Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Instruments
2.2. Synthetic Procedures
- (S)-2-(6-methoxynaphthalen-2-yl)-N-(phenylcarbamothioyl)propanamide (8). Yield: 28%. Light-yellow crystalline solid. Melting point: 137–139 °C. IR (ATR) νmax (cm−1): 1149.16, 1688.36, 3031.36, and 3169.36. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (3H, d, J = 6.8, CH3Nap), 3.86 (3H, s, OCH3Nap), 4.22 (1H, q, J = 6.8, CHNap), 7.15–7.84 (11H, m, ArH), 11.67 (1H, s, NHCS), and 12.43 (1H, s, CSNH) (Figure S1a). 13C NMR (100 MHz, DMSO-d6) δ ppm 18.52 (CH3Nap), 45.45 (CHNap), 55.65 (OCH3Nap), 106.20–157.76 (aromatic carbons), 176.65 (CONH), and 179.46 (NHCS) (Figure S1b). m/z = 364.8 [M + H]+, 364.06, 229.90, 184.84, 169.83, 154.05, and 152.88. MS [M + Na]+ calculated for C21H20N2O2S = 387.11377; observed = 387.11342.
- (S)-2-(6-methoxynaphthalen-2-yl)-N-(p-tolylcarbamothioyl)propanamide (9). Yield: 26%. Light-yellow crystalline solid. Melting point: 123–124 °C. IR (ATR) νmax (cm−1): 1154.72, 1682.19, 3023.16, and 3176.53. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (3H, d, J = 7.2, CH3Nap), 2.29 (3H, s, CH3), 3.87 (3H, s, OCH3Nap), 4.22 (1H, q, J = 6.8, CHNap), 7.16–7.85 (10H, m, ArH), 11.64 (1H, s, NHCS), and 12.37 (1H, s, CSNH) (Figure S2a). 13C NMR (100 MHz, DMSO-d6) δ ppm 17.45 (CH3Nap), 19.96 (CH3), 44.29 (CHNap), 54.59 (OCH3Nap), 105.14–156.69 (aromatic carbons), 175.56 (CONH), and 178.27 (NHCS) (Figure S2b). m/z = 379.1 [M + H]+, 230.07, 185.06, 169.95, 167.10, 149.98, and 108.19. MS [M + Na]+ calculated for C22H22N2O2S = 401.12942; observed = 401.12959.
- (S)-2-(6-methoxynaphthalen-2-yl)-N-(o-tolylcarbamothioyl)propanamide (10). Yield: 42%. Yellow crystalline solid. Melting point: 110–110.5 °C. IR (ATR) νmax (cm−1): 1157.26, 1686.27, 3025.90, and 3177.30. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (3H, d, J = 6.8, CH3Nap), 2.17 (3H, s, CH3), 3.86 (3H, s, OCH3Nap), 4.22 (1H, q, J = 6.8, CHNap), 7.15–7.84 (10H, m, ArH), 11.68 (1H, s, NHCS), and 12.08 (1H, s, CSNH) (Figure S3a). 13C NMR (100 MHz, DMSO-d6) δ ppm 18.02 (CH3Nap), 18.61 (CH3), 45.43 (CHNap), 55.66 (OCH3Nap), 106.22–157.77 (aromatic carbons), 176.58 (CONH), and 180.30 (NHCS) (Figure S3b). m/z = 379.2 [M + H]+, 230.13, 185.12, 170.08, 167.09, 153.11, and 150.08. MS [M + Na]+ calculated for C22H22N2O2S = 401.12942; observed = 401.12956.
