INTRODUCTION:

A highly appreciable number of five membered heterocycles, containing nitrogen & sulphur atoms, have turned out to be potential chemotherapeutic and pharmaco therapeutic agents. The biological profile of Thiadiazole derivatives is veryextensive¹. Thiadiazole is a 5-membered heterocyclic system containing two nitrogens and one sulphur atom. Various useful synthetic analogues with improved therapeutic properties can be obtained from a single lead compound by structural modification. The same principle is applicable to the group of thiadiazoles².The four isomeric forms are possible for thiadiazoles. They are 1,2,3-thiadiazoles,1,2,4-thiadiazole³,1,2,5-thiadiazole⁴,1,3,4-thiadiazoles⁵. The cyclic tautomer is the preferred structures for the 1,2,3-thiadiazoles,however benzo-fused analogues of 1,2,3-thiadiazole and of the 1,2,5-isomers also exist. Thiadiazole moiety act as “hydrogen binding domain” and “two electron donar system”. It is also act as apharmacophore. Nucleophilic substitution reactions are common in the thiadiazoles⁶.

The presence of –N=C-S moiety,1,3,4-thiadiazole derivatives also shows very good antimicrobial activity⁷besides this it also shows, antioxidant/radio protective activities, anti-inflammatory, molluscicidal activity, carbonic anahydrase inhibitor, anticancer, anticonvulsant, antifungal, antibacterial, anticholinergic, antihistaminic, antidepressant, antituberculosis, other activities.

Tautomer form of 1,2,3-thiadiazole

Anti Oxidant/ Radio Protective Activity:

Some novel 5-[(2-(substituted phenyl)-1H-benzimidazole-1-yl) methyl]-N-methyl-1,3,4-Thiadiazole-2-amines were synthesized and tested for antioxidant properties by Kus et al ⁸

Using various invitro systems. (B), which is the most active derivative inhibited Lipid peroxidation slightly at 10-³_M concentration.

Thiol and aminothiol compounds are among the most efficient chemical radio protectors. Prouillac et al ⁸synthesized thiol and aminothiol compounds derived from thiadiazole structures (C- a and C-b). They examined them for their ability to scavenge free radicals (DPPHŸ, ABTSŸ+, OHŸ). Thiol derivatives with a thiadiazole structure are the most active compounds scavenging DPPH Ÿand ABTSŸ⁺free radicals, with an IC₅₀ of 0.053 ±0.006 and0.023 ±0.002 mM, respectively, for the derivative (C-a). Moreover compound (C-a) at 60µM gave 83%protection against 2-deoxyribose degradation by ŸOH. In both the test thiol derivatives were most efficient. Compound (C-a) totally inhibit DNA strand breaks at the concentration of 50µM.

The antioxidant activity evaluated by Cressier et al⁸demonstrated that the thiol, thiosulfonic acid and phosphorothioate derivatives of thiadiazoles (A-a and A-b) exhibit evident antioxidant activity. Anti oxidant activity of thiol derivatives shows the hypothesis of a directlink between thiol function and an aromatic ring to be a good one. The thiol catches theradical and after, the aromatic ring permit’s the trapping of this radical. Moreover aminothiol derivative of thiadiazole shows a better activity.

(A) A(a)= X =CH₂ ;A-b = X = O

(B) B(a)= R = SH, R₂ =SCH₂CH₃

B(b)= R = SH, R₂ = CH₂CH₃

B(c )=R = NHCH₂CH₂SH.HCl, R₂=CH₂CH

C(a)

R = -SCH₂CH_3, -CH₂CH₃

R¹ = -SH,- NHCH₂CH₂SH

C(b)

R = -SCH₂CH_3, -CH₂CH₃

R¹= -SO₃H, -PO(OH)₂

In vitro Inhibition of Cyclooxygenase and 5-Lipoxygenase activities (1,3,4-Thiadiazole analogs) of the Fenamates:

N-Arylanthranilic acids known generally as the fenamates ,are non steroidal anti-inflammatory drugs (NSAIDS)that block the metabolism of arachidonic acid by the enzyme cyclooxyygenase. Substitution of the carboxylic acid functionality of several fenamates with the acidic heterocycles provided dual inhibitors of CO and 5-lipoxygenase (5-LO)activities when tested in an intact rat basophilic leukemia (RBL-1)cell line was studied by Diane H.Boschelli et.al⁹. They synthesized many compounds in which 5-(2-[[3-(Trifluoromethyl)phenyl]amino]phenyl]-1,3,4-thiadiazole-2(3H)-thiones are the most potent inhibitors of 5-LO and CO activities. Remaining compounds having moderate activity. Both of the above heterocyclic analogues off lufenmic acid are also active in Carrageen-induced rat foot pad edema (CFE),a model of acute inflammation. When dosed orally the LD_50s for compound(D )in CFE is 4.7mg\kg.

