecular formula, C19H17NO3S2; melting point, 156–158 °C; brown solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.76.
- (Z)-3-Benzyl-2-thioxo-5-(3,4,5-trimethoxybenzylidene)thiazolidin-4-one (9).1H NMR (CDCl3, 500 MHz) δ 7.65 (s, 1H, vinyl H), 7.46 (d, 2H, J = 7.0 Hz, 2-H, 6-H), 7.33–7.25 (m, 3H, 3-H, 4-H, 5-H), 6.70 (s, 2H, 2′-H, 6′-H), 5.32 (s, 2H, benzyl H2), 3.92 (s, 3H, OCH3), 3.91 (s, 6H, 2 × OCH3); 13C NMR (CDCl3, 125 MHz) δ 192.9, 167.7, 153.7, 140.6, 134.8, 133.6, 129.0, 128.7, 128.6, 128.2, 121.8, 107.9, 61.1, 56.3, 47.6; LR-MS (ESI+) m/z 402 (M + H)+, 424 (M + Na)+; yield, 78% molecular formula, C20H19NO4S2; melting point, 108–110 °C; copper-colored solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.78.
- (Z)-3-Benzyl-5-(4-hydroxy-3,5-dimethoxybenzylidene)-2-thioxothiazolidin-4-one (10).1H NMR (CDCl3, 500 MHz) δ 7.63 (s, 1H, vinyl H), 7.46 (d, 2H, J = 7.0 Hz, 2-H, 6-H), 7.33–7.25 (m, 3H, 3-H, 4-H, 5-H), 6.71 (s, 2H, 2′-H, 6′-H), 5.96 (s, 1H, OH), 5.31 (s, 2H, benzyl H2), 3.94 (s, 6H, 2 × OCH3); 13C NMR (CDCl3, 125 MHz) δ 192.9, 167.8, 147.5, 137.9, 134.9, 134.0, 128.9, 128.6, 128.1, 124.9, 120.1, 107.8, 56.5, 47.5; LR-MS (ESI+) m/z 388 (M + H)+, 410 (M + Na)+; LR-MS (ESI−) m/z 386 (M − H)−; yield, 92%; molecular formula, C19H17NO4S2; melting point, 151–153 °C; copper-colored solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.68.
- (Z)-3-Benzyl-5-(3-bromo-4-hydroxybenzylidene)-2-thioxothiazolidin-4-one (11).1H NMR (CDCl3, 500 MHz) δ 7.62 (s, 1H, 2′-H), 7.60 (s, 1H, vinyl H), 7.46 (d, 2H, J = 7.0 Hz, 2-H, 6-H), 7.37 (d, 1H, J = 8.5 Hz, 6′-H), 7.33–7.27 (m, 3H, 3-H, 4-H, 5-H), 7.11 (d, 1H, J = 8.5 Hz, 5′-H), 5.93 (brs, 1H, OH), 5.32 (s, 2H, benzyl H2); 13C NMR (CDCl3, 125 MHz) δ 192.6, 167.8, 154.4, 134.8, 134.5, 131.9, 131.4, 129.0, 128.6, 128.2, 127.6, 121.8, 117.0, 111.4, 47.6; LR-MS (ESI−) m/z 404 (M − H)−, 406 (M − H + 2)−; yield, 47%; molecular formula, C17H12BrNO2S2; melting point, 154–156 °C; yellow solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.34.
- (Z)-3-Benzyl-5-(3,5-dibromo-4-hydroxybenzylidene)-2-thioxothiazolidin-4-one (12).1H NMR (DMSO-d6, 500 MHz) δ 10.95 (brs, 1H, OH), 7.81 (s, 2H, 2′-H, 6′-H), 7.74 (s, 1H, vinyl H), 7.36–7.26 (m, 5H, Ph), 5.23 (s, 2H, benzyl H2); 13C NMR (DMSO-d6, 125 MHz) δ 193.1, 167.2, 153.7, 135.3, 134.8, 131.3 (2 × C), 129.0, 128.1, 127.8, 121.8, 112.9, 47.6; LR-MS (ESI−) m/z 482 (M − H)−, 484 (M − H + 2)−, 486 (M − H + 4)−; yield, 80%; molecular formula, C17H11Br2NO2S2; melting point, 179–181 °C; copper-colored solid; Rf (hexane:ethyl acetate = 3:1 on silica gel TLC) = 0.26.