- (S)-2-(6-methoxynaphthalen-2-yl)-N-((2-methoxyphenyl)carbamothioyl)propanamide (11). Yield: 38%. Light-yellow crystalline solid. Melting point: 159–160 °C. IR (ATR) νmax (cm−1): 1156.80, 1684.26, 2976.29, and 3208.73. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (3H, d, J = 6.8, CH3Nap), 3.84 (3H, s, OCH3), 3.86 (3H, s, OCH3Nap), 4.22 (1H, q, J = 6.8, CHNap), 6.94–8.49 (10H, m, ArH), 11.63 (1H, s, NHCS), and 12.71 (1H, s, CSNH) (Figure S4a). 13C NMR (100 MHz, DMSO-d6) δ ppm 18.44 (CH3Nap), 45.37 (CHNap), 55.65 (OCH3Nap), 56.47 (OCH3), 106.18–157.75 (aromatic carbons), 176.47 (CONH), and 178.24 (NHCS) (Figure S4b). m/z = 395.3 [M + H]+, 230.18, 185.19, 183.18, 170.20, 153.22, and 124.24. MS [M + Na]+ calculated for C22H22N2O3S = 417.12433; observed = 417.12460.
- (S)-N-((2-fluorophenyl)carbamothioyl)-2-(6-methoxynaphthalen-2-yl)propanamide (12). Yield: 33%. White crystalline solid. Melting point: 146–147 °C. IR (ATR) νmax (cm−1): 1144.87, 1685.51, 2937.68, and 3183.02. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (3H, d, J = 6.8, CH3Nap), 3.87 (3H, s, OCH3Nap), 4.23 (1H, q, J = 7.2, CHNap), 7.16–8.00 (10H, m, ArH), 11.85 (1H, s, NHCS), and 12.34 (1H, s, CSNH) (Figure S5a). 13C NMR (100 MHz, DMSO-d6) δ ppm 17.45 (CH3Nap), 44.37 (CHNap), 54.60 (OCH3Nap), 105.15–156.72 (aromatic carbons), 175.66 (CONH), and 179.43 (NHCS) (Figure S5b). m/z = 383.1 [M + H]+, 230.14, 185.10, 171.07, 169.13, 153.11, and 152.06. MS [M + Na]+ calculated for C21H19FN2O2S = 405.10435; observed = 405.10465.
- Methyl (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)carbamothioyl)phenylalaninate (13). Yield: 30%. White crystalline solid. Melting point: 58–60 °C. IR (ATR) νmax (cm−1): 1173.47, 1693.18, 1742.27, 2933.81, and 3183.77. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (3H, d, J = 6.8, CH3Nap), 3.15 (2H, dd, J = 5.6, J = 10, CH2-Phe), 3.64 (3H, s, R-C(=O)OCH3), 3.86 (3H, s, OCH3Nap), 4.10 (1H, q, J = 6.4, CHNap), 5.05 (1H, q, J = 6.4, CH-Phe), 7.05–7.82 (11H, m, ArH), 10.97 (1H, s, NHCS), and 11.59 (1H, s, CSNH) (Figure S6a). 13C NMR (100 MHz, DMSO-d6) δ ppm 18.61 (CH3Nap), 36.63 (CH2-Phe), 45.39 (CHNap), 52.73 (R-C(=O)OCH3), 55.66 (OCH3Nap), 58.95 (CH-Phe), 106.21–157.75 (aromatic carbons), 170.79 (R-C(=O)OCH2CH3), 176.50 (CONH), and 180.82 (NHCS) (Figure S6b). m/z = 451.1 [M + H]+, 419.11, 391.28, 185.06, 180.16, 169.90, and 153.19. MS [M + Na]+ calculated for C25H26N2O4S = 473.15055; observed = 473.15096.
