Synthesis and Characterization of Celecoxib Derivatives as Possible Anti-Inflammatory, Analgesic, Antioxidant, Anticancer and Anti-HCV Agents †
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activity
2.2.1. Anti-inflammatory Activity, Carrageenan-Induced Oedema
Compounds | Dose mg/kg (per os) | Swelling in thickness (× 10−2 mm) ± SEM | |||
---|---|---|---|---|---|
(percent inhibitory activity) | |||||
90 min | 180 min | 270 min | 360 min | ||
Control | |||||
72.0 ± 6.6 | 92.0 ± 8.1 | 121.0 ± 9.8 | 129.0 ± 7.8 | ||
1a | 100 | 58.1 ± 6.6 (19.4) | 72.9 ± 11.9 (19.7) | 72.7 ± 16.7 (39.5) | 77.9 ± 11.7 ** (39.7) |
50 | 70.0 ± 6.5 (2.7) | 72.0 ± 5.1 (21.7) | 90.0 ± 9.3 * (25.6) | 100.0 ± 6.5 * (22.4) | |
200 | 54.6 ± 7.9 (25.0) | 74.2 ± 8.2 (19.3) | 117.5 ± 9.8 (2.9) | 97.4 ± 5.6 ** (24.5) | |
1d | 100 | 95.9 ± 10.2 | 100.6 ± 5.8 (18.3) | 110.7 ± 11.0 (8.5) | 88.7 ± 9.3 * (31.2) |
50 | 70.0 ± 4.7 (2.7) | 77.0 ± 2.0 (16.3) | 112.0 ± 7.3 (7.4) | 125.0 ± 5.9 (3.1) | |
200 | 45.9 ± 10.9 (36.2) | 65.3 ± 6.4 (29.0) | 98.2 ± 9.8 (19.0) | 91.0 ± 3.3 ** (29.5) | |
1e | 100 | 88.4 ± 2.6 | 83.9 ± 3.4 (8.8) | 88.7 ± 11.4 (26.7) | 83.4 ± 9.6 ** (35.4) |
50 | 47.0 ± 3.3 * (34.7) | 57.0 ± 6.2 ** (38.0) | 92.0 ± 1.2 * (23.9) | 106.0 ± 6.7(17.8) | |
200 | 76.9 ± 5.7 | 83.0 ± 6.8 | 110.5 ± 7.5 | 103.7 ± 5.2 * (19.6) | |
2c | 100 | 83.4 ± 8.7 | 90.6 ± 11.7 | 91.7 ± 16.7 (24.2) | 118.2 ± 7.1 (8.3) |
50 | 65.0 ± 6.1 (9.7) | 74.0 ± 8.8 (19.5) | 95.0 ± 10.0 (21.4) | 110.0 ± 7.1 (14.7) | |
200 | 69.5 ± 8.3 (3.4) | 75.6 ± 8.3 (17.8) | 133.2 ± 14.3 | 120.1 ± 5.3 (6.9) | |
2d | 100 | 73.2 ± 11.1 | 100.6 ± 5.8 | 98.2 ± 16.7 (21.6) | 120.9 ± 9.3 (6.3) |
50 | 47.0 ± 3.3 * (34.7) | 47.0 ± 3.7 ** (48.9) | 89.0 ± 6.5 * (26.4) | 110.0 ± 6.7 (14.7) | |
200 | 80.6 ± 9.4 | 86.0 ± 9.4 (6.5) | 121.0 ± 12..8 | 108.6 ± 5.6 (15.8) | |
Celecoxib | 25 | 57.0 ± 6.9 (20.8) | 42.0 ± 3.3 ** (54.3) | 94.0 ± 10.4 (22.3) | 103.0 ± 7.5 * (20.1) |
2.2.2. Analgesic Activity
Compounds | Writhing test (Mean ± SEM) (% inh.) | Ulcer score | Lipid peroxidation |
---|---|---|---|
(200 mg/kg) | (nmol TBARS/g wet weight) | ||
Control | 17.4 ± 3.7 | 0/5 | 387.7 ± 27.9 |
Celecoxib (25 mg/kg) | 8.0 ± 1.3 (54) * | 0/5 | 417.8 ± 23.3 |
ASA (200 mg/kg) | 4.4 ± 0.9 (74.7) ** | 3/5 | 436.1 ± 17.1 |
1a | 5.6 ± 0.9 (67.8) ** | 0/5 | 387.7 ± 12.8 |
1d | 14.0 ± 3.0 (19.5) | 0/5 | 429.2 ± 23.2 |
1e | 24.0 ± 3.0 (−37.9) | 0/5 | 406.9 ± 27.0 |
2c | 11.8 ± 1.4 (32.2) | 0/5 | 330.4 ± 9.7 |
2d | 12.0 ± 2.6 (31) | 0/5 | 350.2 ± 9.9 |
