Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. In Vitro COX Inhibitory Assay
Compd. No. | COX-1 | COX-2 | SI b |
---|---|---|---|
(IC50 µM) a | (IC50 µM) a | ||
12 | 4.64 | 1.27 | 3.64 |
13 | 5.69 | 1.64 | 3.48 |
14 | 3.50 | 1.09 | 3.21 |
15 | 3.37 | 1.06 | 3.17 |
16 | 2.45 | 0.85 | 2.89 |
17 | 5.01 | 1.72 | 2.91 |
18 | 5.10 | 0.85 | 6.03 |
Indomethacin | 0.73 | 32.6 | 0.02 |
Celecoxib | 15.6 | 0.32 | 48.75 |
2.2.2. In Vivo Biological Evaluation
Anti-Inflammatory Activity
Compd. | % Inhibition in Edema Thickness | Potency a | Ulcerogenicity | |||
---|---|---|---|---|---|---|
1 h | 2 h | 3 h | UI b | % Protection c | ||
Control | - | - | - | 0 | 0 | 100 |
12 | 21.20 | 37.40 | 44.79 | 1.10 | 4.66 | 66.38 |
13 | 16.13 | 35.43 | 52.31 | 1.28 | 4.41 | 68.18 |
14 | 8.30 | 9.84 | 16.37 | 0.40 | 4.66 | 66.38 |
15 | 10.60 | 16.54 | 24.91 | 0.61 | 2.68 | 80.66 |
16 | 29.95 | 37.80 | 50.58 | 1.24 | 2.26 | 83.69 |
17 | 27.19 | 40.55 | 49.47 | 1.21 | 2.26 | 83.69 |
18 | 6.91 | 17.72 | 22.42 | 0.55 | 4.41 | 68.18 |
19 | 13.82 | 22.44 | 38.79 | 0.95 | 0 | 100 |
Ibuprofen | 25.81 | 33.46 | 40.82 | 1.00 | 13.86 | 0 |
Analgesic Activity
Acute Ulcerogenicity Studies
Histopathological Studies
2.3. Molecular Docking Study
2.3.1. Docking Study into COX-1 Enzyme
Compd. | ΔGb a (kcal/mol) | Ki b | Hydrogen Bonds between Atoms of Compounds and Amino Acids of COX-1 | RMSD c (Å) | |
---|---|---|---|---|---|
Atom of Compd. | Amino Acid | ||||
12 | −9.00 | 250.88 nM | 5-Ph-NH | OH of Tyr355 | 2.92 |
5-Ph-NHC=O | HN of Arg120 | ||||
13 | −9.34 | 142.76 nM | 7-CN | HN of Arg120 | 3.41 |
14 | −6.41 | 20.18 µM | 6-NH | OH of Tyr355 | 1.99 |
15 | −6.65 | 13.26 µM | 10-CN | HO of Tyr385 | 0.83 |
2-C=O | HO of Ser530 | ||||
2-C=O | HN of Leu531 | ||||
16 | −8.14 | 1.08 µM | 5-Ph-CONH | OH of Tyr355 | 2.27 |
17 | −10.31 | 27.77 nM | 6-NHS=O | HO of Tyr355 | 2.29 |
18 | −0.68 | 316.74 mM | 5-Ph-NHC=O | HN of Arg120 | 2.62 |
19 | −9.71 | 76.20 nM | 6-NHC=O | HN of Arg120 | 3.49 |
Ibuprofen | −9.40 | 128.86 nM | COO | H1N of Arg120 | 0.62 |
COOH | H2N of Arg120 |
2.3.2. Docking Study into COX-2 Enzyme
Compd. | ΔGb a (kcal/mol) | Ki b | Hydrogen Bonds between Atoms of Compounds and Amino Acids of COX-2 | RMSD c (Å) | |
---|---|---|---|---|---|
Atom of Compd. | Amino Acid | ||||
12 | −8.79 | 362.12 nM | 5-Ph-NH | O=C of Glu524 | 3.39 |
5-Ph-NHC=O | H1N of Arg120 | ||||
5-Ph-NHC=O | H2N of Arg120 | ||||
5-NH | OH of Tyr355 | ||||
7-CN | HN of His90 | ||||
13 | −10.01 | 46.35 nM | 5-NHC=O | H1N of Arg120 | 0.49 |
H2N of Arg120 | |||||
14 | −9.82 | 63.40 nM | -- d | 1.13 | |
15 | −8.73 | 400.2 nM | 10-CN | HO of Ser530 | 1.78 |
16 | −8.81 | 347.43 nM | 6-Ph-C=O | HN of Arg120 | 1.13 |
17 | −11.63 | 3.00 nM | 5-Ph-NH | O=C of Leu352 | 1.45 |
6-NHS=O1 | H1N of Arg120 | ||||
6-NHS=O1 | H2N of Arg120 | ||||