- Methyl (((S)-2-(6-methoxynaphthalen-2-yl)propanoyl)carbamothioyl)tryptophanate (14). Yield: 32%. White crystalline solid. Melting point: 91–93 °C. IR (ATR) νmax (cm−1): 1154.16, 1683.78, 1740.19, 3017.40, and 3190.00. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (3H, d, J = 6.8, CH3Nap), 3.16 (2H, dd, J = 4.0, J = 12, CH2-Trp), 3.63 (3H, s, R-C(=O)OCH3), 3.88 (3H, s, OCH3Nap), 4.12 (1H, q, J = 6.8, CHNap), 5.10 (1H, q, J = 6, CH-Trp), 6.69–7.82 (11H, m, ArH), 10.94 (1H, s, NHCS), 11.00 (1H, s, NH-Trp), and 11.58 (1H, s, CSNH) (Figure S7a). 13C NMR (100 MHz, DMSO-d6) δ ppm 17.54 (CH3Nap), 25.91 (CH2-Trp), 44.28 (CHNap), 51.64 (R-C(=O)OCH3), 54.61 (OCH3Nap), 57.82 (CH-Trp), 105.14–156.68 (aromatic carbons), 170.12 (R-C(=O)OCH3), 175.33 (CONH), and 179.65 (NHCS) (Figure S7b). m/z = 490.2 [M + H]+, 329.12, 261.06, 202.09, 185.10, 170.09, and 160.11. MS [M + Na]+ calculated for C27H27N3O4S = 512.16145; observed = 512.16195.
2.3. In Vivo Studies in Wistar Albino Rats: Toxicity and Anti-Inflammatory Potential
2.3.1. Acute Oral Toxicity Assessment
2.3.2. Assessment of In Vivo Anti-Inflammatory Potential
2.4. Investigation of COX-2 and 5-LOX Inhibitory Activity
2.5. In Vitro Cytotoxicity Studies
2.5.1. Cell Cultures
2.5.2. MTT Assay
2.5.3. Annexin V/7AAD Assay
2.5.4. Cell Cycle Analysis
2.5.5. Assessment of Apoptosis
2.5.6. Statistical Analysis
3. Results and Discussion
3.1. General Procedure for the Synthesis of Thiourea Derivatives of Naproxen
3.2. Acute Oral Toxicity Assessment
3.3. In Vivo Assessment of the Anti-Inflammatory Potential of Novel Compounds 8–14
3.4. Investigation of COX-2 and 5-LOX Enzyme Inhibitory Properties
3.5. In Vitro Cytotoxicity Studies
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 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | Control Group |
---|---|---|---|---|---|---|---|---|
Organ | ||||||||
Kidney | 0.32 ± 0.02 | 0.29 ± 0.03 | 0.31 ± 0.04 | 0.33 ± 0.05 | 0.32 ± 0.04 | 0.28 ± 0.06 | 0.29 ± 0.04 | 0.35 ± 0.02 |
Heart | 0.31 ± 0.01 | 0.29 ± 0.03 | 0.34 ±0.04 | 0.32 ± 0.02 | 0.35 ± 0.03 | 0.30 ± 0.04 | 0.31 ± 0.02 | 0.32 ± 0.01 |
Liver | 2.65 ± 0.15 | 3.01 ± 0.27 | 2.67 ± 0.15 | 2.83 ± 0.20 | 2.76 ± 0.36 | 3.09 ± 0.27 | 2.03 ± 0.42 | 2.84 ± 0.09 |
Stomach | 0.51 ± 0.06 | 0.56 ± 0.03 | 0.58 ± 0.04 | 0.54 ± 0.05 | 0.59 ± 0.05 | 0.50 ± 0.06 | 0.53 ± 0.04 | 0.55 ± 0.03 |
