Synthetic Methods, Chemistry, and the Anticonvulsant Activity of Thiadiazoles

The chemistry of heterocyclic compounds has been an interesting field of study for a long time. Heterocyclic nucleus 1,3,4-thiadiazole constitutes an important class of compounds for new drug development. The synthesis of novel thiadiazole derivatives and investigation of their chemical and biological behavior have gained more importance in recent decades. The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an active area of intensive investigation in medicinal chemistry. During the recent years, there has been intense investigation of different classes of thiadiazole compounds, many of which possess extensive pharmacological activities, namely, antimicrobial activity, anticonvulsant, antifungal antidiabetic, anti-inflammatory, antioxidant, and antituberculosis activities, and so forth. The resistance towards available drugs is rapidly becoming a major worldwide problem. The need to design new compounds to deal with this resistance has become one of the most important areas of research today. Thiadiazole is a versatile moiety that exhibits a wide variety of biological activities. Thiadiazole moiety acts as “hydrogen binding domain” and “two-electron donor system.” It also acts as a constrained pharmacophore. On the basis of the reported literature, we study here thiadiazole compounds and their synthetic methods chemistry and anticonvulsant activity.


Introduction
Epilepsy is the name of a brain disorder characterized predominantly by recurrent and unpredictable interruptions of normal brain function, called epileptic seizures [1,2]. The current therapy of epilepsy with antiepileptic drugs is associated with side effects, dose-related and chronic toxicity, and teratogenic effects [3,4]. Epilepsy is not a singular disease entity but a variety of disorders reflecting underlying brain dysfunction that may result from many different causes. Therefore, there is continuing demand for new anticonvulsant agents. So, there is an urgent requirement for the dieovery and development of some novel anticonvulsant agents with more selective activity and lower toxicity for the effective treatment of epilepsy. Several five-membered aromatic systems having three heteroatoms at symmetrical positions such as thiadiazoles have been studied extensively owing to their interesting pharmacological activities. There is a broad variety of heterocyclic compounds which are having medicinal importance, and recently, much attention has been focused on thiadiazole derivatives in view of their broad spectrum activities. Thiadiazole is one such heterocyclic nucleus. There are several isomers of thiadiazole, that is 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole [5], 1,3,4-Thiadiazole is the main isomer of thiadiazole series having versatile pharmacological activities.

Thiadiazole
Thiadiazole is a heterocyclic organic compound that has a five-member ring having one sulphur and two nitrogen atoms [6]. 1,3,4-Thiadiazoles represent one of the most biologically active classes of compounds, possessing a wide spectrum of activities. Thiadiazoles have become very important 2 International Journal of Medicinal Chemistry compounds in medicine, agriculture, and many fields of technology. A large number of 1,3,4-thiadiazoles have been patented in the agricultural field as herbicides and bactericides [7]. X-ray analysis shows the following structure parameter for 1,3,4-thiadiazole ring (see Table 1 and Structure (1)):

Chemistry of Thiadiazole
A recent literature survey revealed that the 1,3,4-thiadiazole moiety has been widely used by the medicinal chemist in the past to explore its biological activities. The development of 1,3,4-thiadiazole chemistry is linked to the discovery of phenylhydrazines and hydrazine in the late nineteenth century. The first 1,3,4-thiadiazole was described by Fischer in 1882, but the true nature of the ring system was demonstrated first in 1890 by Freund and Kuh.

1,3,4-Thiadiazoles
1,3,4-Thiadiazole was first described in 1882 by Fischer and further developed by Bush and his coworkers, but true nature of the ring system was demonstrated first in 1956 by Goerdler et al. [8]. The advent of sulphur drugs and the later discovery of mesoionic compound greatly accelerated the rate of progress in the field of thiadiazole. Thiadiazole carrying mercapto, hydroxyl, and amino substituents can exist in many tautomeric forms. The 1,3,4-thiadiazoles are conveniently divided into three subclasses: (a) aromatic systems which include the neutral thiadiazoles and constitute a major part of this paper; (b) mesoionic systems which are defined as fivemembered heterocycles which are not covalent or polar and possess a sextet of electrons in association with the five atoms comprising the ring; (c) nonaromatic systems such as the 1,3,4-thiadiazoles and the tetrahydro 1,3,4-thiadiazoles. In the partially reduced systems, the position of the double bond is denoted by the prefix Δ, with being a Δ 2 -1,3,4thiadiazole (Structures (6), (7), and (8)).

