Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011–2020)
Abstract
:1. Introduction
2. The Synthesis of Pyrazole Scaffold Molecules
2.1. Cyclocondensation of Hydrazines with 1,3-Dielectrophilic Derivatives
2.1.1. Cyclocondensation of Hydrazines with 1,3-Dicarbonyl and Related Compounds
2.1.2. Cyclocondensation of Hydrazines with Enones and Related Compounds
2.1.3. Cyclocondensation of Hydrazines with Ynones and Related Compounds
2.1.4. Cyclocondensation of Hydrazines with Vinyl Ketones Bearing a Leaving Group
2.2. 1,3-Dipolar Cycloadditions
2.2.1. Diazoalkanes as 1,3-Dipoles
2.2.2. Nitrilimines as 1,3-Dipoles
2.2.3. Sydnones as 1,3-Dipoles
2.2.4. Azo Compounds as [NN] Fragments
2.3. New Approaches to Reactions for Pyrazole Synthesis
3. The Functionalization of Pyrazoles
3.1. The Synthesis of Fluorine-Containing and Fluoroalkyl Substituted Pyrazoles
3.1.1. The Synthesis of Monofluorine-Substituted Pyrazoles
3.1.2. The Synthesis of Difluoromethylpyrazoles
3.1.3. The Synthesis of Trifluoromethyl Pyrazoles
3.2. N-Alkylation, N-Arylation, and N-Alkenylation of Pyrazoles
3.2.1. The Synthesis of N-Alkylated Pyrazoles
3.2.2. The Synthesis of N-Alkenylated Pyrazoles
3.2.3. The Synthesis of N-Arylated Pyrazoles
3.3. The Amination of Pyrazoles
3.4. The Selanylation of Pyrazoles.
3.5. The Borylation of Pyrazoles
4. Applications of Pyrazoles in Neurodegenerative Diseases
4.1. Applications of Pyrazoles in Alzheimer’s Disease (AD) Treatment
4.1.1. Acetylcholinesterase (AChE) Inhibitors
4.1.2. Protein Aggregation Inhibitors
4.1.3. Phosphodiesterase (PDE) Inhibitors
4.1.4. Dual Leucine Zipper Kinase (DLK) Inhibitors
4.1.5. Monoamine Oxidases B (MAO-B) Inhibitors
4.2. Applications of Pyrazoles in Parkinson’s Disease (PD) Treatment
4.2.1. Antioxidants
4.2.2. Protein Aggregation Inhibitors
4.2.3. Adenosine Receptor A2A Receptor Antagonists
4.2.4. Phosphodiesterase-10A (PDE10A) Enzyme Inhibitors
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Ki1 or IC50 2 Values for Cholinesterase Inhibitors | ||||
---|---|---|---|---|
Compound | R | AChE | BuChE | AChE/BuChE |
3a 1 | H | 58.17 ± 4.84 nM | 74.82 ± 18.62 nM | 0.77 |
3b 1 | Me | 64.71 ± 13.04 nM | 80.36 ± 22.74 nM | 0.80 |
3c 1 | Et | 47.93 ± 4.92 nM | 58.12 ± 9.27 nM | 0.82 |
3d 1 | Ph | 44.66 ± 10.06 nM | 50.36 ± 13.88 nM | 0.88 |
3e 1 | 2, 5-dimethylphenyl | 78.34 ± 17.83 nM | 77.62 ± 18.32 nM | 1.00 |
3f 1 | 3, 4-dimethylphenyl | 48.16 ± 9.63 nM | 65.27 ± 12.73 nM | 0.73 |
3g 1 | 2-nitrophenyl | 56.23 ± 11.74 nM | 71.63 ± 8.93 nM | 0.78 |
3h 1 | 4-bromophenyl | 60.27 ± 15.67 nM | 88.36 ± 20.03 nM | 0.68 |
164 1 | -- | 126.13 ± 9.37 nM | 145.84 ± 13.44 nM | 0.86 |
165 2 | -- | 0.055 ± 0.143 µM | 8.863 ± 0.22 µM | 0.006 |
166 2 | -- | 0.017 ± 0.02 µM | 6.331 ±0.017 µM | 0.003 |
167 2 | -- | 3.148 ± 0.139 µM | 1.22 ± 0.05 µM | 2.58 |
168 2 | -- | 2.632 ± 0.021 µM | 6.901 ± 0.01 µM | 0.38 |
169 2 | -- | 0.069 ± 0.06 µM | 6.3 ± 0.6 µM | 0.01 |
170 2 | -- | 1937 ± 66 nM | 1166 ± 88 nM | 1.60 |
IC50 Value (nM) | ||||
---|---|---|---|---|
Compound | hMAO-A | hMAO-B | hMAO-A/hMAO-B | Ki (nM) |
187 | >10,000 | 0.59 ± 0.09 | >16,959 | 0.26 ± 0.04 |
188 | >10,000 | 0.68 ± 0.04 | >14,706 | 0.30 ± 0.02 |
189 | ≥10,000 | 0.66 ± 0.06 | ≥15,151 | 0.29 ± 0.03 |
IC50 Value | ||||||
---|---|---|---|---|---|---|
Compound | R | PDE10A (nM) | PDE3A (103 × nM) | PDE3B (103 × nM) | PDE4A (103 × nM) | PDE4B (103 × nM) |
195a | 3-OMe | 0.40 ± 0.02 | 123 ± 21 | 82.7 ± 10 | 3.85 ± 0.23 | 3.43 ± 0.21 |
195b | 4-OMe | 0.28 ± 0.06 | 27.5 ± 2.5 | 3.85 ± 0.95 | 2.56 ± 0.11 | 1.79 ± 0.10 |
195c | 6-OMe | 1.82 ± 0.25 | 78.0 ± 4.0 | 9.75 ± 1.25 | 3.37 ± 0.18 | 2.56 ± 0.09 |
196a | 3-OMe | 0.24 ± 0.05 | 18.7 ± 3.1 | 16.9 ± 2.1 | 199 ± 16.0 | 31.5 ± 3.60 |
196b | 4-OMe | 0.36 ± 0.03 | 29.0 ± 4.0 | 4.80 ± 1.20 | 4.18 ± 0.33 | 5.06 ± 0.40 |
196c | 6-OMe | 1.78 ± 0.03 | 1.5 ± 0.5 | 3.00 ± 0.14 | 5.60 ± 0.52 | 7.10 ± 0.58 |
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Li, X.; Yu, Y.; Tu, Z. Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011–2020). Molecules 2021, 26, 1202. https://doi.org/10.3390/molecules26051202
Li X, Yu Y, Tu Z. Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011–2020). Molecules. 2021; 26(5):1202. https://doi.org/10.3390/molecules26051202
Chicago/Turabian StyleLi, Xuefei, Yanbo Yu, and Zhude Tu. 2021. "Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011–2020)" Molecules 26, no. 5: 1202. https://doi.org/10.3390/molecules26051202