Quantitative Structure–Neurotoxicity Assessment and In Vitro Evaluation of Neuroprotective and MAO-B Inhibitory Activities of Series N′-substituted 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazides
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Neurotoxicity Evaluation
2.2.1. Effects of the Evaluated Hydrazide-Hydrazones on Isolated Rat Brain Synaptosomes
2.2.2. Effects of the Evaluated Hydrazide-Hydrazones on Glutathione (GSH) Level in Isolated Rat Brain Synaptosomes
2.2.3. Effects of the Evaluated Hydrazide-Hydrazones on Isolated Rat Brain Microsomes
2.2.4. Effects of the Evaluated Hydrazide-Hydrazones on Isolated Rat Brain Mitochondria
2.3. Quantitative Structure–Neurotoxicity Assessment for the Evaluated N′-Substituted Xanthinylthio Propanehydrazones
2.3.1. QSTR Model Based on Data for the Relative Synaptosomal Vitality (RV)
n = 15 r2 = 0.608 SEE = 0.063 F = 9.32 q2 = 0.523 r2scr = 0.144
2.3.2. QSTR Model Based on Data for the Relative Increase in Microsomal MDA Production (RMDA)
n = 15 r2 = 0.600 SEE = 0.382 F = 9.751 q2 = 0.4553 r2scr = 0.153
2.4. Evaluation of the Neuroprotection Effects of the Studied N′-substituted 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazides
2.4.1. Protective Effects in a Model of 6-OHDA-Induced Oxidative Stress in Isolated Rat Synaptosomes
2.4.2. Protective Effects in a Model of Iron Ascorbate (Fe2+/AA)-Induced Lipid Peroxidation in Isolated Rat Microsomes
2.4.3. Protective Effects in a Model of Tert-Butylhydroxyperoxide(t-BuOOH)-Induced Oxidative Stress in Isolated Rat Mitochondria
2.5. Investigation of the Influence of the Newly Obtained Derivatives on the Activity of Human Recombinant MAO-B Enzyme
3. Discussion
3.1. Neurotoxicity Evaluation
3.2. Quantitative Structure–Neurotoxicity Assessment for the Evaluated Xanthinylthio Propanehydrazones
3.3. Studies on the Neuroprotective Activity of Newly Synthesized Derivatives
3.4. Investigation of the Influence of the Newly Obtained Derivatives on the Activity of Human Recombinant MAO-B Enzyme
4. Materials and Methods
4.1. Chemistry
4.2. Biological Evaluation
4.2.1. Animals
4.2.2. Isolation and Incubation of Rat Brain Synaptosomes and Mitochondria
4.2.3. Synaptosomal Viability
4.2.4. Determination of Reduced Glutathione (GSH) in Brain Synaptosomes
4.2.5. Model of 6-OHDA-Induced Neurotoxicity in Synaptosomes
4.2.6. Tert-Butyl Hydroperoxide (t-BuOOH)-Induced Oxidative Stress in Isolated Brain Mitochondria
4.2.7. Measurement of GSH Content in Brain Mitochondria
4.2.8. Preparation of Brain Microsomes Using Ultracentrifugation
4.2.9. FeSO4/Ascorbic Acid-Induced Lipid Peroxidation in Isolated Brain Microsomes
4.2.10. MDA Assay in Brain Microsomes and Mitochondria
4.2.11. Measurement of Monoamine Oxidase B Activity
4.3. Quantitative Structure–Neurotoxicity Assessment for the Evaluated Xanthinylthio Propanehydrazones
4.4. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Compound | R1 | R2 | R3 | R4 | R5 | R6 |
---|---|---|---|---|---|---|
6a | H | H | H | H | H | H |
6b | H | H | NO2 | H | H | H |
6c | Cl | H | H | H | Cl | H |
6d | H | H | H | Cl | H | H |
6e | H | H | Br | H | H | H |
6f | H | H | CF3 | H | H | H |
6g | H | OCH3 | OCH3 | H | H | H |
6h | H | OCH3 | OCH3 | OCH3 | H | H |
6i | H | OCH3 | OH | OCH3 | H | H |
6j | H | H | OH | OCH3 | H | H |
6k | OCH3 | OCH3 | H | H | H | H |
6l | OH | H | H | H | H | H |
6m | CH3 | H | CH3 | H | CH3 | H |
6n | OH | OCH3 | H | H | H | H |
6o | H | NO2 | H | H | H | H |
6p | H | NO2 | OH | OCH3 | H | H |
Compound ID | RV | RMDA | LogP_ACD | Dipole (D) | xc3 |
---|---|---|---|---|---|
1 | 1.000 | 1.000 | −0.13 | 2.657 | 1.253 |
6a | 0.743 | 1.938 | 3.410 | 8.639 | 1.869 |
6b | 0.703 | 2.063 | 3.330 | 8.706 | 2.369 |
6c | 0.689 | 1.563 | 4.800 | 11.438 | 2.272 |
6d | 0.730 | 1.750 | 4.210 | 7.708 | 2.158 |
6e | 0.743 | 2.563 | 4.340 | 9.912 | 2.158 |
6f | 0.757 | 3.000 | 4.380 | 9.161 | 3.379 |
6g | 0.716 | 2.438 | 3.530 | 16.350 | 2.202 |
6h | 0.703 | 2.563 | 3.400 | 20.764 | 2.338 |
6i | 0.743 | 2.313 | 2.790 | 21.067 | 2.39 |
6j | 0.730 | 2.063 | 3.040 | 17.462 | 2.271 |
6k | 0.959 | 1.188 | 3.130 | 9.319 | 2.134 |
6l | 0.973 | 1.125 | 3.490 | 7.687 | 2.067 |
6m | 0.716 | 2.250 | 4.790 | 8.943 | 2.561 |
6n | 0.689 | 2.063 | 3.360 | 8.788 | 2.191 |
6o | 0.757 | 1.750 | 3.510 | 8.591 | 2.369 |
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Kondeva-Burdina, M.; Mitkov, J.; Valkova, I.; Peikova, L.; Georgieva, M.; Zlatkov, A. Quantitative Structure–Neurotoxicity Assessment and In Vitro Evaluation of Neuroprotective and MAO-B Inhibitory Activities of Series N′-substituted 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazides. Molecules 2022, 27, 5321. https://doi.org/10.3390/molecules27165321
Kondeva-Burdina M, Mitkov J, Valkova I, Peikova L, Georgieva M, Zlatkov A. Quantitative Structure–Neurotoxicity Assessment and In Vitro Evaluation of Neuroprotective and MAO-B Inhibitory Activities of Series N′-substituted 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazides. Molecules. 2022; 27(16):5321. https://doi.org/10.3390/molecules27165321
Chicago/Turabian StyleKondeva-Burdina, Magdalena, Javor Mitkov, Iva Valkova, Lily Peikova, Maya Georgieva, and Alexander Zlatkov. 2022. "Quantitative Structure–Neurotoxicity Assessment and In Vitro Evaluation of Neuroprotective and MAO-B Inhibitory Activities of Series N′-substituted 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazides" Molecules 27, no. 16: 5321. https://doi.org/10.3390/molecules27165321