Synthetic Procedures of 1,3,4-Thiadiazoles
(a) Formation of One Bond. The most common procedure for the synthesis of 5-substituted 2-amino-thiadiazole is the acylation of a thiosemicarbazide followed by dehydration. Sulphuric acid, polyphosphoric acid, and phosphorous halides are some of the reagents used. The most recent procedure utilizes 1.5 moles of methane sulphonic as a dehydrating agent and the thiadiazoleare obtained in the high yield and good purity. 5-Alkyl-2-methyl amino-1,3,4thiadiazoles are prepared from a suitable carboxylic acid and methyl thio-semicarbazide in the presence of three parts of polyphosphoric acid and one part of concentreted sulphuric acid. 2-alkylamino-1,3,4-thiadiazole substituted in the 5th position can be prepared in high yields by the reaction of 4-alkylthiosemicarbazides with orthoformate esters in the presence of small amount of concentreted hydrochloric acid [9] (Scheme 1).
(b) Formation of Two Bonds. This is the most widely used procedure for the synthesis of thiadiazoles, thiazolidines, and mesoionic thiadiazoles.
(1) Cyclization. The parent molecule 1,3,4-thiadiazole was synthesized in 1956 by a four-step reaction sequence start utilizing hydrazine and from thiosemicarbazide. A second procedure utilizes hydrazine and potassium dithioformate. Dehydration of DMF with thionyl chloride or phosgene gives the formamide chloride which on treatment with N,N Diformylhydrazine gives the dihydrochloride of the free base which is liberated with sodium ethoxide, which then cyclizes to thiadiazole in the presence of hydrogen sulphide in an overall yield of 65%. 2-Amino 1,3,4-thiadiazole is also prepared from thiosemicarbazide and a mixture of formic and hydrochloric acid in a tedious procedure with an overall yield of 65% (Scheme 2).
(2) Dipolar Cycloadditions. This procedure has been widely used during the last decade for both synthetic and mechanistic reasons.

5.2.1.
Reactivity. Some of the characteristic reactions of the 1,3,4-thiadiazole nucleus are ring opening by strong base ease of nucleophilic attack and the formation of mesoionic compounds by quaternization. The substituents in the 2 and 5 positions have a large effect in determining the reactivity of the molecule as a whole. Thus, the ambient nucleophilicity of 2-aminothiazoles gives rise to electrophilic attack on both the amino group and the nuclear nitrogen atom. Ring formation between these two nitrogen atoms is also a common reaction. 2-Mercaptothiazoles react similarly to arenethiols while a methyl group on the thiadiazole ring has reactivity similar to that in a picoline. Nucleophiles easily displace halogen atom from the thiadiazole nucleus. This is due to the electronegativity of the two nuclear nitrogen atoms which impart a low electron density to the carbon atom of the nucleus.
(1) Reaction with Electrophile. Because unsaturation rings have excessive e − , the two nitrogen atoms e − are pulled towards them and ring carbon atoms remain with low e − density and consequently no electrophilic substitution possible in unsubstituted 1,3,4-thiadiazole ring.
(a) Attack at Ring Nitrogen (Quaternization). Ratio of 3 or 4 substituted product depends on ring substitution, in which nitrogen has high e − density (Scheme 13).

Reaction Involving Formation.
On heating, 2-amino thiadiazole reacts with many dicarbonyl group containing compounds and forms various types of rings attached to thiadiazole (Scheme 25).

Scheme 13
which, on treatment with methyl iodide, gives the expected 2-ethyl homologue (R=Me); if (R=Li) is allowed to warm from −78 ∘ C to 25 ∘ C the dimer is formed, which on heating above 150 ∘ C converts into starting material. The dimerization proceeds via intermediates and not the ketone amine (Scheme 31).

