Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemical Reagents, Purification, and Instrumentation
2.2. Synthesis of (3-fluorophenyl)(5-nitro-1H-indol-1-yl)methanone (2)
2.3. Synthesis of (5-amino-1H-indol-1-yl)(3-fluorophenyl)methanone (3)
2.4. General Procedure of Urea Derivatives (4a–n)
2.4.1. 1-Ethyl-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)urea (4a)
2.4.2. Ethyl ((1-(3-fluorobenzoyl)-1H-indol-5-yl)carbamoyl)glycinate (4b)
2.4.3. 1-(2-Chloroethyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)urea (4c)
2.4.4. 1-Cyclohexyl-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)urea (4d)
2.4.5. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-nitrophenyl)urea (4e)
2.4.6. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-methoxyphenyl)urea (4f)
2.4.7. 1-(3,5-Dimethoxyphenyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)urea (4g)
2.4.8. 1-(3,5-Dichlorophenyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)urea (4h)
2.4.9. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-fluorophenyl)urea (4i)
2.4.10. 1-(3,4-Dichlorophenyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)urea (4j)
2.4.11. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)urea (4k)
2.4.12. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-fluorophenethyl)urea (4l)
2.4.13. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-phenoxyphenyl)urea (4m)
2.4.14. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-morpholinophenyl)urea (4n)
2.5. General Procedure of Thiourea Derivatives (5a–j)
2.5.1. 1-Ethoxycarbonyl-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)thiourea (5a)
2.5.2. 1-(2-Chloroethyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)thiourea (5b)
2.5.3. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-morpholinophenyl)thiourea (5c)
2.5.4. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(2-morpholinoethyl)thiourea (5d)
2.5.5. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(2-(piperidin-1-yl)ethyl)thiourea (5e)
2.5.6. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(furan-2-ylmethyl)thiourea (5f)
2.5.7. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(4-nitrophenyl)thiourea (5g)
2.5.8. 1-(3,5-Dimethoxyphenyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)thiourea (5h)
2.5.9. 1-(3,4-Dichlorophenyl)-3-(1-(3-fluorobenzoyl)-1H-indol-5-yl)thiourea (5i)
2.5.10. 1-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-3-(pyridin-3-yl)thiourea (5j)
2.6. General Procedure of Amide Derivatives (6a–e)
2.6.1. N-(1-(3-Fluorobenzoyl)-1H-indol-5-yl)-2-nitroisonicotinamide (6a)
2.6.2. Ethyl (1-(3-fluorobenzoyl)-1H-indol-5-yl)carbamate (6b)
2.6.3. Ethyl 2-((1-(3-fluorobenzoyl)-1H-indol-5-yl)amino)-2-oxoacetate (6c)
2.6.4. 3,4-Dichloro-N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)benzamide (6d)
2.6.5. N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)-4-oxo-4H-chromene-3-carboxamide (6e)
2.7. Synthesis of Methyl 1H-indole-5-carboxylate (10)
2.8. General Procedure of Methyl Ester Derivatives (7a and 7b)
2.8.1. Methyl 1-(3-fluorobenzoyl)-1H-indole-5-carboxylate (7a)
2.8.2. Methyl 1-(3,4-dichlorobenzoyl)-1H-indole-5-carboxylate (7b)
2.9. General Procedure of the Free NH Indole Derivatives 8a–e
2.9.1. N-(4-iodophenyl)-1H-indole-5-carboxamide (8a)
2.9.2. N-(4-bromophenyl)-1H-indole-5-carboxamide (8b)
2.9.3. N-(3-chloro-4-fluorophenyl)-1H-indole-5-carboxamide (8c)
2.9.4. N-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-indole-5-carboxamide (8d)
2.9.5. N-(benzo[d][1,3]dioxol-5-yl)-1H-indole-5-carboxamide (8e)
2.10. MAO Assays
2.11. Kinetic Study of MAO-B Inhibition Mode
2.12. Molecular Modeling Study
2.13. In Vitro Cellular and Cell-Free Bio-Assay
2.13.1. Materials
2.13.2. PC12 Cell Culture
2.13.3. Drug Treatment
2.13.4. Measurements of Cell Viability
2.13.5. Measurement of ROS Production Using H2-DCFDA
2.13.6. Assessment of DPPH Radical Scavenging Activity
2.13.7. Statistical Analysis
3. Results and Discussion
3.1. Chemical Synthesis
3.2. Primary Screening at Single Dose of 10 µM over MAO-B
3.3. Dose-Dependent Assay over MAO-B
3.4. Selectivity Assay of Compounds 7b, 8a, 8b, and 8e over Both Isoforms of MAO
3.5. Kinetic Study to Define the Interaction Mode of Compounds 8a and 8b with MAO-B
3.6. Molecular Modeling Study
- The active N-substituted indole compound 7b has similar activity to the free (NH) indole derivatives.
- The 3,4-dichlorophenyl substituent is superior to the alkyl substitutions.
