Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. Synthesis of AntiOXCIN2 and AntiOXCIN3
2.1.2. Synthesis of Mitochondria-Targeted Agents Inspired on Piperine
General Procedure for the Obtention of Phtalimidylalkylltriphenylphosphonium Salts
General Procedure for the Obtention of Aminoalkylltriphenylphosphonium Salts
Synthesis of (2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)Penta-2,4-Dienoic Acid (12)
Piperic Acid Amidation
Demethylenation Reaction
2.2. Enzymatic Assays
2.2.1. Acetylcholinesterase and Butyrylcholinesterase
Evaluation of Eel Acetylcholinesterase and Equine Butyrylcholinesterase Inhibitory Activity
Evaluation of Human Acetylcholinesterase and Human Butyrylcholinesterase Inhibitory Activities
Crystallization, X-ray Data Collection and Processing
2.2.2. Evaluation of Human Monoamine Oxidase Inhibitory Activity
2.3. Oxygen Radical Absorbance Capacity (ORAC-FL) Assay
2.4. Electrochemical Measurements
2.5. In Vitro Toxicology
2.5.1. Materials
2.5.2. Cell Lines and Culture Conditions
2.5.3. Cytotoxicity
2.5.4. Statistical Analysis
2.6. Evaluation of the Chromatographic Hydrophobicity Index
2.7. Estimation of Drug-Like Properties
3. Results and Discussion
3.1. Chemistry
3.2. Cholinesterase Inhibition Studies
3.2.1. Evaluation of Electric Eel Acetylcholinesterase and Equine Butyrylcholinesterase Inhibitory Activities
3.2.2. Evaluation of Human Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activities
3.2.3. Crystallographic Studies with Human Cholinesterases
3.3. Monoamine Oxidase Inhibition Studies
3.4. Antioxidant Activity
3.5. Electrochemical Studies
3.6. Evaluation of Cytotoxicity Profile
3.7. Evaluation of Drug-Like Properties
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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PDB Entry Code | 6ZWE | 6ZWI |
---|---|---|
X-ray source | PROXIMA 2 | PROXIMA 2 |
Wavelenght | 0.9801 | 0.9801 |
Resolution range | 78.09–3.0 (3.107–3.0) | 41.48–1.85 (1.916–1.85) |
Space group | P 61 | I 4 2 2 |
Unit cell | a = 211.35, b = 211.35, c = 115.9 α = β = 90.0, γ = 120 | a = 154.3, b = 154.3, c = 127.7 α = β = γ = 90.0 |
Total reflections | 2352044 (194838) | 3366060 (268864) |
Unique reflections | 59080 (5885) | 65496 (6485) |
Multiplicity | 39.8 (33.1) | 51.4 (41.5) |
Completeness (%) | 99.87 (99.66) | 99.96 (99.92) |
Mean I/sigma(I) | 20.81 (2.80) | 29.97 (0.81) |
Wilson B-factor | 85.22 | 47.10 |
R-merge | 0.1637 (1.526) | 0.1014 (6.341) |
R-meas | 0.1658 (1.55) | 0.1025 (6.418) |
R-pim | 0.02615 (0.2668) | 0.01425 (0.9876) |
CC1/2 | 0.999 (0.933) | 1 (0.31) |
CC * | 1 (0.982) | 1 (0.688) |
Reflections used in refinement | 59025 (5879) | 65488 (6482) |
Reflections used for R-free | 1180 (118) | 1309 (129) |
R-work | 0.1982 (0.3401) | 0.1878 (0.3676) |
R-free | 0.2411 (0.3895) | 0.2241 (0.3844) |
Number of non-hydrogen atoms | 8782 | 4808 |
macromolecules | 8363 | 4294 |
ligands | 274 | 286 |
solvent | 145 | 228 |
Protein residues | 1073 | 527 |
RMS(bonds) | 0.004 | 0.016 |
RMS(angles) | 0.88 | 1.27 |
Ramachandran favored (%) | 95.03 | 95.62 |
Ramachandran allowed (%) | 4.87 | 4.19 |
