Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen
Abstract
1. Introduction
2. Results and Discussion
2.1. General Procedure for the Synthesis of Thiourea Derivatives of Naproxen
2.2. Acute Oral Toxicity Evaluation
2.3. Carrageenan-Induced Paw Edema and Determination of the Anti-Inflammatory Activity
2.4. Investigation of COX-2 and 5-LOX Enzyme Inhibitory Properties
2.5. Molecular Docking Simulation
2.5.1. Molecular Docking of Tested Compounds into COX-2
2.5.2. Molecular Docking of the Tested Compounds into 5-LOX
3. Materials and Methods
3.1. Chemicals and Instruments
3.2. Synthetic Procedures
3.3. Evaluation of Toxicity Profile and Anti-Inflammatory Activity in Wistar Albino Rats
3.3.1. Acute Oral Toxicity Evaluation
3.3.2. Evaluation of Anti-Inflammatory Activity in Wistar Albino Rats
3.4. Investigation of COX-2 and 5-LOX Inhibitory Activity
3.5. Molecular Docking 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 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | Control Group |
---|---|---|---|---|---|---|---|---|
Organ | ||||||||
Kidney | 0.31 ± 0.03 | 0.34 ± 0.04 | 0.32 ± 0.06 | 0.33 ± 0.07 | 0.30 ± 0.03 | 0.35 ± 0.05 | 0.29 ± 0.03 | 0.33 ± 0.01 |
Heart | 0.32 ± 0.02 | 0.33 ± 0.04 | 0.31 ± 0.03 | 0.30 ± 0.03 | 0.31 ± 0.03 | 0.34 ± 0.02 | 0.33 ± 0.03 | 0.31 ± 0.01 |
Liver | 2.73 ± 0.24 | 3.07 ± 0.38 | 2.85 ± 0.17 | 2.45 ± 0.15 | 2.97 ± 0.33 | 3.01 ± 0.29 | 2.64 ± 0.46 | 2.91 ± 0.10 |
Stomach | 0.54 ± 0.05 | 0.57 ± 0.04 | 0.50 ± 0.05 | 0.50 ± 0.05 | 0.53 ± 0.04 | 0.55 ± 0.03 | 0.50 ± 0.04 | 0.53 ± 0.04 |
Rat Paw Thickness (mm) (% of Inhibition) | |||||
---|---|---|---|---|---|
Experimental Groups | 0 h | 1 h | 2 h | 3 h | 4 h |
Compound 1 2.5 mg/kg | 4.57 ± 0.31 | 6.50 ± 0.40 (20.275%) | 6.50 ± 0.40 (11.111%) | 6.20 ± 0.30 (10.502%) | 5.53 ± 0.29 (33.333%) |
Compound 1 5.0 mg/kg | 4.40 ± 0.36 | 7.00 ± 0.10 (−7.216%) | 6.50 ± 0.17 (3.448%) | 5.8 ± 0.20 (23.288%) | 5.27 ± 0.29 (40.230%) |
Compound 1 10.0 mg/kg | 4.47 ± 0.51 | 7.03 ± 0.12 (−5.842%) | 6.60 ± 0.10 (1.916%) | 6.10 ± 0.17 (10.502%) | 5.27 ± 0.50 (44.800%) * |
Compound 2 2.5 mg/kg | 4.37 ± 0.15 | 6.57 ± 1.16 (9.278%) | 6.07 ± 0.72 (21.839%) | 5.77 ± 0.42 (23.288%) | 5.30 ± 0.26 (35.632%) |
Compound 2 5.0 mg/kg | 4.77 ± 0.21 | 7.03 ± 0.47 (6.529%) | 6.40 ± 0.53 (24.904%) | 5.70 ± 0.20 (48.858%) * | 5.53 ± 0.29 (47.126%) * |