Amino Substituents.
The reaction of unsubstituted 2amino-1,3, and 4-thiadiazole with 1,3-dicarbonyl compounds is independent of the nature of the dicarbonyl compounds. The reaction of pentane-2-4-dione gives the 4,6-dimethyl 1,2thiocyanatepyrimidine. The formation may proceed via the cation. With ethylacetoacetate, however, if a mixture formed also being converted in to on heating.
Anticonvulsant Activity of Thiadiazole Derivatives. A series of 3-aryl amino/amino-4-aryl-5-imino-D2-1,2,4-thiadiazole has been synthesized and screened for anticonvulsant activity. All the synthesized compounds were evaluated against maximal electroshock-induced seizure (MES) and subcutaneouspentylenetetrazole-(ScPTZ-) induced seizure models in mice. Among the compounds tested, all showed protection from MES seizures, whereas only (104) (105) was found to be active in the ScPTZ test. The present results revealed that a number of 3-aryl amino/amino-4-aryl-5-imino-D2-1,2,4thiadiazoles exhibit a range of activities in anticonvulsant screen [78].  A series of new substituted 1,2,4-thiadiazoles were synthesized by appropriate route and screened for anticonvulsant, neurotoxic, and sedative-hypnotic activities. The structures of the synthesized compounds were confirmed by IR spectroscopy, C-13 NMR, and elemental (nitrogen and sulphur) analysis. After i.p. injection of the compounds to mice or rate at doses of 30, 100, and 300 mg/kg, body weights were examined in the maximal electroshock-induced seizure (MES) and subcutaneouspentylenetetrazole-(scPTZ-) induced seizure models after 0.5 and 4 h. All the compounds showed protection against MES screen after 0.5 h. Compounds were active at the doses of 100 mg/kg and 300 mg/kg dose i.p. It may be concluded that the synthesized compounds were potent against MESinduced seizures than ScPTZ-induced seizures [79] (Structure (106)). A series of five-membered heterocyclics were synthesized by the reaction between isoniazid and various substituted isothiocyanates and tested for their anticonvulsant activity by determining their ability to provide protection against convulsions induced by electroconvulsiometer. Among the synthesized compounds, (107f) 2-(4-chlorophenyl) amino-5-(4-pyridyl)-1,3,4-thiadiazole and (108f) 2-(4-chlorophenyl)amino-5-(4-pyridyl)-1,3,4-oxadiazole were found promising compounds of the series [80].   (111a), (111b), and (111c) showed good anticonvulsant activity in the test models [82]. Two new series of 2,5-disubstituted-1,3,4-thiadiazoles were synthesized for their possible anticonvulsant, antibacterial, and antifungal activities. The degree of protection afforded by these compounds at a dose of 100 mg/kg i.p. against pentylenetetrazole-induced convulsions in mice ranged from 0% to 90%. Among these compounds, 112a (90%) and 112g (70%) showed maximum protection [83]. methyl]-1,3,4-thiadiazol-2-yl}-N-arylamines have been prepared. Behavioral effects, induced by the members of both series, in conjunction with their activity in some specific tests (forced swim, pentetrazol convulsions) on mice, show that these derivatives cross the blood-brain barrier and could develop an antidepressant activity comparable to that of imipramine. Blood-brain barrier penetration is also supported by the lipophilicity data obtained for all analogs [84]. (Structure (113)). The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted- [1,2,4]triazolo [3, 4-b] [1,3,4]thiadiazole derivatives and their partially dehydrogenated products 5,6-dihydro-6-substituted- [1,2,4]triazolo [3, 4-b] [1,3,4]thiadiazole derivatives. The bioevaluation demonstrated that most compounds in the series exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6-(4-chlorophenyl)- [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazole (117) emerged as the most promising candidate on the basis of its favorable ED50 value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 117 against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-induced seizure tests suggested that compound 117 displayed broad-spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system [86]. Synthesis and pharmacological evaluation of a number of substituted 1,3,4-thiadiazole the first member of the series 2-(aminomethyl)-5-(2-biphenyl)-1,3,4-thiadiazole (118) was found to possess potent anticonvulsant property in rats and mice and compared favourable with the standard anticonvulsant drug phenytoin, Phenobarbital and carbamazepine in a number of test situations. The potency of compound was maintained on alkylation of the side chain nitrogen atom; however, aryl substitution on chain lengthening caused a drop in potency replacement of the two biphenyl group by phenyl or benzyl also lead to inactive compound [87]. Various N-(5-chloro-6-substituted-benzothiazol-2-yl)-N -(substituted phenyl)- [1,3,4]thiadiazole-2,5-diamines were designed and synthesized starting from substituted acetophenones. Structures of all the compounds were confirmed on the basis of spectral and elemental analyses. All the newly synthesized compounds were screened for their anticonvulsant activity and were compared with the standard drug phenytoin sodium. Interestingly, all the compounds showed protections against seizures in the range 50%-100% indicative of the promising nature of the compounds against seizure spread. Compound 119 showed complete protection against MES-induced seizures [88].  A series of 1,2,4-thiadiazoles (120a-e) were prepared and evaluated for anticonvulsant activity by Siddiqui et al. The compound with para-chloro substitution (120c) showed maximal activity in MES test and blocked strychnine seizures to some extent whereas other compounds of the series were less active [89].  121(a-w) were designed, synthesized in good yields. The compounds were evaluated for anticonvulsant activity. The compounds were potent in MES test and were less neurotoxic as compared to standard drug phenytoin [90]. A series of thiadiazole derivatives were synthesized with differently substituted benzoic acids which were cyclized to give differently substituted thiazolidin-4-one. Elemental analysis, IR, HNMR,C NMR, and mass spectral data confirmed the structure of the synthesized compounds. The derivatives of these moieties were evaluated for anticonvulsant activity by MES model and neurotoxicity by rotarod method. The synthesized compounds showed good potential for anticonvulsant activity besides this, and the compounds also showed neurotoxic effect. It was observed that compounds with OCH3 at 3, 4 position of phenyl ring showed less protection against convulsions as compared to compounds having unsubstituted phenyl ring [91].
The synthesis and anticonvulsant activity of a series of 2aryl-5-hydrazino-1,3,4-thiadiazoles are described. The combination of preferred aromatic substituents in the 2-position coupled with alkyl substitution on the hydrazine moiety led to a number of potent compounds lacking sedation, ataxia, or lethality. 5-(2-Biphenylyl)-2-(1-methylhydrazino)-1,3,4-thiadiazole (4m) represents a new class of anticonvulsant agent and compares favorably with the standard drugs phenytoin, phenobarbital, and carbamazepine [92] (Structure (122)).   methanone]-semicarbazones were synthesized and evaluated for their anticonvulsant potential using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPFZ) models. The minimal motor impairment (neurotoxicity) was determined by rotarod test. The results of the present study confirmed the requirements of various structural features of four binding site pharmacophore model for anticonvulsant activity [93].