Ramachandran outliers (%) | 0.09 | 0.19 |
Rotamer outliers (%) | 0.11 | 0.43 |
Clashscore | 11.09 | 5.34 |
Average B-factor | 97.42 | 56.31 |
macromolecules | 96.06 | 53.61 |
ligands | 143.73 | 96.23 |
solvent | 88.44 | 57.18 |
Compound | IC50/µM | SI (1) b | IC50/µM | SI (2) c | ||
---|---|---|---|---|---|---|
eeAChE | eqBChE | hAChE | hBChE | |||
1 | ___ a | ___a | ___ | ___ e | ___ e | ___ |
2 | 6.39 ± 0.28 | 0.0282 ± 0.0014 | 226 | 11 ± 1 | 0.20 ± 0.04 | 55 |
3 | 5.74 ± 0.32 | 0.0179 ± 0.0009 | 314 | 2.0 ± 0.2 | 3.0 ± 0.4 | 0.67 |
4 | 2.23 ± 0.12 | 0.0619 ± 0.0042 | 36 | 22 ± 2 | 3.0 ± 0.2 | 7.3 |
5 | 2.14 ± 0.06 | 0.0341 ± 0.0029 | 62 | 9.0 ± 0.5 | 23 ± 2 | 0.39 |
AntiOXCIN2 | 6.32 ± 0.14 d | 0.124 ± 0.007 d | 51 d | ___ e | ___ e | ___ |
AntiOXCIN3 | 5.08 ± 0.22 | 0.325 ± 0.09 | 16 | ___ e | ___ e | ___ |
Donepezil | 0.0129 ± 0.0008 | 2.50 ± 0.09 | 0.0052 | ___ e | ___ e | ___ |
Compound | IC50/µM | SI (3) b | |
---|---|---|---|
hMAO-A | hMAO-B | ||
1 | ___ a,d | 1.05 ± 0.08 d | >10 c,d |
2 | 0.888 ± 0.022 | 12.4 ± 1.9 | 0.07 |
3 | 1.23 ± 0.13 | 4.64 ± 0.29 | 0.26 |
4 | 5.17 ± 0.54 | 13.5 ± 1.1 | 0.38 |
5 | 2.17 ± 0.28 | 10.9 ± 0.7 | 0.20 |
AntiOXCIN2 | ___ a | ___ a | __ |
AntiOXCIN3 | ___ a | ___ a | __ |
R-(−)-Deprenyl | 20.1 ± 1.9 | 0.0386 ± 0.0043 | 522 |
Rasagiline | 3.65 ± 0.31 | 147.3 ± 249 | 24 |
Safinamide | ___ a | 0.0231 ± 0.0026 | >433 c |
Clorgyline | 0.00274 ± 0.00047 | 2.21 ± 0.26 | 0.00124 |
Compound | ORAC-FL Index | Ep/mV |
---|---|---|
1 | ___ | n.d. |
2 | ___ | 942; 1070 |
3 | ___ | 931; 1083 |
4 | 3.3 ± 0.1 | 125 |
5 | 3.1 ± 0.3 | 144 |
AntiOXCIN2 | 2.8 ± 0.1 | 166 a |
AntiOXCIN3 | 2.6 ± 0.1 | 164 a |
Compound | CHI a | CHI LogPoct b | MW c | TPSA c | HBA c | HBD c | RB c |
---|---|---|---|---|---|---|---|
1 | 73.4 | 2.35 | 285.3 | 38.77 | 3 | 0 | 4 |
2 | 42.8 | 1.27 | 614.5 | 61.15 | 4 | 1 | 12 |
3 | 45.8 | 1.41 | 642.6 | 61.15 | 4 | 1 | 14 |
4 | 34.4 | 1.59 | 602.5 | 83.15 | 4 | 3 | 12 |
5 | 37.2 | 1.73 | 630.6 | 83.15 | 4 | 3 | 14 |
AntiOXCIN2 | 37.9 | 1.76 | 619.7 | 83.15 | 4 | 3 | 14 |
AntiOXCIN3 | 41.4 | 1.92 | 647.8 | 83.15 | 4 | 3 | 16 |
CNS+ drugs | ___ | ___ | <500 [60] | <90 [60] | <7 [61] | <3 [61] | <8 [61] |
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Chavarria, D.; Da Silva, O.; Benfeito, S.; Barreiro, S.; Garrido, J.; Cagide, F.; Soares, P.; Remião, F.; Brazzolotto, X.; Nachon, F.; et al. Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases. Antioxidants 2021, 10, 329. https://doi.org/10.3390/antiox10020329
Chavarria D, Da Silva O, Benfeito S, Barreiro S, Garrido J, Cagide F, Soares P, Remião F, Brazzolotto X, Nachon F, et al. Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases. Antioxidants. 2021; 10(2):329. https://doi.org/10.3390/antiox10020329
Chicago/Turabian StyleChavarria, Daniel, Ophelie Da Silva, Sofia Benfeito, Sandra Barreiro, Jorge Garrido, Fernando Cagide, Pedro Soares, Fernando Remião, Xavier Brazzolotto, Florian Nachon, and et al. 2021. "Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases" Antioxidants 10, no. 2: 329. https://doi.org/10.3390/antiox10020329