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EHOOPrAHH^ECKAa XHMH3, 2014, moM 40, № 1, c. 108-116
SYNTHESIS OF NEW 2,5-DISUBSTITUTED-1,3,4-THIADIAZOLE DERIVATIVES AND THEIR IN VIVO ANTICONVULSANT ACTIVITY
© 2014 r. K. P. Harishfl#, K. N. Mohana", L. Mallesha4
aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006 India bPG Department of Chemistry, JSS College of Arts, Commerce and Science, Ooty Road, Mysore-25, India
Received May 17, 2013; in final form July 3, 2013
A series of 2,5-disubstituted-1,3,4-thiadiazole derivatives were synthesized by the reaction of 3-(2-cyanopro-pan-2-yl)-AL(5-(piperazine-1-yl)-1,3,4-thiadiazol-2-yl)benzamide with various sulfonyl chlorides and evaluated for their anticonvulsant activity in MES test. Rotorod method was employed to determine the neurotoxicity. The purity of the compounds is confirmed on the basis of their elemental analysis. The structures of all the new compounds are established on the basis of 1H NMR and mass spectral data. Out of fifteen compounds, three were found to be potent anticolvunstants. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg).
Keywords: 1,3,4-thiadiazole, anticonvulsant, neurotoxicity
DOI: 10.7868/S0132342314010059
INTRODUCTION
Epilepsy is usually described as a group of common chronic neurological disorders characterized by recurrent unprovoked seizures due to excessive neuronal firing or synchronous neuronal activity in the brain [1]. The known potential causes of epilepsy include brain tumors, infections, traumatic head injuries, perinatal insults, developmental malformations, cerebrovascular diseases, and febrile seizures [2]. The anti-convulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticon-vulsants are also being increasingly used in the treatment of bipolar disorder. Anticonvulsants are more accurately called antiepileptic drugs (AEDs), sometimes referred to as antiseizure drugs.
Several generations of anticonvulsants are available, such as phenytoin, phenobarbital, benzodiaz-epines, etosuximide, carbamazepine, and valproate. They are useful in the treatment of other diseases, such as neuropathic pain and bipolar disorders, conditions associated with significant morbidity and mortality [3—5]. The newest generation of anticonvulsants, including vigabatrin, lamotrigine, gabapentin, tiagab-ine, topiramate, felbamate, and zonisamide, represents a step forward toward better anticonvulsant drugs [6—9]. New anticonvulsant agents are discovered through conventional screening and/or structure modification rather than a mechanism driven design.
# Corresponding author (phone: +91-9845677501; e-mail: dhruva-harishp@gmail.com).
Five-member heterocyclic compounds showed various types of biological activities, among them 1,3,4-thiadiazoles are associated with diverse biological activities, probably by the virtue of —N=C—S— grouping [10]; some ofthem possess antibacterial [11], antifungal [12], and anticonvulsant [13] activities. Similarly, 2,5-disubstituted-1,3,4-thiadiazoles also display wide spectrum of activities such as antibacterial [14] and anticonvulsant [15]. The therapeutic importance of these rings have prompted us to develop selective molecules in which a substituent could be arranged in a pharmacophore pattern to display higher pharmacological activity. In the present study, some new 2,5-disubstituted-1,3,4-thiadiazole derivatives (VlIa—o) have been synthesized and their anticonvul-sant effects were determined through maximal elec-troshock (MES) seizure test.
RESULTS AND DISCUSSION
The new 2,5-disubstituted-1,3,4-thiadiazole derivatives (VIIa—o) were synthesized according to Scheme. We believe that this synthesizing approach represents the most efficient route to a diverse array of 2,5-disubstituted heterocycles yet reported [16—21]. Readily available starting materials and simple synthesizing procedures make this method very attractive and convenient for the synthesis of various thiadiazoles. Formation ofproducts was confirmed by elemental analyses, 1H NMR, and mass spectra. The 1H NMR spectra of (VIIg) showed piperazine ring in the region of 5,
3.243.56. The mass spectra of (Vllg) showed molecular ion peak at m/z 909.07, which is in agreement with the molecular formula, C33H24F12N6O5S3. The elemental analysis data showed good agreement (within ± 0.4%)
109
between the experimentally determined values and the theoretically calculated values. The chemical structures and physical data of all the synthesized compounds are presented in Table 1.
H2N
S ,N ,N
S HC°°H N \ CH3C°OH , N \_Br
-NH2 HCl U / CH3COONa, Br2 U /
N 2 /—S S—S
H I
H2N
II
h2n
III
T-N.
K2CO3 /—-S
H2N
IV
O
III mono BOC piperazine N -N N—^
TBTU, TEA
O
N ^r-N N—^
^-S N—' O
O^.NH
V
V-
4 N HCl in dioxane
VI
VIIa—o
Rx = H, RSO2
Scheme. Synthetic route of 2,5-disubstituted-1,3,4-thiadiazole derivatives (VIIa—o).