3.2. Mushroom Tyrosinase Inhibition Assay [36,37]
3.3. Kinetic Experiment in the Presence of (Z)-BBTT Analogs 1–3 and 6 Using Mushroom Tyrosinase [38,39,40]
3.4. Docking Simulation of Mushroom Tyrosinase and (Z)-BBTT Analogs 1–3 and 6 [41,42]
3.5. Cell Culture [42,43]
3.6. Cytotoxicity Assay on B16F10 Murine Melanoma Cells [44]
3.7. Cellular Melanin Level Measurement in the Presence of (Z)-BBTT Analogs 1 and 3 in B16F10 Cells [44]
3.8. Cellular Tyrosinase Activity Measurement in the Presence of (Z)-BBTT Analogs 1 and 3 in B16F10 Cells [44]
3.9. Measurement of In Situ Cellular Tyrosinase Activity in B16F10 Cells [44,45]
3.10. ABTS•+ Scavenging Activity [46,47]
3.11. DPPH Radical-Scavenging Activity [48,49]
3.12. ROS-Scavenging Activity [50,51]
3.13. Cytotoxicity Assay on HaCaT Cells [42]
3.14. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | R | IC50 (μM) | |
---|---|---|---|
l-Tyrosine | l-Dopa | ||
a Kojic acid | 19.22 ± 1.29 | 26.54 ± 0.17 | |
1 | 4-Hydroxy | 4.69 ± 0.58 | 38.10 ± 2.26 |
2 | 3,4-Dihydroxy | 5.75 ± 0.81 | 27.47 ± 1.84 |
3 | 2,4-Dihydroxy | 0.09 ± 0.01 | 0.27 ± 0.04 |
4 | 4-Hydroxy-3-methoxy | 45.52 ± 2.49 | 121.24 ± 4.90 |
5 | 3-Hydroxy-4-methoxy | 39.01 ± 2.15 | 91.01 ± 8.55 |
6 | 4-Methoxy | 19.11 ± 2.03 | 33.54 ± 0.30 |
7 | 3,4-Dimethoxy | 56.19 ± 1.98 | 70.64 ± 1.25 |
8 | 2,4-Dimethoxy | 18.57 ± 1.23 | 51.14 ± 2.05 |
9 | 3,4,5-Trimethoxy | >200 | 97.23 ± 7.73 |
10 | 4-Hydroxy-3,5-dimethoxy | >200 | >200 |
11 | 3-Bromo-4-hydroxy | 66.26 ± 2.11 | 114.88 ± 2.28 |
12 | 3,5-Dibromo-4-hydroxy | >200 | >200 |
Substitution | a Tyrosinase Inhibition |
---|---|
R2 = OH | ↑↑↑↑ when R4 = OH |
R3 = OH | ↓↓ when R4 = OMe |
↑ when R4 = OH | |
R4 | OH > MeO in the presence of l-tyrosine |
OH ≈ MeO in the presence of l-dopa |
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Park, H.S.; Jung, H.J.; Park, H.S.; Kim, H.J.; Park, Y.; Chun, P.; Chung, H.Y.; Moon, H.R. Design, Synthesis, and Anti-Tyrosinase, Anti-Melanogenic, and Antioxidant Activities of Novel (Z)-3-Benzyl-5-Benzylidene-2-Thioxothiazolidin-4-One Analogs. Molecules 2025, 30, 517. https://doi.org/10.3390/molecules30030517
Park HS, Jung HJ, Park HS, Kim HJ, Park Y, Chun P, Chung HY, Moon HR. Design, Synthesis, and Anti-Tyrosinase, Anti-Melanogenic, and Antioxidant Activities of Novel (Z)-3-Benzyl-5-Benzylidene-2-Thioxothiazolidin-4-One Analogs. Molecules. 2025; 30(3):517. https://doi.org/10.3390/molecules30030517
Chicago/Turabian StylePark, Hyeon Seo, Hee Jin Jung, Hye Soo Park, Hye Jin Kim, Yujin Park, Pusoon Chun, Hae Young Chung, and Hyung Ryong Moon. 2025. "Design, Synthesis, and Anti-Tyrosinase, Anti-Melanogenic, and Antioxidant Activities of Novel (Z)-3-Benzyl-5-Benzylidene-2-Thioxothiazolidin-4-One Analogs" Molecules 30, no. 3: 517. https://doi.org/10.3390/molecules30030517
APA StylePark, H. S., Jung, H. J., Park, H. S., Kim, H. J., Park, Y., Chun, P., Chung, H. Y., & Moon, H. R. (2025). Design, Synthesis, and Anti-Tyrosinase, Anti-Melanogenic, and Antioxidant Activities of Novel (Z)-3-Benzyl-5-Benzylidene-2-Thioxothiazolidin-4-One Analogs. Molecules, 30(3), 517. https://doi.org/10.3390/molecules30030517