(D)

Molluscicidal Activity:

Nizamuddio et al ¹⁰synthesized ,some new 6-carboethoxy-(2-substitued)-1,3,4-thiadiazole[2,3-b]pyrimidine-5-ones and 5-amino-(2-substituted)-1,3,4-thiadiazoles [2,3-b]pyrimidine-7-ones and subjected them for molluscicidal activity and evaluated against the snail Lymnaea acuminate which is a vector of giant lever flukes, Fasciolagigantic and Fasciola hepatica. The molluscicidal data indicated that all tested compounds showed strong to moderate activities. Themolluscicidal activity of the entire compounds is dose and time dependent .The studies clearly indicate that thiadiazolopyramidinone system with amino group has greater activity than other comparable systems. Presence of amino group in pyrimidine ring increases activity many fold. Molluscicidal activity depends on the nature of substituents also for the same system. The electron donating substituents such as methyl, methoxy group enhanced the molluscicidal activity. On the other hand the electron with drawing substituents such as chloro decreased the molluscicidal activity.

(E) R= -CH_3,-OCH_3,-Cl

CARBONIC ANAHYDRASE INHIBITORS:

A series of 2-substituted-1,3,4-thiadiazole-5-sulfamide (F) were assayed by Smaine et al⁸. as inhibitors of several Carbonic anhydrase is forms, the cytosolic CAI and II, the membrane-associated CAIV and the mitochondrial CA VA and VB. The new compounds were low lownanomolar inhibitors of hCA VA and hCA VB. These sulfamides were made the first selective CA VA/VB inhibitors.

Almajan et al⁸ assayed a series of heterocyclic mercaptans incorporating 1,3,4-thiadiazole for inhibition of three physiologically relevant CA isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX. The best inhibitors were simple derivative 5-amino-1,3,4-thiadiazole-2-thiol (G)and its acetylated derivative. 5-(2pyridylcarboxamido)-1,3,4thiadiazole-2-thiol is the first hCA I selective inhibitor.

(F)

(G)

Anti-Cancer Activity:

Terzioglu and Gursov¹¹ have evaluated the anti cancer properties of 2,6-dimethyl-N¹-substituted phenylmethylene-imidazo[2,1-b]-1,3,4-thiadiazole-5-carbohydrazide hydrazones. 2,6-dimethyl-N¹-(2-hydroxyphenyl methylidene)-imidazo[2,1-b]-1,3,4-thiadiazole-5-carbohydrazide [H] has the most favourable cytotoxicity, being more active than chlorambucil,5-fluorouracil and melfalan.

Hollaet al.¹²have tested 1,4-bis-(1,2,4-triazolo[3,4,-b]-1,3,4-thiadiazol-3-ylmethoxy)phenylene and 1,4-bis(6-aryl(mercapto)-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazol-3-ylmethoxy)phenylenes for their anticancer properties. The experiments were performed on 60 cell lines; three of the tested 1,4-bis-(6-aryl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-3-yl(methoxy)phenylenes and two of the 1,4-bis-(6-mercapto)-1,2,4-triazolo-[3,4-b-]-1,3,4-thiadiazol-3-yl methoxy)phenylenes [I] showed good activity against a number of cell lines. A number of imidazo(2,1-b)-1,3,4-thiadiazoles were tested for their antitumor activity by Gadadet al.¹³ 5-Formyl and 5-bromo derivatives showed high anti tumor properties in most cell lines; substitution at 6-position produced different selective cytotoxicity.

[H]

[I]

Anticonvulsant Activity:

Doganet al.¹⁴ have reported anti-convulsant activities of a seriesof 2-amino-5-(3-hydroxy-2-naphthyl)-1,3,4-thiadiazole derivatives. Their anti-convulsant properties were determined against phenylenetetrazole induced convulsions in mice. 2(m-flurophenyl-amino)-5-(3-hydroxy-2-naphthyl)-1,3,4-thiadiazole [J] showed similar protection to that of sodium valproate.

Similar studies have been perfomed by Srivastavaet al.¹⁵for 2-benzylidinenylamino-5-(N⁹-carbazoylmethyl)-1,3,4-thiadiazoles and 1-(5-N⁹–carbazoylmethyl)-1,3,4-thiadiazol-2-yl)-4- phenyl-3-chloro-2-oxoazetidines;some of the compounds showed promising protection.

Archanaet al.¹⁶have screened a series of 5-(2¹-indoyl (phenolthiazinyl)methylene-5¹-aminoethylene-1¹,3¹,4¹-thiadiazol-2¹-yl)-2-thiobarbituric acids for their anti-convulsant properties. The most active appeared to be 5-(2¹phenathiazinyl methylene-5¹-aminomethylene-2¹,3¹,4¹-thiadiazol-2¹-yl)-2-thiobarbituric acid[K] being more active than the standard drug phenytoin sodium.

