Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Evaluation of Biological Activities
2.2.1. Luciferase Reporter and MTT Analysis
2.2.2. Western Blot Analysis
2.2.3. Anti-Inflammatory Activity
2.3. Prediction of ADMET Properties
3. Materials and Methods
3.1. Experimental Compounds
3.1.1. General Procedures
3.1.2. Procedure for the Synthesis of the Mollugin 2
3.1.3. General Procedure for the Synthesis of the Intermediate 3a–i
3.1.4. General Procedure for the Synthesis of the Intermediate 5a–k
3.1.5. General Procedure for the Synthesis of the Intermediate 7a–b
3.1.6. General Procedure for the Preparation of Target Compounds 4a–i
Methyl 2,2-dimethyl-6-(2-oxo-2-(phenylamino)ethoxy)-2H-benzo [h] chromene-5-carboxyate (4a)
Methyl 6-(2-((4-chlorophenyl)amino)-2-oxoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (4b)
Methyl 6-(2-((4-bromophenyl)amino)-2-oxoethoxy)-2,2-dimethyl-2H-Benzo [h] chromene-5-carboxylate (4c)
Methyl 6-(2-((4-methoxyphenyl)amino)-2-oxoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (4d)
Methyl 2,2-dimethyl-6-(2-oxo-2-(p-tolylamino)ethoxy)-2H-benzo [h] chromene-5-carboxylate (4e)
Methyl 6-(2-((4-fluorophenyl)amino)-2-oxoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (4f)
Methyl 2,2-dimethyl-6-(2-oxo-2-(o-tolylamino)ethoxy)-2H-Benzo [h] chromene-5-carboxylate (4g)
Methyl 2,2-dimethyl-6-(2-oxo-2-(m-tolylamino)ethoxy)-2H-benzo [h] chromene-5-carboxylate (4h)
Methyl 6-(2-((4-(cyanomethyl)phenyl)amino)-2-oxoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (4i)
3.1.7. General Procedure for the Preparation of Target Compounds 6a–k
Methyl 6-(2-((1-benzylpiperidin-4-yl)amino)-2-oxoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (6a)
Methyl 2,2-dimethyl-6-(2-((3-methylpyridin-4-yl)amino)-2-oxoethoxy)-2H-benzo [h] chromene-5-carboxylate (6b)
Methyl 6-(2-((4-chlorobenzyl)amino)-2-oxoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (6c)
Methyl 2,2-dimethyl-6-(2-oxo-2-(quinolin-6-ylamino)ethoxy)-2H-benzo [h] Chromene-5-carboxylate (6d)
Methyl 2,2-dimethyl-6-(2-oxo-2-(pyridin-4-ylamino)ethoxy)-2H-benzo [h] chromene-5-carboxylate (6e)
Methyl 6-(2-(cyclopropylamino)-2-oxoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (6f)
Methyl 6-(2-(benzhydrylamino)-2-oxoethoxy)-2,2-Dimethyl-2H-benzo [h] chromene-5-carboxylate (6g)
Methyl 2,2-dimethyl-6-(2-oxo-2-(pyrazin-2-ylamino)ethoxy)-2H-benzo [h] chromene-5-carboxylate (6h)
Methyl 2,2-dimethyl-6-(2-((6-methylpyridin-3-yl)amino)-2-oxoethoxy)-2H-benzo [h] chromene-5-carboxylate (6i)
Methyl 2,2-dimethyl-6-(2-oxo-2-(quinolin-8-ylamino)ethoxy)-2H-benzo [h] chromene-5-carboxylate (6j)
