Recent Update on 1,3,4-Thiadiazole Derivatives: As Anticonvulsant Agents

Vinit Raj , Amit Rai , Mahendra Singh*

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1,3,4-thiadiazole is one of the most potent heterocyclic containing carbonic anhydrase and antibacterial inhibitor from the natural and synthetic origin. It possessed potent anticonvulsant activity in wide range preclinical in vitro and in vivo models. Recently, various 1,3,4-thiadiazole derivatives have been synthesized and evaluated their anticonvulsant activity. This review is a demonstration to compile the medicinal chemistry, anticonvulsant screening and their structural activity relationship as well as pharmacophoric pattern of various synthesized 1,3,4-thiadiazole derivatives.

Key words: 1,3,4-thiadiazole, anticonvulsant, structure activity relationship and mechanism of action. 



In the last few years, heterocyclic compounds were not only used for development the heterocyclic derivatives, but also argumentation of the application in pharmaceutical and chemical field. Till date various heterocyclic compounds had been synthesized and evaluated for their significance. Firstly, Fischer was introduced 1,3,4- thiadiazole in 1882, whereas Freund and Kuh were described the true nature of the ring. In addition, thiadiazole is a widespread and important five-member heterocyclic system which contains two nitrogen atoms and a sulfur atom. 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole isomer of thiadiazole was discovered and evaluated for the biological activity.  


As per previous literature survey indicated that 1,3,4-thiadiazole have been most promised isomer than the other. Due to the sulfur atom of 1,3,4-thiadiazole ring produced the inductive effect, in this way shown very weak base property and possesses relatively high aromaticity[1-3]. 


In addition, the nitrogen atoms of 1,3,4-thiadiazole ring is also shown to be very electron underprovided due to the electron-withdrawing effect and comparatively still toward electrophilic substitution, but susceptible to nucleophilic attack. Thus, possessing the substitution into the 2′ or a 5` position of this ring and these substitutions involves highly activating reaction.

Till date many 1,3,4-thiadiazole nucleus containing drugs are available in the market such as acetazolamide, methazolamide, megazol and whereas 1,2,4-thiadiazole ring containing drug is the antibiotic cefozopram [4,5]. 



In this review, We give an overview to synthesis as well as the structure activity relationship of 1,3,4-thiadiazole derivatives. On the basis of the literature survey of cited references 1, 3 , 4-thiadiazole ring contain compound shown the medicinal importance to treatment the epileptic condition. 


Till date various molecular target had been investigated for the treatment of epilepsy as following

2.1. Nonsynaptic mechanisms

Alterations in ionic microenvironment; e.g., increased extracellular K+, decreased extracellular Ca++

Decreases in size of extracellular space

Failure of ion transport: Na+ , K+ pump or Cl- , K+ co-transport

- Presynaptic terminal bursting

- Ephaptic interactions

2.2. Synaptic mechanisms

- 1. Depression of GABA-ergic inhibition

2. NMDA receptor activation; voltage-dependent EPSPs

- 3. Frequency potentiation of EPSPs

4. Actions of modulators

These molecular targets related to blockage of voltage-dependent sodium channels to inhibit release of excitatory neurotransmitters, enhanced GABA-ergic transmission, inhibition of T-type calcium channels or kainite/AMPA receptors and a combination of the above actions [2].

Another approach has been identified in 1952. In which, 1,3,4-thiadiazole containing acetazolamide AZA targets carbonic anhydrase, in the brain has a significant role in the neurone-glia metabolic relationship. Carbonic anhydrase acted on the seizure by the mechanism that CAs catalyzes interconversion of CO2 and HCO3 the latter of which combines with hydrogen exchange across the glial membrane for sodium and chloride as well as contributed the current through the γ-amino butyrate A (GABAA) receptors. CAs are also involved in the maintenance of Cl− and K + concentrations in glial cells [15, 16, 17]. 

2.3. Essential Pharmacophore for anticonvulsant activity 

A pharmacophore based approach is one of the few applicable tools in modern drug design. Which is essential to develop new ligands with high affinity of binding to a given protein receptor. Whereas, this is the 3D arrangement of features in the biologically active compound that is responsible for its against a particular protein target. On the facts, if the 3D structure is available for several ligands bound to the same binding site of the same protein and in this way, observing their common arrangement of ligands into the binding site of a protein, referred to as the pharmacophore. Thiadiazole ring expressed diverse biological activities, might be due to the presence of =N-C-S moiety [18].