- Among the 3,4-dichlorophenyl compounds, the thiourea linker is the most active, whereas in the alkyl substituent series it is the least active.
- The active N-substituted indole and free (NH) indole compounds are highly selective towards MAO-B.
3.7. Biological Evaluation Using PC12 Cells and Cell-Free Bio-Assay
3.7.1. Assessment of the Cytotoxicity over PC12 Cells
3.7.2. Protective Effect against 6-OHDA-Induced Cytotoxicity in PC12 Cells
3.7.3. Protective Effect against Rotenone-Induced Cytotoxicity in PC12 Cells
3.7.4. Effect on 6-OHDA- or Rotenone-Induced ROS Generation in PC12 Cells
3.7.5. DPPH Radical Scavenging Activity
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Comp. | C5 Linker | R (C5 Substitution) | N1 Indole Substitution | % Inhibition of MAO-B at 10 µM |
---|---|---|---|---|
4a | 3-Fluorobenzoyl | 46.2 ± 1.1 | ||
4b | 9.9 ± 1.5 | |||
4c | 26.6 ± 0.6 | |||
4d | 44.0 ± 0.8 | |||
4e | 47.9 ± 1.6 | |||
4f | 32.5 ± 1.4 | |||
4g | 55.7 ± 0.2 | |||
4h | 38.6 ± 1.6 | |||
4i | 37.0 ± 0.9 | |||
4j | 53.5 ± 0.3 | |||
4k | 42.1 ± 1.7 | |||
4l | 42.0 ± 0.6 | |||
4m | 38.1 ± 0.5 | |||
4n | 32.9 ± 0.3 | |||
5a | 3-Fluorobenzoyl | 15.5 ± 1.1 | ||
5b | 45.6 ± 1.2 | |||
5c | 43.9 ± 1.1 | |||
5d | 46.8 ± 0.2 | |||
5e | 44.7 ± 0.5 | |||
5f | 34.1 ± 0.7 | |||
5g | 30.6 ± 0.9 | |||
5h | 32.5 ± 0.5 | |||
5i | 59.8 ± 0.4 | |||
5j | 51.1 ± 0.4 | |||
6a | 3-Fluorobenzoyl | 26.8 ± 1.3 | ||
6b | 33.8 ± 2.3 | |||
6c | 35.5 ± 1.5 | |||
6d | 53.0 ± 0.3 | |||
6e | 59.6 ± 0.3 | |||
7a | 3-Fluorobenzoyl | 49.8 ± 0.3 | ||
7b | 3,4-Dichlorobenzoyl | 84.1 ± 0.0 | ||
8a | Free NH | 99.3 ± 0.0 | ||
8b | 99.4 ± 0.0 | |||
8c | 34.2 ± 0.2 | |||
8d | 15.3 ± 0.8 | |||
8e | 89.6 ± 0.4 |
MAO-A | |||||||||
---|---|---|---|---|---|---|---|---|---|
Cpd | Inhibition% (100 µM) | S.E.M | Inhibition% (30 µM) | S.E.M | Inhibition% (10 µM) | S.E.M | MAO-A IC50 (µM) | MAO-B IC50 (µM) | Selectivity Index (SI) a |
7b | <10 | 2.789 | <10 | 1.449 | <10 | 0.334 | >100 | 0.3278 | >305 |
8a | 23.48 | 21.66 | 21.66 | 0.920 | 17.16 | 0.687 | >100 | 0.0274 | >3649 |
8b | 30.07 | 1.474 | 27.88 | 0.965 | 15.07 | 0.764 | >100 | 0.0305 | >3278 |
8e | <10 | 1.959 | <10 | 1.009 | <10 | 0.689 | >100 | 0.4532 | >220 |
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Elsherbeny, M.H.; Kim, J.; Gouda, N.A.; Gotina, L.; Cho, J.; Pae, A.N.; Lee, K.; Park, K.D.; Elkamhawy, A.; Roh, E.J. Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress. Antioxidants 2021, 10, 1641. https://doi.org/10.3390/antiox10101641
Elsherbeny MH, Kim J, Gouda NA, Gotina L, Cho J, Pae AN, Lee K, Park KD, Elkamhawy A, Roh EJ. Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress. Antioxidants. 2021; 10(10):1641. https://doi.org/10.3390/antiox10101641
Chicago/Turabian StyleElsherbeny, Mohamed H., Jushin Kim, Noha A. Gouda, Lizaveta Gotina, Jungsook Cho, Ae Nim Pae, Kyeong Lee, Ki Duk Park, Ahmed Elkamhawy, and Eun Joo Roh. 2021. "Highly Potent, Selective, and Competitive Indole-Based MAO-B Inhibitors Protect PC12 Cells against 6-Hydroxydopamine- and Rotenone-Induced Oxidative Stress" Antioxidants 10, no. 10: 1641. https://doi.org/10.3390/antiox10101641