In vivo anticonvulsant activity. All the synthesized thiadiazole analogues were screened for their anticonvulsant potential through MES model. For several decades, antiepileptic drug research has focused on identifying new potential drugs based on their anticonvulsant activity against a single acute seizure induced by various stimulators, usually in mice and rats. All the established antiepileptic drugs have anticonvulsant activity at least in the MES model [22]. In the present study, the anticonvulsant activity of the fifteen newly synthesized 2,5-disubstituted-1,3,4-thiadiazole derivatives (Vila—o) was evaluated by MES model at the dose of 100 mg/kg and the results are summarized in Table 2. Compounds (Vllg), (Vllj), and (VIIo) demonstrated significant protective effect on MES induced seizure and the effect of (Vllg) was similar to that of the standard (phenytoin). Similarly, compounds (Vllb), (Vlld—f), (Vlli), and (Vllk-n) also showed moderate protective effect and a significant difference in protectiveness was observed when compared to the standard group. Compounds (Vila, c, h) have relatively low anticonvulsant potencies.
All the compounds were examined for their neurotoxicity using rotorod method given in the dose of 100 mg/kg. Except compounds (Vila), (VIIc), and (VIIh) none of the compounds showed neurotoxicity. These compounds showed 25% toxicity compared to the standard 2 h after oral administration (Table 3).
From the results obtained, the structure activity relationship (SAR) can be drawn for the (VIIa—o) series. In this connection, different electron donating or electron withdrawing groups attached to phenyl ring as substituent linked to sulfonyl group are studied for anticonvulsant efficacy. In the present series of compounds, the active compounds possess all the requirements essential for anticonvulsant activity, as proposed by Dimmock et al. [23]. On correlating the structures of the synthesized compounds with their anticonvulsant activity, it has been observed that compounds bearing the groups like nitro, phenoxy and halogens on phenyl ring possess high potency in MES. The SAR study of these compounds indicate that the introduction of a piperazine group at position 5 of thi-adiazole ring and 3,5-bis(trifluoromethyl) positions of
Table 1. Chemical structure and melting range of 2,5-disubstituted-1,3,4-thiadiazole derivatives (Vlla—o)
Compound R Structure mp (°C)
(Vila) N O OWN S O y H CN 243-245
(Vllb) OWN S O / y H 212-214
(VIIc) -CH3 xt O na ^ ii II 7—N N—S-CH3 a-/ \_/ ii 3 O. /N s O H C^\CN 92-94
(Vlld) Cl Cl O Cl na ^ O /^S O N s O Cl y H C^\CN 122-124
(Viie) CN O N'N O O=S=O O 162-164
Table 1. (Contd.)
R
Structure
mp (°C)
0
1
N
CN O
n-n N^s'"
-N
O )-N
106-108
\ /
CN
O N
N
O
"K/
100-102
\ /
CN
O N
N
O
n-s- -
O
170-172
Fv
F
F
—N
R F
Nlk/
F
F
F
149-141
V/
CN
O N
N
O
N
170-172
1
Table 1. (Contd.)
Compound
R
Structure
mp (°C)
(VIIl)
vv
=N
CN
O N
N
O
N-|- _
N
N
185-187
(VlIm)
CN
O N~N\
N v-N
N S
O=S=O
NO2
O
NT ^
ttJ
o2n
162-164
(VlIn)
V /-Br
CN
O
N~N
O=I=O
N
O
^ d
V/
Br
222-224
(VIIo)
F
VAt-F
F
CN
O N
N
F
O
,N—|—,
F
O
F
154-156
the benzenesulfonyl moiety (compound (VIIg)) showed the best anticonvulsant activity. Compounds (VlIj) and (VIIo) possessing trifluoromethyl substituent at different positions of the benzenesulfonyl moiety showed good anticonvulsant activity in the MES model. Both compounds did not exhibit neurotoxicity at the highest administered dose.
The presence of nitro group in (VIIm) and halogen groups in (VIId), (VIIk), and (VIIn) showed moderate anticonvulsant activity. The presence of cyano group
in (VIIl) at aryl ring has moderate activity. Although naphthalene group in (Vile), dimethyl, in (Vllb), and feri-butyl, in (Vlli) were moderately active in the MES test; compounds with phenyl ring in (Vila) and (Vllh) exhibited considerable anticonvulsant activity in comparison to methyl group in (VIIc). These compounds ((Vila), (VIIc), and (VIIh)) contribute to the 25% neurotoxicity at 2 h. Among the synthesized compounds (VIIa—o), all the compounds showed activity in the range of 10.13—75.81% in comparison to phenytoin, which completely inhibited the convul-
sions produced by electro-convulsometer, but compound (Vllg), having electron withdrawing groups, showed excellent anticonvulsant activity. It has been established that there are at least three parameters for anticonvulsant drugs, that is (i) lipophilic domain (L), (ii) hydrophobic unit (R), and (iii) electron donar (D) system [23]. Thus the proposed pharmacophore model for (VIIg) includes all the above factors important for bioactivity (see figure).
In conclusion, a series of new 2,5-disubstituted-1,3,4-thiadiazole derivatives (Vlla—o) were synthesized in good yield, characterized by different spectral studies, and their anticonvulsant activity has been evaluated. Various thiadiazole derivatives with electron withdrawing groups showed potent anticonvulsant
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