2.2.3. Acute Ulcerogenesis
2.2.4. Acute Toxicity
2.2.5. Antioxidant Activity, Lipid Peroxidation in Stomach
2.2.6. Tissue Damage/Antioxidant Effects of Compound 1a in Various Tissues
Parameters | Control | Celecoxib | Comp. 1a | Control | Celecoxib | Comp. 1a |
---|---|---|---|---|---|---|
(100 mg/kg) | (200 mg/kg ) | |||||
LPO (nmol/gtissue) | 8.80 ± 0.82 | 9.56 ± 1.80 | 9.78 ± 1.30 | 15.28 ± 2.06 | 11.74 ± 2.25 | 13.72 ± 3.05 |
MPO (U/gtissue) | 0.54 ± 0.31 | 0.63 ± 0.30 | 0.50 ± 0.28 | 0.21 ± 0.01 | 0.19 ± 0.06 | 0.15 ± 0.08 |
GSH (µmol/g tissue) | 24.06 ± 4.07 | 20.58 ± 4.25 | 22.68 ± 1.20 | 21.80 ± 6.40 | 22.14 ± 1.04 | 24.58 ± 4.47 |
SOD (U/g tissue) | 18.67 ± 14.70 | 22.78 ± 14.45 | 21.15 ± 9.98 | 10.36 ± 5.22 | 13.60 ± 11.98 | 11.72 ± 5.10 |
Parameters | Control | Celecoxib | Comp. 1a | Control | Celecoxib | Comp. 1a |
---|---|---|---|---|---|---|
(100 mg/kg) | (200 mg/kg ) | |||||
LPO (nmol/g tissue) | 13.42 ± 3.43 | 11.12 ± 2.41 | 10.96 ± 2.01 | 15.18 ± 2.15 | 11.30 ± 2.52 | 12.56 ± 2.96 |
MPO (U/g tissue) | 4.97 ± 1.87 | 3.36 ± 1.57 | 3.18 ± 2.66 | 3.59 ± 1.37 | 4.75 ± 1.59 | 4.59 ± 1.01 |
GSH (µmol/g tissue) | 20.76 ± 5.60 | 22.24 ± 4.17 | 17.02 ± 5.23 | 18.77 ± 5.52 | 21.68 ± 5.56 | 18.26 ± 3.28 |
SOD (U/g tissue) | 15.09 ± 5.94 | 17.79 ± 7.47 | 20.26 ± 8.71 | 14.14 ± 8.81 | 16.83 ± 9.71 | 15.37 ± 7.33 |
Parameters | Control | Celecoxib | Comp. 1a | Control | Celecoxib | Comp. 1a |
---|---|---|---|---|---|---|
(100 mg/kg) | (200 mg/kg ) | |||||
LPO (nmol/g tissue) | 7.25 ± 0.27 | 7.12 ± 0.26 | 8.66 ± 2.23 | 8.71 ± 1.86 | 10.48 ± 2.69 | 11.04 ± 2.11 |
MPO (U/gtissue) | 0.28 ± 0.19 | 0.52 ± 0.26 | 0.27 ± 0.13 | 0.32 ± 0.10 | 0.46 ± 0.26 | 0.38 ± 0.14 |
GSH (µmol/g tissue) | 22.98 ± 2.95 | 28.06 ± 1.45 | 27.22 ± 2.41 | 26.42 ± 7.48 | 26.42 ± 3.46 | 25.16 ± 2.76 |
SOD (U/g tissue) | 20.72 ± 7.28 | 16.85 ± 5.24 | 16.56 ± 4.13 | 22.41 ± 6.42 | 19.04 ± 5.60 | 21.17 ± 4.15 |
Parameters | Control | Celecoxib | Comp. 1a | Control | Celecoxib | Comp. 1a |
---|---|---|---|---|---|---|
(100 mg/kg) | (200 mg/kg ) | |||||
LPO (nmol/g tissue) | 7.53 ± 0.58 | 8.18 ± 2.16 | 8.36 ± 2.61 | 8.42 ± 1.74 | 8.26 ± 1.01 | 9.40 ± 2.08 |
MPO (U/gtissue) | 0.33 ± 0.21 | 0.60 ± 0.23 | 0.73 ± 0.32 | 1.42 ± 0.37 | 1.48 ± 0.46 | 1.95 ± 0.60 |
GSH (µmol/g tissue) | 18.88 ± 4.13 | 22.36 ± 2.45 | 18.7 ± 5.52 | 16.26 ± 2.81 | 20.2 ± 3.26 | 18.74 ± 3.03 |
SOD (U/g tissue) | 20.84 ± 4.83 | 24.84 ± 10.65 | 19.17 ± 7.41 | 20.19 ± 4.86 | 20.41 ± 13.73 | 19.22 ± 10.76 |
2.2.7. Anticancer Activity