Methyl 2,2-dimethyl-6-(2-oxo-2-(quinolin-2-ylamino)ethoxy)-2H-benzo [h] chromene-5-carboxylate (6k)
3.1.8. General Procedure for the Preparation of Target Compounds 8a–c
Methyl 6-(2-bromoethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (8a)
Methyl 2,2-dimethyl-6-(2-(phenylamino)ethoxy)-2H-benzo[h]chromene-5-carboxylate (8b)
Methyl6-(2-((4-fluorophenyl)amino)ethoxy)-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate (8c)
3.2. Biological Evaluation
3.2.1. Cell Culture
3.2.2. Antibodies and Reagents
3.2.3. Plasmids, Transfections, and Luciferase Reporter Assay
3.2.4. Measurement of Cell Viability by MTT Assay
3.2.5. Western Blot Assay
3.3. Animals
Evaluation of Anti-Inflammatory Activity in Vivo
3.4. Prediction of ADMET Properties
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Compound | IC50 (μM) | |
---|---|---|
NF-κB a | Cytotoxicity b | |
Mollugin | >100 | >100 |
4a | >100 | >100 |
4b | >100 | >100 |
4c | >100 | >100 |
4d | 88.25 | >100 |
4e | 55.12 | >100 |
4f | 18.53 | >100 |
4g | >100 | >100 |
4h | >100 | >100 |
4i | 22.93 | >100 |
Compound | IC50 (μM) | |
---|---|---|
NF-κB a | Cytotoxicity b | |
6a | 49.28 | >100 |
6b | 41.91 | >100 |
6c | 23.09 | >100 |
6d | 3.81 | >100 |
6e | >100 | >100 |
6f | >100 | >100 |
6g | >100 | >100 |
6h | 4.93 | >100 |
6i | >100 | >100 |
6j | 18.57 | >100 |
6k | >100 | >100 |
Compound | IC50 (μM) | |
---|---|---|
NF-κB a | Cytotoxicity b | |
8a | >100 | >100 |
8b | >100 | >100 |
8c | >100 | >100 |
Dose (mg/kg) | Number of Mice | Edema Mean ± SD (mg) | Inhibition Rate (%) | |
---|---|---|---|---|
DMSO | 100 | 6 | 6.5333 ± 0.1795 | - |
ibuprfen | 100 | 6 | 3.3167 ± 0.5550 *** | 49.75 |
mesalazine | 100 | 6 | 3.2167 ± 1.1067 *** | 51.26 |
mollugin | 100 | 6 | 3.0333 ± 0.9655 *** | 54.04 |
4a | 100 | 6 | 4.0500 ± 0.6188 *** | 38.64 |
4b | 100 | 6 | 2.9167 ± 0.8029 *** | 55.81 |
4c | 100 | 6 | 3.3500 ± 1.0579 *** | 49.24 |
4d | 100 | 6 | 2.5167 ± 0.6890 *** | 61.87 |
4e | 100 | 6 | 3.8667 ± 1.2023 *** | 41.41 |
4f | 100 | 6 | 1.1167 ± 0.2544 *** | 83.08 |
4g | 100 | 6 | 3.8000 ± 0.5066 *** | 42.42 |
4h | 100 | 6 | 2.4833 ± 1.5464 *** | 62.37 |
4i | 100 | 6 | 2.7000 ± 0.4619 *** | 59.09 |
6a | 100 | 6 | 2.8667 ± 1.2645 *** | 56.57 |
6b | 100 | 6 | 2.4333 ± 0.1795 *** | 63.13 |
6c | 100 | 6 | 1.7667 ± 0.3037 *** | 73.23 |
6d | 100 | 6 | 3.1000 ± 0.4899 *** | 76.77 |
6e | 100 | 6 | 2.2500 ± 0.3403 *** | 65.91 |
6f | 100 | 6 | 2.8167 ± 0.6962 *** | 57.32 |
6g | 100 | 6 | 2.7333 ± 0.4819 *** | 58.59 |
6h | 100 | 6 | 1.8000 ± 0.6880 *** | 72.73 |
6i | 100 | 6 | 3.7667 ± 1.1571 *** | 42.93 |
