The synthesis of new pyrazine substituted 1,3,4-thiadiazole derivatives was carried out in good yield by the reaction of pyrazine substituted 1,3,4-thiadiazoles with various sulfonyl chlorides. A chemical structure of all the new compounds was confirmed by 1H NMR and mass spectral data. The new compounds were screened for their anticonvulsant activity against maximal electroshock (MES) seizure method. Rotarod method was employed to determine the neurotoxicity. Few compounds showed significant changes in anticonvulsant activity. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg).
Epilepsy has been recognized as a neurological disorder, affecting a large section of people across the world. The word epilepsy usually describes a group of common chronic neurological disorders characterized by recurrent unprovoked seizures due to excessive neuronal firing or synchronous neuronal activity in the brain [
Pyrazines and its derivatives play an important role in the drug discovery realm. In particular the structural analogue of purines derivatives presents various pharmacological activities such as antibacterial [
Melting range was determined by Veego Melting Point VMP III apparatus. Elemental analyses were recorded on VarioMICRO superuser V1.3.2 Elementar. 1H NMR spectra were recorded on Bruker DRX-500 spectrometer at 400 MHz using DMSO-d6 as solvent and TMS as an internal standard. Mass spectral data were obtained by LC/MSD Trap XCT. Silica gel column chromatography was performed using Merck 7734 silica gel (60–120 mesh) and Merck-made TLC plates.
Thiosemicarbazide (
To a stirred solution of
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To a mixture of
Male wistar rats procured from the National Institute of Nutrition, Hyderabad (190–220 g), were used in the present study. The animals were kept in individual cages for one week to acclimatize for the laboratory conditions. They were allowed to free access of water and food.
All the experimental procedures were carried out in accordance with Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines. The study was reviewed and approved by the Institutional Animal Ethics Committee, G Pulla Reddy College of Pharmacy, Hyderabad, India.
Maximal electroshock seizure model was used in the present study to evaluate the anticonvulsant activity of the compounds on male wistar rats. Seizures were induced in rats by delivering electro shock of 150 mA for 0.2 s by means of a convulsiometer through a pair of ear clip electrodes. The test compounds (100 mg/kg) were administered by oral route in the form of solution (the compounds were dissolved in 1% sodium carboxymethyl cellulose), 30 minutes before the maximal electroshock seizure test. The animals were observed closely for 2 minutes. The percentage of inhibition of seizure relative to control was recorded and calculated [
Acute neurological toxicity in mice was evaluated by rotarod test [
In the present study, data were analyzed by one way analysis of variance (ANOVA) followed by dunnett test to compare difference between the groups.
New pyrazine substituted 1,3,4-thiadiazole derivatives
Chemical structure and melting range of pyrazine substituted 1,3,4-thiadiazole derivatives
Compound | R | Structure | M.p. (°C) |
---|---|---|---|
|
|
|
244–246 |
|
|
|
136–138 |
|
|
|
170–172 |
|
|
|
200–202 |
|
|
|
138–140 |
|
|
|
228–230 |
|
|
|
260–262 |
|
|
|
160–162 |
|
|
|
220–222 |
|
|
|
166–168 |
|
|
|
252–254 |
|
|
|
88–90 |
|
|
|
226–228 |
|
|
|
234–236 |
|
|
|
170–172 |
In the present study, the anticonvulsant activity of the synthesized compounds
Effect of compounds in the maximal electroshock seizure test.
Treatment |
|
% Protection |
---|---|---|
|
6.51 | 48.70 |
|
7.38 | 37.20 |
|
8.17 | 9.43 |
|
2.00 | 74.52 |
|
6.85 | 45.41 |
|
3.47 | 58.60 |
|
1.75 | 74.88 |
|
8.10 | 10.00 |
|
8.05 | 10.62 |
|
2.53 | 68.10 |
|
4.70 | 50.31 |
|
8.12 | 9.96 |
|
2.10 | 69.43 |
|
4.49 | 55.34 |
|
2.96 | 65.20 |
Standard | 1.98 | 75.88 |
Control (vehicle) | 8.21 | — |
% Protection = (control
Neurotoxicity screening of the compounds
Compound | Neurotoxicity screen | |||
---|---|---|---|---|
0.5 h | 1 h | 2 h | 4 h | |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 1/4 | 1/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 1/4 | 1/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 1/4 | 1/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
|
0/4 | 0/4 | 0/4 | 0/4 |
Standard | 0/4 | 0/4 | 0/4 | 0/4 |
The data in the table represent the ratio between the numbers of the animals that exhibited neurotoxicity against the number of tested animals.
The structural activity relationship study of these compounds indicate that the introduction of a piperazine group of pyrazine ring and 3,5-bis(trifluoromethyl) positions of the benzenesulfonyl moiety showed the best anticonvulsant activity in
In conclusion, a series of new pyrazine substituted 1,3,4-thiadiazole derivatives
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Dr. B. Veeresh, B. Madhava Reddy, and Nagula Naresh Kumar, Department of Pharmacology and Toxicology, G Pullareddy College of Pharmacy, Hyderabad, India, for carrying out Anticonvulsant activity.