2.2.8. Effect on HCV NS5B Polymerase Enzyme Inhibition
Compound | Ar/R | Anti-NS5B Activity | IC50 (µM) |
---|---|---|---|
(% Inh., 100 µM) | |||
1a | -C2H5 | 49.4 | N.D. |
1b | -C6H5 | 53.5 | N.D. |
1c | -CH2C6H5 | 82.3 | 36.2 ± 1.2 |
1d | -C6H4-(4-NO2) | 68 | 45.5 ± 1.2 |
1e | -C6H4-(4-CF3) | 14.6 | N.D. |
2a | -C2H5 | 8.2 | N.D. |
2b | -C6H5 | N.D. | N.D. |
2c | -CH2C6H5 | 19.4 | N.D. |
2d | -C6H4-(4-NO2) | 31.3 | N.D. |
2e | -C6H4-(4-CF3) | 9.4 | N.D. |
Celecoxib | 9.5 |
3. Experimental
3.1. General
3.2. Chemistry
3.2.1. General Procedure for the Synthesis of N-(Substituted aryl/alkyl carbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 1a–e
3.2.2. Synthesis of N-(3-Substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 2a–e
Method I (Thermal)
Method II (Microwave Assisted Synthesis for 2d and 2e)
3.3. Biological Activities
3.3.1. Anti-inflammatory Activity, Carrageenan-Induced Oedema
3.3.2. Analgesic Activity, Koster Test
3.3.3. Gastric–Ulcerogenic Effect
3.3.4. Acute Toxicity
3.3.5. Antioxidant Activity, Lipid Peroxidation in Stomach and in Various Tissues (Liver, Kidney, Colon, Brain)
3.3.5.1. LPO and GSH Assays
3.3.5.2. MPO Assay
3.3.5.3. SOD Assay
3.3.5.4. Statistical Analysis of Data
3.3.6. Cancer Cell Growth Inhibitory Assay
3.3.7. NS5B Inhibition Assay
Molecular Modeling
4. Conclusions
Acknowledgments
References
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Küçükgüzel, Ş.G.; Coşkun, İ.; Aydın, S.; Aktay, G.; Gürsoy, Ş.; Çevik, Ö.; Özakpınar, Ö.B.; Özsavcı, D.; Şener, A.; Kaushik-Basu, N.; et al. Synthesis and Characterization of Celecoxib Derivatives as Possible Anti-Inflammatory, Analgesic, Antioxidant, Anticancer and Anti-HCV Agents. Molecules 2013, 18, 3595-3614. https://doi.org/10.3390/molecules18033595
Küçükgüzel ŞG, Coşkun İ, Aydın S, Aktay G, Gürsoy Ş, Çevik Ö, Özakpınar ÖB, Özsavcı D, Şener A, Kaushik-Basu N, et al. Synthesis and Characterization of Celecoxib Derivatives as Possible Anti-Inflammatory, Analgesic, Antioxidant, Anticancer and Anti-HCV Agents. Molecules. 2013; 18(3):3595-3614. https://doi.org/10.3390/molecules18033595
Chicago/Turabian StyleKüçükgüzel, Ş. Güniz, İnci Coşkun, Sevil Aydın, Göknur Aktay, Şule Gürsoy, Özge Çevik, Özlem Bingöl Özakpınar, Derya Özsavcı, Azize Şener, Neerja Kaushik-Basu, and et al. 2013. "Synthesis and Characterization of Celecoxib Derivatives as Possible Anti-Inflammatory, Analgesic, Antioxidant, Anticancer and Anti-HCV Agents" Molecules 18, no. 3: 3595-3614. https://doi.org/10.3390/molecules18033595