Rat Paw Thickness (mm) (% of Inhibition) | |||||
---|---|---|---|---|---|
Experimental Groups | 0 h | 1 h | 2 h | 3 h | 4 h |
Compound 8 2.5 mg/kg | 3.70 ± 0.44 | 5.67 ± 0.15 (19.728%) | 5.43 ± 0.15 (21.212%) | 5.07 ± 0.21 (26.126%) | 4.53 ± 0.50 (44.444%) * |
Compound 8 5.0 mg/kg | 4.13 ± 0.31 | 6.0 ± 0.36 (23.810%) * | 5.8 ± 0.44 (24.242%) | 5.40 ± 0.44 (31.532%) | 4.96 ± 0.35 (44.889%) * |
Compound 8 10.0 mg/kg | 4.27 ± 0.15 | 6.0 ± 0.40 (29.252%) * | 5.60 ± 0.44 (39.394%) * | 5.27 ± 0.38 (45.946%) * | 5.07 ± 0.21 (46.667%) * |
Compound 9 2.5 mg/kg | 4.77 ± 0.15 | 6.60 ± 0.10 (25.170%) * | 6.33 ± 0.06 (28.788%) * | 5.97 ± 0.06 (35.135%) | 5.70 ± 0.26 (37.778%) |
Compound 9 5.0 mg/kg | 4.63 ± 0.29 | 6.53 ± 0.32 (22.449%) | 6.23 ± 0.23 (27.273%) | 5.90 ± 0.17 (31.532%) | 5.50 ± 0.36 (42.222%) * |
Compound 9 10.0 mg/kg | 4.30 ± 0.20 | 6.20 ± 0.17 (22.449%) * | 5.83 ± 0.29 (30.303%) * | 5.33 ± 0.15 (44.144%) * | 5.05 ± 0.09 (50.000%) * |
Compound 10 2.5 mg/kg | 4.17 ± 0.60 | 6.17 ± 0.51 (18.367%) | 6.07 ± 0.83 (13.636%) | 5.77 ± 0.85 (13.514%) | 5.17 ± 0.75 (33.333%) |
Compound 10 5.0 mg/kg | 4.73 ± 0.15 | 6.47 ± 0.51 (29.252%) | 6.13 ± 0.47 (36.364%) * | 5.77 ± 0.32 (44.144%) * | 5.67 ± 0.40 (37.778%) |
Compound 10 10.0 mg/kg | 4.23 ± 0.38 | 6.20 ± 0.36 (19.728%) | 5.93 ± 0.31 (22.727%) | 5.70 ± 0.44 (20.721%) | 5.20 ± 0.44 (35.556%) |
Compound 11 2.5 mg/kg | 5.40 ± 0.80 | 7.30 ± 0.60 (22.449%) | 6.97 ± 0.67 (28.788%) * | 6.67 ± 0.80 (31.532%) | 6.50 ± 0.80 (26.667%) |
Compound 11 5.0 mg/kg | 5.07 ± 0.32 | 6.97 ± 0.12 (22.449%) | 6.73 ± 0.15 (24.242%) | 6.27 ± 0.23 (35.135%) | 6.07 ± 0.15 (33.333%) |
Compound 11 10.0 mg/kg | 5.13 ± 0.32 | 7.33 ± 0.06 (10.204%) | 6.93 ± 0.12 (18.182%) | 6.63 ± 0.15 (18.919%) | 6.17 ± 0.31 (31.111%) |
Compound 12 2.5 mg/kg | 4.60 ± 0.36 | 6.83 ± 0.38 (8.844%) | 6.43 ± 0.40 (16.667%) | 6.00 ± 0.30 (24.324%) | 5.53 ± 0.06 (37.778%) |
Compound 12 5.0 mg/kg | 4.07 ± 0.06 | 6.07 ± 0.64 (18.367%) | 5.83 ± 0.49 (19.697%) | 5.57 ± 0.38 (18.919%) | 5.03 ± 0.12 (35.556%) |
Compound 12 10.0 mg/kg | 4.37 ± 0.38 | 6.33 ± 0.21 (19.728%) | 6.03 ± 0.06 (24.242%) | 5.60 ± 0.10 (33.333%) | 5.17 ± 0.21 (46.667%) * |
Compound 13 2.5 mg/kg | 4.70 ± 0.17 | 7.0 ± 0.10 (6.122%) | 6.60 ± 0.10 (13.636%) | 6.13 ± 0.12 (22.523%) | 5.83 ± 0.06 (24.444%) |