Compound 2 10.0 mg/kg | 4.63 ± 0.06 | 6.5 ± 0.40 (23.024%) | 6.17 ± 0.67 (29.502%) | 5.53 ± 0.15 (50.685%) * | 5.33 ± 0.25 (51.724%) * |
Compound 3 2.5 mg/kg | 4.30 ± 0.28 | 6.25 ± 0.21 (19.588%) | 6.0 ± 0.57 (21.839%) | 5.50 ± 0.42 (34.247%) | 5.10 ± 0.14 (44.737%) |
Compound 3 5.0 mg/kg | 4.13 ± 0.25 | 6.40 ± 0.79 (6.529%) | 5.73 ± 0.38 (26.437%) * | 5.44 ± 0.28 (28.584%) | 4.97 ± 0.42 (42.529%) * |
Compound 3 10.0 mg/kg | 3.90 ± 0.20 | 6.23 ± 0.25 (3.780%) | 5.80 ± 0.26 (12.644%) | 5.27 ± 0.15 (25.114%) | 4.67 ± 0.38 (47.217%) * |
Compound 4 2.5 mg/kg | 4.03 ± 0.06 | 5.93 ± 0.25 (21.649%) | 5.40 ± 0.10 (37.165%) * | 5.17 ± 0.15 (37.900%) | 4.90 ± 0.10 (40.523%) * |
Compound 4 5.0 mg/kg | 4.40 ± 0.62 | 6.10 ± 0.44 (29.897%) * | 5.97 ± 0.25 (27.969%) | 5.70 ± 0.46 (28.767%) | 5.22 ± 0.50 (43.218%) * |
Compound 4 10.0 mg/kg | 4.23 ± 0.06 | 6.00 ± 0.10 (27.148%) * | 5.70 ± 0.20 (32.567%) * | 5.30 ± 0.17 (41.553%) * | 4.90 ± 0.20 (54.013%) * |
Compound 5 2.5 mg/kg | 3.57 ± 0.12 | 5.73 ± 0.12 (10.653%) | 5.37 ± 0.25 (17.241%) | 5.20 ± 0.20 (10.502%) | 4.57 ± 0.15 (31.034%) |
Compound 5 5.0 mg/kg | 3.10 ± 0.00 | 5.05 ± 0.07 (19.588%) | 4.85 ± 0.07 (19.540%) | 4.40 ± 0.14 (28.767%) | 3.95 ± 0.07 (41.379%) |
Compound 5 10.0 mg/kg | 4.00 ± 0.28 | 5.5 ± 0.71 (38.144%) * | 5.35 ± 0.64 (37.931%) * | 5.90 ± 0.71 (39.726%) | 4.75 ± 0.49 (48.276%) |
Compound 6 2.5 mg/kg | 4.03 ± 0.06 | 6.17 ± 0.31 (11.753%) | 5.87 ± 0.23 (15.709%) | 5.37 ± 0.55 (26.941%) | 4.93 ± 0.21 (37.931%) |
Compound 6 5.0 mg/kg | 4.47 ± 0.35 | 6.47 ± 0.57 (17.526%) | 6.17 ± 0.06 (21.839%) | 5.77 ± 0.06 (28.767%) | 5.27 ± 0.21 (44.724%) |
Compound 6 10.0 mg/kg | 4.30 ± 0.62 | 6.20 ± 0.20 (21.649%) | 6.17 ± 0.23 (14.176%) | 5.27 ± 0.72 (47.103%) | 5.03 ± 0.76 (49.425%) * |
Compound 7 2.5 mg/kg | 5.13 ± 0.29 | 7.03 ± 0.15 (21.649%) | 6.47 ± 0.21 (38.697%) * | 6.10 ± 0.20 (47.032%) * | 5.87 ± 0.21 (49.425%) * |
Compound 7 5.0 mg/kg | 5.27 ± 0.40 | 7.10 ± 0.17 (24.399%) | 6.80 ± 0.20 (29.502%) * | 6.43 ± 0.32 (36.073%) | 6.03 ± 0.61 (47.126%) |
Compound 7 10.0 mg/kg | 4.80 ± 0.53 | 6.87 ± 0.25 (14.777%) | 6.50 ± 0.36 (21.839%) | 6.03 ± 0.21 (32.420%) | 5.47 ± 0.38 (54.123%) * |
1% DMSO | 4.40 ± 0.08 | 6.83 ± 0.30 | 6.58 ± 0.30 | 6.23 ± 0.46 | 5.85 ± 0.31 |
Naproxen 2.5 mg/kg | 4.23 ± 0.40 | 6.20 ± 0.10 (18.900%) | 5.87 ± 0.12 (24.904%) | 5.60 ± 0.17 (25.114%) | 5.03 ± 0.25 (44.828%) |
