Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Anticonvulsant Activity in MES and scPTZ Models and Neurotoxicity in the Rota-Rod Test
2.3. Anticonvulsant Activity Evaluation of Compound 4g in Other Seizure Models
2.4. The Role of the GABAergic System in the Anticonvulsant Mechanism of 4g
3. Materials and Methods
3.1. Instruments and Reagents
3.2. Synthesis Method and Spectral Data
3.2.1. General Procedure for the Preparation of Intermediates 1, 2 and 3
3.2.2. General Procedure for the Preparation of Target Compounds 4a–m
3.2.3. Spectral Data
3.3. Pharmacology
3.3.1. Animals and Experimental Conditions
3.3.2. The Maximal Electroshock (MES) Test
3.3.3. Subcutaneous Pentylenetetrazole Induced Seizures Test (scPTZ)
3.3.4. Neurotoxicity Screening
3.3.5. Quantification Trials
3.3.6. 3-Mercaptopropionic Acid-Induced Seizures Test
3.3.7. Bicuculline-Induced Seizures Test
3.3.8. Determination of Brain GABA Concentrations by ELISA
3.3.9. Test for the Effects of Thiosemicarbazide on the Anti-MES Action of 4g
3.3.10. Statistical Analysis
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of the compounds (4a–m) are available from the authors. |
Compds. | R | Intraperitioneal Injection in Mice a | |||||
---|---|---|---|---|---|---|---|
MES Screening b | scPTZ Screening c | NT Screening d | |||||
0.5 h | 4 h | 0.5 h | 4 h | 0.5 h | 4 h | ||
4a | C3H7 | 100 | 300 | 300 | - | - | - |
4b | C5H9 | 300 | - | - | - | - | - |
4c | C7H15 | - | - | - | - | - | - |
4d | CH2C6H5 | - | - | - | - | - | - |
4e | CH2C6H4(2-F) | 100 | - | 100 | 100 | - | - |
4f | CH2C6H4(3-F) | 100 | - | 100 | 100 | - | - |
4g | CH2C6H4(4-F) | 100 | 30 | 30 | 30 | 300 | 300 |
4h | CH2C6H4(2-Cl) | 100 | 100 | - | 300 | - | - |
4i | CH2C6H4(3-Cl) | 100 | 100 | - | - | - | - |
4j | CH2C6H4(4-Cl) | 300 | - | - | - | - | - |
4k | CH2C6H3(2,4-Cl2) | 300 | - | - | - | - | - |
4l | CH2C6H4(4-CH3) | 300 | 300 | - | 300 | - | - |
4m | CH2C6H4(4-OCH3) | - | - | - | - | - | - |
Compounds | ED50 a | TD50 b | PI c | ||
---|---|---|---|---|---|
MES | scPTZ | MES | scPTZ | ||
4g | 23.7 (21.5–26.0) | 18.9 (17.2–20.8) | 284.0 (258.2–312.4) | 12.0 | 15.0 |
Carbamazepine | 9.8 (8.9–10.8) | >100 | 44.0 (40.2–48.1) | 4.5 | <0.44 |
Valproate | 264 (247–338) | 149 (123–177) | 418 (369–450) | 1.6 | 2.8 |
Compound | Doses (mg/kg) | Test Time (h) | Clonic Seizures (%) | Tonic Seizures (%) | Lethality (%) |
---|---|---|---|---|---|
DMSO | - | 0.5 | 100 | 100 | 60 |
Carbamazepine | 30 | 0.5 | 100 | 0 *** | 0 ** |
4g | 30 | 0.5 | 100 | 20 ** | 30 * |
Compound | Doses (mg/kg) | Test Time (h) | Clonic Seizures (%) | Tonic Seizures (%) | Lethality (%) |
---|---|---|---|---|---|
DMSO | - | 0.5 | 100 | 100 | 100 |
Carbamazepine | 30 | 0.5 | 100 | 0 *** | 20 ** |
4g | 30 | 0.5 | 100 | 0 *** | 30 ** |
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Share and Cite
Song, M.-X.; Wang, Z.-Y.; He, S.-H.; Yu, S.-W.; Chen, S.-L.; Guo, D.-F.; Zhao, W.-H.; Deng, X.-Q. Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones. Molecules 2018, 23, 756. https://doi.org/10.3390/molecules23040756
Song M-X, Wang Z-Y, He S-H, Yu S-W, Chen S-L, Guo D-F, Zhao W-H, Deng X-Q. Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones. Molecules. 2018; 23(4):756. https://doi.org/10.3390/molecules23040756
Chicago/Turabian StyleSong, Ming-Xia, Zhen-Yuan Wang, Shi-Hui He, Sheng-Wang Yu, Shi-Long Chen, Dong-Fu Guo, Wen-Hao Zhao, and Xian-Qing Deng. 2018. "Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones" Molecules 23, no. 4: 756. https://doi.org/10.3390/molecules23040756