Compound 13 5.0 mg/kg | 4.43 ± 0.31 | 6.90 ± 0.10 (−0.680%) | 6.43 ± 0.32 (9.091%) | 5.90 ± 0.36 (20.721%) | 5.47 ± 0.23 (31.111%) |
Compound 13 10.0 mg/kg | 4.80 ± 0.36 | 6.77 ± 0.42 (19.728%) | 6.40 ± 0.36 (27.273%) * | 6.10 ± 0.36 (29.730%) | 5.80 ± 0.30 (33.333%) |
Compound 14 2.5 mg/kg | 4.40 ± 0.53 | 6.53 ± 0.42 (12.925%) | 6.23 ± 0.25 (16.667%) | 5.90 ± 0.26 (18.919%) | 5.33 ± 0.49 (37.778%) |
Compound 14 5.0 mg/kg | 4.93 ± 0.12 | 6.77 ± 0.38 (25.170%) | 6.53 ± 0.42 (27.273%) | 6.17 ± 0.25 (33.333%) | 5.80 ± 0.10 (42.222%) * |
Compound 14 10.0 mg/kg | 4.87 ± 0.25 | 7.03 ± 0.21 (11.565%) | 6.47 ± 0.06 (27.273%) * | 6.03 ± 0.25 (36.937%) | 5.67 ± 0.21 (46.667%) * |
1% DMSO | 4.50 ± 0.09 | 6.95 ± 0.35 | 6.70 ± 0.32 | 6.35 ± 0.43 | 6.00 ± 0.32 |
Naproxen 2.5 mg/kg | 4.38 ± 0.45 | 6.35 ± 0.15 (19.728%) | 6.02 ± 0.15 (25.758%) | 5.75 ± 0.20 (26.126%) | 5.18 ± 0.20 (46.667%) * |
Naproxen 5.0 mg/kg | 4.25 ± 0.15 | 6.02 ± 0.20 (27.891%) * | 5.52 ± 0.30 (42.424%) * | 5.22 ± 0.30 (47.748%) * | 4.98 ± 0.24 (51.111%) * |
Naproxen 10.0 mg/kg | 4.32 ± 0.32 | 5.88 ± 0.23 (36.054%) * | 5.55 ± 0.45 (43.939%) * | 5.35 ± 0.32 (45.946%) * | 4.95 ± 0.35 (57.778%) * |
Compound | COX-2 Percent of Inhibition | 5-LOX Percent of Inhibition |
---|---|---|
8 | 36.23 ± 16.45 | 34.63 ± 5.84 |
9 | 26.84 ± 6.07 | 12.94 ± 5.47 |
10 | 12.64 ± 4.99 | 27.92 ± 0.57 |
11 | 16.18 ± 13.72 | 31.24 ± 5.45 |
12 | 13.82 ± 6.41 | 29.72 ± 8.56 |
13 | 23.12 ± 9.83 | 19.84 ± 13.22 |
14 | 29.80 ± 12.12 | 46.24 ± 0.40 |
IC50 (µM) | MDA-MB-231 | HeLa | ||||
---|---|---|---|---|---|---|
Compound | 24 h | 48 h | 72 h | 24 h | 48 h | 72 h |
Compound 1 | >200 | >200 | >200 | >200 | >200 | 104 ± 8 |
Compound 2 | >200 | >200 | 130.5 ± 10.4 | >200 | >200 | >200 |
Compound 3 | >200 | >200 | >200 | >200 | 120.5 ± 9.3 | 11.7 ± 4.3 |
Compound 4 | >200 | >200 | 110.2 ± 12.9 | >200 | 100.9 ± 12.2 | 90.8 ± 8.3 |
Compound 5 | >200 | >200 | 120.3 ± 14.8 | >200 | 160 ± 13 | 107 ± 10 |
Compound 6 | >200 | >200 | >200 | >200 | >200 | >200 |
Compound 7 | >200 | >200 | >200 | >200 | >200 | >200 |
Compound 8 | >200 | >200 | >200 | >140.5 ± 7.2 | 97.6 ± 10.9 | 9.1 ± 2.5 |
Compound 9 | >200 | >200 | 111.7 ± 18.1 | >200 | >200 | 120.4 ± 8.7 |
Compound 10 | 100.9 ± 11.2 | 70.5 ± 8.3 | 42.2 ± 9.8 | >200 | 110.7 ± 8.3 | 85.3 ± 9.1 |