6-NHS=O2 | HO of Tyr355 | ||||
18 | −10.93 | 9.80 nM | 6-NH | O=C of Glu524 | 5.79 |
6-NHC=O | HO of Tyr355 | ||||
19 | −10.27 | 29.51 nM | 7-CN | HO of Ser530 | 1.59 |
S58 Ligand e | −11.49 | 3.81 nM | 3-CF | HN of Arg120 | 0.38 |
p-Ph-S=O1 | HN of His90 | ||||
p-Ph-S=O2 | HN of Arg513 | ||||
p-Ph-SONH | O=C of Phe518 |
2.3.3. Docking Study into 5-LOX Enzyme
Compd. | ΔGb a (kcal/mol) | Ki b | Hydrogen Bonds between Atoms of Compounds and Amino Acids of 5-LOX | RMSD c (Å) | |
---|---|---|---|---|---|
Atom of Compd. | Amino Acid | ||||
12 | −8.78 | 365.81 nM | 5-Ph-NH | O=C of Gln363 | 5.80 |
5-Ph-NHC=O | HO of Tyr181 | ||||
7-CN | HN of Ala424 | ||||
13 | −9.22 | 174.81 nM | 5-Ph-NH | O=C of Gln363 | 5.42 |
5-Ph-NHC=O | HO of Tyr181 | ||||
7-CN | HN of Asn425 | ||||
14 | −7.48 | 3.31 µM | 6-NH | OH of Tyr181 | 2.73 |
15 | −7.89 | 1.66 µM | 2-C=O | HO of Thr364 | 5.86 |
5-C=O | HN of His367 | ||||
16 | −11.06 | 7.78 nM | 5-Ph-NHC=O | HN of Gln363 | 2.68 |
6-NH | OH of Tyr181 | ||||
17 | −10.84 | 11.26 nM | 6-NHS=O1 | HN of Gln363 | 3.55 |
6--NHS=O2 | HN of His367 | ||||
18 | +6.69 | -- d | 5-Ph-NH | O=C of Ile673 | 4.25 |
7-CN | HN of Gln363 | ||||
19 | −12.16 | 1.23 nM | 6-NHC=O | HO of Tyr181 | 3.24 |
ACD Ligand e | −4.50 | 502.87 µM | -- d | 2.27 |
3. Experimental Section
3.1. General Information
3.2. Chemistry
3.3. Biological Evaluation
3.3.1. In Vitro COX-1/2 Inhibitory Assay
3.3.2. In Vivo Biological Evaluation
Animals
Anti-Inflammatory Activity
Analgesic Activity
Acute Ulcerogenicity Study
Histopathological Study
3.4. Molecular Docking Study
3.4.1. Preparation of the COX-1, COX-2, and 5-LOX Protein and Ligands (12–19)
3.4.2. Preparation of the Flexible Residue File
3.4.3. Calculation of Affinity Maps by Using AutoGrid
3.4.4. Defining the Docking Parameters and Running the Docking Simulation
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Gouda, A.M.; Ali, H.I.; Almalki, W.H.; Azim, M.A.; Abourehab, M.A.S.; Abdelazeem, A.H. Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability. Molecules 2016, 21, 201. https://doi.org/10.3390/molecules21020201
Gouda AM, Ali HI, Almalki WH, Azim MA, Abourehab MAS, Abdelazeem AH. Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability. Molecules. 2016; 21(2):201. https://doi.org/10.3390/molecules21020201
Chicago/Turabian StyleGouda, Ahmed M., Hamed I. Ali, Waleed H. Almalki, Mohamed A. Azim, Mohammed A. S. Abourehab, and Ahmed H. Abdelazeem. 2016. "Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability" Molecules 21, no. 2: 201. https://doi.org/10.3390/molecules21020201
APA StyleGouda, A. M., Ali, H. I., Almalki, W. H., Azim, M. A., Abourehab, M. A. S., & Abdelazeem, A. H. (2016). Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability. Molecules, 21(2), 201. https://doi.org/10.3390/molecules21020201