Naproxen 5.0 mg/kg | 4.10 ± 0.10 | 5.87 ± 0.23 (27.148%) | 5.37 ± 0.31 (41.762%) | 5.07 ± 0.35 (47.083%) | 4.83 ± 0.21 (49.448%) |
Naproxen 10.0 mg/kg | 4.17 ± 0.30 | 5.73 ± 0.20 (35.395%) | 5.40 ± 0.40 (43.295%) | 5.20 ± 0.30 (45.205%) | 4.80 ± 0.40 (56.322%) |
Compound | COX-2 Percent of Inhibition | COX-2 (IC50 µM) | 5-LOX Percent of Inhibition | 5-LOX (IC50 µM) |
---|---|---|---|---|
1 | 24.73 ± 1.11 | - | 34.25 ± 1.04 | 19.16 ± 0.96 |
2 | 18.77 ± 4.37 | - | 25.12 ± 1.83 | 39.77 ± 1.98 |
3 | 23.39 ± 0.57 | - | 47.02 ± 4.32 | 9.52 ± 1.51 |
4 | 37.71 ± 0.28 | - | 77.20 ± 0.26 | 0.30 ± 0.12 |
5 | 19.58 ± 4.55 | - | 46.19 ± 4.87 | 16.74 ± 1.79 |
6 | 23.99 ± 5.36 | - | 23.63 ± 2.14 | - |
7 | 24.23 ± 5.77 | - | 20.72 ± 4.19 | - |
Naproxen | 72.15 ± 1.40 | 0.20 ± 0.02 | Not tested | Not tested |
Celecoxib | 85.02 ± 0.31 | 0.07 ± 0.01 | Not tested | Not tested |
Zileuton | Not tested | Not tested | 64.85 ± 0.39 | 0.36 ± 0.10 |
Compound | COX-2 | 5-LOX |
---|---|---|
1 | −14.40 | −7.70 |
2 | −14.90 | −7.47 |
3 | −14.13 | −6.74 |
4 | −14.94 | −8.39 |
5 | −14.42 | −7.30 |
6 | −8.76 | −7.77 |
7 | −9.41 | −7.98 |
Naproxen | −13.13 | - |
Zileuton | - | −8.77 |
NDGA | - | −10.67 |
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Nedeljković, N.; Dobričić, V.; Bošković, J.; Vesović, M.; Bradić, J.; Anđić, M.; Kočović, A.; Jeremić, N.; Novaković, J.; Jakovljević, V.; et al. Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen. Pharmaceuticals 2023, 16, 666. https://doi.org/10.3390/ph16050666
Nedeljković N, Dobričić V, Bošković J, Vesović M, Bradić J, Anđić M, Kočović A, Jeremić N, Novaković J, Jakovljević V, et al. Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen. Pharmaceuticals. 2023; 16(5):666. https://doi.org/10.3390/ph16050666
Chicago/Turabian StyleNedeljković, Nikola, Vladimir Dobričić, Jelena Bošković, Marina Vesović, Jovana Bradić, Marijana Anđić, Aleksandar Kočović, Nevena Jeremić, Jovana Novaković, Vladimir Jakovljević, and et al. 2023. "Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen" Pharmaceuticals 16, no. 5: 666. https://doi.org/10.3390/ph16050666
APA StyleNedeljković, N., Dobričić, V., Bošković, J., Vesović, M., Bradić, J., Anđić, M., Kočović, A., Jeremić, N., Novaković, J., Jakovljević, V., Vujić, Z., & Nikolić, M. (2023). Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen. Pharmaceuticals, 16(5), 666. https://doi.org/10.3390/ph16050666