6j | 100 | 6 | 1.6333 ± 0.4384 *** | 75.25 |
6k | 100 | 6 | 2.1833 ± 0.6414 *** | 66.92 |
8a | 100 | 6 | 2.8167 ± 0.9370 *** | 57.32 |
8b | 100 | 6 | 1.5500 ± 0.3594 *** | 76.52 |
8c | 100 | 6 | 2.3833 ± 0.7104 *** | 63.89 |
Time (h) | Dose (mg/kg) | Number of Mice | Inhibition(%) | ||
---|---|---|---|---|---|
4f | 6d | Ibuprfen | |||
1 | 100 | 6 | 27.53% *** | 25.76% *** | 22.98% *** |
2 | 100 | 6 | 37.12% *** | 33.84% *** | 33.33% *** |
3 | 100 | 6 | 46.46% *** | 41.92% *** | 44.95% *** |
4 | 100 | 6 | 58.08% *** | 52.53% *** | 47.47% *** |
6 | 100 | 6 | 77.78% *** | 67.68% *** | 44.44% *** |
9 | 100 | 6 | 43.94% *** | 37.63% *** | 34.60% *** |
12 | 100 | 6 | 35.35% *** | 31.82% *** | 19.95% ** |
24 | 100 | 6 | 26.01% *** | 25.25% *** | 14.65% * |
Time (h) | Dose (mg/kg) | Number of Mice | Inhibition(%) | ||
---|---|---|---|---|---|
4f | 6d | Ibuprfen | |||
6 | 100 | 6 | 74.32% *** | 62.39% *** | 43.32% *** |
6 | 50 | 6 | 53.08% *** | 46.32% *** | 32.68% ** |
6 | 25 | 6 | 46.46% ** | 41.92% ** | 28.95% * |
Compound | Absorption a | AS b | BBB c | CYP2D6 d | PPB e |
---|---|---|---|---|---|
4f | 0 | −5.805 | 2 | FALSE | TRUE |
6d | 0 | −6.028 | 2 | FALSE | TRUE |
mollugin | 0 | −4.383 | 2 | FALSE | TRUE |
Compound | R | Yield |
---|---|---|
Mollugin | — | — |
4a | H | 62% |
4b | 4-Cl | 70% |
4c | 4-Br | 65% |
4d | 4-OCH3 | 70% |
4e | 4-CH3 | 51% |
4f | 4-F | 55% |
4g | 2-CH3 | 67% |
4h | 3-CH3 | 72% |
4i | 4-CH2CN | 69% |
6a | 53% | |
6b | 57% | |
6c | 64% | |
6d | 60% | |
6e | 58% | |
6f | 72% | |
6g | 74% | |
6h | 64% | |
6i | 56% | |
6j | 48% | |
6k | 54% | |
8a | Br | 80% |
8b | C6H5NH- | 77% |
8c | 4-FC6H5NH- | 69% |
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Zhang, L.-H.; Li, M.-Y.; Wang, D.-Y.; Jin, X.-J.; Chen, F.-E.; Piao, H.-R. Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives. Molecules 2022, 27, 7925. https://doi.org/10.3390/molecules27227925
Zhang L-H, Li M-Y, Wang D-Y, Jin X-J, Chen F-E, Piao H-R. Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives. Molecules. 2022; 27(22):7925. https://doi.org/10.3390/molecules27227925
Chicago/Turabian StyleZhang, Lin-Hao, Ming-Yue Li, Da-Yuan Wang, Xue-Jun Jin, Fen-Er Chen, and Hu-Ri Piao. 2022. "Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives" Molecules 27, no. 22: 7925. https://doi.org/10.3390/molecules27227925
APA StyleZhang, L. -H., Li, M. -Y., Wang, D. -Y., Jin, X. -J., Chen, F. -E., & Piao, H. -R. (2022). Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives. Molecules, 27(22), 7925. https://doi.org/10.3390/molecules27227925