Compound 11 | >200 | >200 | >200 | >200 | >200 | >200 |
Compound 12 | >200 | >200 | >200 | 135.4 ± 16.8 | 103.2 ± 9.5 | 72.8 ± 6.9 |
Compound 13 | >200 | >200 | 99.5 ± 8.2 | >200 | >200 | >200 |
Compound 14 | >200 | >200 | 117.4 ± 15.3 | >200 | 150.7 ± 14.2 | 110.1 ± 11.5 |
Naproxen | >200 | >200 | >200 | >200 | >200 | >200 |
IC50 (µM) | MRC-5 | HCT 116 | ||||
Compound | 24 h | 48 h | 72 h | 24 h | 48 h | 72 h |
Compound 1 | >200 | >200 | >200 | >200 | >200 | >200 |
Compound 2 | >200 | >200 | >200 | >200 | 110.8 ± 15.2 | 82.8 ± 10.6 |
Compound 3 | >200 | >200 | >200 | >200 | >200 | >200 |
Compound 4 | >200 | >200 | >200 | 200 | 106.4 ± 12.9 | 71.6 ± 9.9 |
Compound 5 | >200 | >200 | >200 | >200 | 157.7 ± 9.3 | 108.6 ± 14.2 |
Compound 6 | >200 | >200 | >200 | >200 | >200 | >200 |
Compound 7 | >200 | >200 | >200 | >200 | >200 | 100.4 ± 11.3 |
Compound 8 | >200 | >200 | >200 | >200 | >200 | 100.7 ± 15.5 |
Compound 9 | >200 | >200 | >200 | >200 | 105.2 ± 14.8 | 52.9 ± 8.1 |
Compound 10 | >200 | >200 | >200 | 120.4 ± 8.8 | 97.2 ± 6.8 | 33.3 ± 5.5 |
Compound 11 | >200 | >200 | >200 | >200 | >200 | >200 |
Compound 12 | >200 | >200 | >200 | >200 | 159.3 ± 17.5 | 68.8 ± 9.5 |
Compound 13 | >200 | >200 | >200 | >200 | >200 | 99.6 ± 4.9 |
Compound 14 | >200 | >200 | >200 | 150.2 ± 7.6 | 107.5 ± 12.7 | 47.1 ± 5.4 |
Naproxen | >200 | >200 | >200 | >200 | >200 | >200 |
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Nedeljković, N.; Nikolić, M.; Čanović, P.; Zarić, M.; Živković Zarić, R.; Bošković, J.; Vesović, M.; Bradić, J.; Anđić, M.; Kočović, A.; et al. Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen. Pharmaceutics 2024, 16, 1. https://doi.org/10.3390/pharmaceutics16010001
Nedeljković N, Nikolić M, Čanović P, Zarić M, Živković Zarić R, Bošković J, Vesović M, Bradić J, Anđić M, Kočović A, et al. Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen. Pharmaceutics. 2024; 16(1):1. https://doi.org/10.3390/pharmaceutics16010001
Chicago/Turabian StyleNedeljković, Nikola, Miloš Nikolić, Petar Čanović, Milan Zarić, Radica Živković Zarić, Jelena Bošković, Marina Vesović, Jovana Bradić, Marijana Anđić, Aleksandar Kočović, and et al. 2024. "Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen" Pharmaceutics 16, no. 1: 1. https://doi.org/10.3390/pharmaceutics16010001