S. N. Pandeya [19] proposed that the following features are important for anticonvulsant activity.

- Hydrophobic aryl ring (Ar),

- A hydrogen bonding domain (HBD),

- An electron-donor group (D) and

Another distal hydrophobic site



                                           Fig6. Pharmacophoric pattern of well-known antiepileptic drugs

2.4. Review literature of 1,3,4-thiadiazole derivatives as an anticonvulsant Christopher B. Chapleo et al. (1986) [20] synthesized a series of 2-aryl-5-hydrazino-l,3,4-thiadiazole derivatives and evaluated them for anticonvulsant activity. Among them, N-methylhydrazine 1 shown potent anticonvulsant activity in rodent models of grand mal epilepsy and it has neither produced neurotoxicity nor cardiovascular actions occur at anticonvulsant doses. 


(a) Unsubsituted Compounds

Substituent in the 2-position of the aromatic ring produced compounds (i.e., 2-6) shown desirable anticonvulsant activity with significantly reduced neurotoxicity in comparison to the 2-CH3 compound 2 and replacement of the 2- phenyl group (4) by a 4-phenyl (6) shown a complete loss of activity. 



(b) N`-Monosubstituted Compounds

The one side substitution at N1 in the 2-chloro and 2-phenyl series resulted in a decrease or loss of activity (i.e., CH3, i-Pr, n-Bu, Ph, CH2Ph, CH2CH2Ph, cyclohexyl). One except benzyl derivative, which possessed a good profile of activity the ether containing group CH2OCH3, in place of CH3 would enhance the activity. The methylhydrazines had shown the most potent anticonvulsant activity in this series, especially the benzyl (7), 2-phenyl (8), and 2- hexyloxy (9) derivatives, although the latter produced sedation as observed in the rotorod screen. 


(c) N2-Monosubstituted Compounds 

The isopropyl derivatives 10, 11 and 12 shown significant anticonvulsant activity; loss of activity observed when introduces 2-hexyloxy substitution in the 13 compound. Unexpectedly, the methyl derivative 14 was shown the loss of anticonvulsant activity in the 2-CH, series and retained some of the antihypertensive activity. From the above suggestion, that better activity could be expected if the isopropyl group was replaced by cyclopentyl or benzyl groups. 


(d) N`, N2-Disubstituted Compounds 

Potent anticonvulsant activity was produced when the disubstitution with lower alkyl groups in the 2-CH3 and 2-C1 series compounds. Although, in the 2-phenyl and 2-hexyloxy series (i.e., 14-17) the potency was somewhat reduced and sedation was not apparent. The position of the isopropyl group in attached to N2, shown the activity in the following compounds 15, 16, 18, 19, and excepted then 20, 21. When the isopropyl group was replaced by the more lipophilic cyclopentyl group (i.e, 22 and 23), then the activity was reduced. 


(e) N2-Disubstitution

Reduction in activity was found when disubstitution on the terminal nitrogen atom with the respective CH3-series. 


(f) Trisubstitution

It was observed that the trimethylated derivatives 26, 27 and 28 have somewhat anticonvulsant activity compared than other compounds of this series. Substitution of the methyl group on N` by larger groups considerably reduced this activity as seen with 29 and 30. Among of all the hydrazines examined, the most promising profile of activity is found in compounds based on the 2-Ph series. 


Michael R. Stillings et al.(1986) [21] synthesized a series of substituted 1,3,4-thiadiazoles derivatives and evaluated for the anticonvulsant activity. Among them, the most potent 2-(aminomethyl)-5-(2-biphenylyl)-1, 3, 4-thiadiazole (31) compound showed anticonvulsant activity in both rats and mice and compared with the standard anticonvulsant drugs phenytoin, phenobarbital, and carbamazepine. This compound was produced 6.5 protective index (PI) (TD50 divided by ED50 i.p. at time of peak effect) as the compared phenytoin, phenobarbital, and carbamazepine were 7, 4.8, and 11, respectively. 


SAR study of the synthesized compounds reveals that the introduction of alkylation of the side-chain nitrogen atom produced the potent compound. However, aryl substitution or chain lengthening decrease the activity. Replacement of 2-biphenylyl group by phenyl or benzyl caused loss of anticonvulsant activity. Whereas, the n-propylamino derivative (32) was devoid of anticonvulsant activity. The branched-chain substitution of derivative (33) still retained significant activity. Further introduction of aryl group in compound 34 and another 2-biphenylyl group of substitution in the phenyl (35) and benzyl (36) derivatives shown the lack of another approach was found if the 2- phenyl group into the benzyl derivative to give the biphenylylmethylene compound (19) caused a marked increase in activity. Introduction of the 2-biphenylyl moiety in compounds 16 and 17, which showed some anticonvulsant activity. 


          Fig16. Structure formulae of Substituted 1,3,4-Thiadiazoles

Christopher B. Couple et al. (1987) [22] synthesized a series of 2-aryl-5-guanidino-1,3,4-thiadaizole derivatives and screened them for anticonvulsant activity. Among them unsubstituted guanidine (40) showed potent anticonvulsant activity in the rat MES model and the level of neurotoxicity shown in acceptable range.

SAR study of synthesized compounds reveals that 40 is the most potent anticonvulsant agent than the other compounds of this series. Considerable of substituted guanidines is an essential key to the reduction or loss of activity of synthesized derivatives. Internalization of the guanidine group into an imidazoline ring also resulted in a loss of activity. However, with the exception of methylated derivative 41, the terminal of methyl group with the substituted guanidines were found to reduction or complete loss of activity and the guanidine grouping into an imidazoline ring also devoid of anticonvulsant activity.


Christopher B. Chapleo et al. (1988) [23] synthesized two novel series of 2-aryl-1, 3, 4-thiadiazole amidines and evaluated for anticonvulsant activity using by MES model. Among them the most potent 42 compound occurred in the 5-[2 (trifluoromethyl) phenyl] series, but the level of sedation was also high. Whenever, the 2-methyl series it was found that the N-buty analogue 43 possessed higher anticonvulsant activity and lesser neurotoxic effects than the parent amidine 44. The N-substituted analogues 45-47 are also more significant effect in the MES test than 44, but less so than 43. However, in the 2-trifluoromethyl series, the parent amidine containing possessed slightly higher anticonvulsant activity than the N-butyl analogue, although both compounds possessed a similar level of neurotoxicity. A similar finding was observed in the 2-phenyl series 48-49 (MES test). 



H. N. Dogan et al. (2002) [24] synthesized two new series of 2,5-disubstituted-1,3,4-thiadiazoles derivatives and evaluated them for anticonvulsant activity. Among these compounds, 50 (90%) and 51 (70%) showed maximum protection at a dose of 100 mg/kg ip against pentylenetetrazole-induced convulsions. The ED50 values of the most effective compounds, 50 and 51 were 33 and 66 mg/kg, respectively. The lower dose (50 mg/kg) was ineffective (50: 50% and 51: 40%) and the higher dose (150 mg/kg) did not increase the efficiency (50: 90% and 51: 70%). Therefore the dose of 100 mg/kg was selected as the best one.


Archanaet al. (2002)[25] synthesized a series of 3-{[5-(alkylbenzylideneamino)-1,3,4-thiadiazol-2yl]methylamino}- 2-methyl-6-monosubstituted quinazolin-4(3H)-one and evaluated them anticonvulsant activity using by in MES models and PTZ model also. Among them the most active compound was 3-({4-[2-(m-methoxy-phydroxyphenyl)-4- oxo-1,3-thiazolidin-3-yl]-1,3,4-thiadiazol-2-yl}methylamino)-2-methyl-6-bromo-quinazolin-4(3H)-one (52). 

The SAR study of synthesized compounds reveals that the presence of a five-membered thiadiazole ring at the 3rd position of 3-amino-2-methyl-6-monosubstituted quinazolin-4(3H)-onyl moieties which were further substituted with alkyl benzylidenyl groups at the 2nd position of five-membered thiadiazole ring are the essential for the anticonvulsant activity. Whenever, compounds having 3-amino-2-methyl-6-bromoquinazolin-4(3H)-onyl moiety showed more protection in comparison to compounds having 3-amino-2-methylquinazolin-4(3H) onyl moiety. It was observed that compounds having phenyl group and 3-methoxy-4-hydroxy phenyl ring produced the maximum percent protection (70 and 80%, respectively) against seizures induced by MES. Compounds substituted with 4- methoxyphenyl group and 3-methoxyphenyl group exhibited 60 and 70% inhibition of seizures, respectively. Compounds having 4-hydroxy phenyl group also elicited remarkable anticonvulsant activity. It may be concluded that substitution with 3-methoxy-4-hydroxyphenyl group is beneficial for anticonvulsant activity.

Further, the next step of the series was characterized by the presence substituted with 3-methoxy, 4-hydroxy phenyl group shown most potent activity of 80 and 90%, respectively 


Hatice N. Dogan et al. (2002) [26] synthesized two new series of 2,5-disubstituted-1,3,4-thiadiazoles and evaluated them for anticonvulsant activity. Among them, compounds 53 (90%) and 54 (70%) showed maximum protection. The acetylation of thiadiazoles retained anticonvulsant effectiveness to a lesser degree. The ED50 values of these compounds were 33 and 66 mg/kg, respectively. Therefore the dose of 100 mg/kg was selected as the best one.