[J]

[K]

Anti-fungal Activity:

Few compounds of 2-(2-methyl thiazol-4-yl)-5-aryl-1,3,4-thiadiazoles [L] and 2-(2-methyl thiazol-4-yl)-5-substituted amino-1,3,4-thiadiazole [M] derivatives were evaluated for their anti-fungal activity invitro against Pythiumaphanideratum, Attermariasolani, and Fusariumudum by poison food technique¹⁷ .The desired concentrations (5,10,20,50ppm) of each compound were incorporated in warm sterile potato dextrose agar (PDA) medium. The mediumshaken well to give uniform dispersal of the compound poured into sterile petridishes in three compounds of 2-(2-methyl thiazol-4-yl)-5-aryl-1,3,4-thiadiazoles [L] and 2-(2-methyl thiazol-4-yl)-5-substituted amino-1,3,4-thiadiazole[M] derivatives were evaluated for their anti-fungal activity invitro against Pythiumaphanideratum, Attermariasolani, and Fusariumudum by poison food technique¹⁷.The desired concentrations (5, 10, 20, 50ppm) of each compound were incorporated in warm sterile potato dextrose agar (PDA)medium. The medium was replicates for each treatment. The plates were inoculated by inoculum disc of 4mm diameter cut from the margin of a 6-day old colony of the test pathogen cultured on PDA and inoculated at 28+/-2 degrees for 7days.

All the compounds tested for their fungicidal activity were found to be active and have significant activity as compared to the reference compounds. No definite structure activity pattern is discernible from the results. Also some derivatives 5-aryl-1,3,4-thiadiazolin-2-thiones were tested for their anti-fungal activity by cup plate method¹⁸and the fungi employed were F.oxysporum and C.lunata. Clotrimazole employed as the standard comparison. And the results revealed that the derivatives of thiadiazoles were found to be relatively more effective towards C. lunata when compared with F. oxysporum. Even though the compounds exhibited reasonable activity, the antifungal activity of these compounds is not comparable with that of the standard employed.

[L]

[M]

ANTI- BACTERIAL ACTIVITY:

The anti-bacterial activity of the following Thiadiazoles [N,O,P] was assayed, systematically against five different strains of bacteria; B. subtilis, B. mycoides, E. coli, P. aeruginosa and P. vulgaris (two gram positive and three gram negative) by agar diffusion method¹⁹. Benzyl penicillin and streptomycin as standards. The results were found that the present compounds are relatively less effective against both the gram-positive bacteria and specifically more effective against the gram-negative. Even amongst the three strains of gram-negative bacteria, the compounds were significantly potent against P. aeruginosathan the other two. But, however, their potency was not at all comparable with that of the standard, since the compounds could exhibit anti-bacterial activity only at considerably higher concentration in comparison to that of standard.

Megazol,(2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazol and a number of its derivatives were found to be effective against Trypanosomabrucei, microbials which cause sleeping sickness in Africa^20-22. It is worth noting that the activity was lost when the thiadiazole ring was exchanged for oxadiazole.

[N]

[O]

[P]

Anti-cholinergic Activity:

The anti-cholinergic activity of the compounds of derivatives of 5-aryl-1,3,4-thiadiazolin-2-thiones [N,O,P] were screened by using rat intestine, following the standard procedure²³. The results were found that the anti-cholinergic potency of new derivatives is not comparable with that of the standard atropine employed in the investigation. They could exhibit the activity only at quite higher dose. But, amongst all the present compounds, compound [P]with a 4-nitro-phenyl and ethyl substituent was found to be more potent with an IC₅₀ value: 141 mcg.

Anti histaminic Activity:

The compounds of derivatives of 5-aryl-1,3,4-thiadiazolin-2-thiones [N,O,P] were screened for their anti-histaminic activity by using isolated Guinea-pig ileum method²⁴ at concentration employed as a reference for comparison. The results were found that the compound [P],with a 4-nitro phenyl and ethyl groups is relatively more potent against all the present compounds with IC₅₀:508µg and the second in order being the compound [P]with 4-nitrophenyl and a dicyclohexylamino groups.

ANTI-DEPRESSANT ACTIVITY:

Clerici and Pocar²⁵ have found that a number of 2-amino-5-sulfanyl-1,3,4-thiadiazoles are characterized by anti-depressant and anxiolytic properties comparable to imipramine or diazepam. The most promising compound, with very low side effects was observed with 2-amino-5-(3-methoxybenzylsulfanyl)-1,3,4-thiadiazole [Q]. Promising anti-depressant activity was also observed for N-{5-[(2-methyl-1H-3-indolyl)methyl]-1,3,4-thiadiazol-2-yl}-N-phenylamine²⁶.

[Q]

Anti-tuberculosis Activity:

The anti- tuberculosis activity (against Mycobacterium tuberculosis) evaluated by Rafalfranski²⁷for a series of N-phenyl-N¹-[4-(5-alkyl/aryl/amino-1,3,4-thiadiazole-2-yl)phenyl]thioureas. The highest activity was observed for N-phenyl-N¹-[4-(5-yclohexylamino-1,3,4-thiadiazole-2-yl)phenylthioureas[R].

Similar studies have been performed by Foroumadi et al.^28,29for anti-tuberculosis activity of some 2-(5-nitro-2-furyl)-and 2-(1-methyl-5-nitro-2-imidazoyl)-1,3,4-thiadiazole-2-sulfides,sulfoxides and sulfones and the most and the most active compound was 2-ethylthio-(5-nitro-2-fuyl)-1,3,4-thiadiazole [S].

Mamoloet al.³⁰ have screened thirty four [5-(pyridine-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid benzylidenehydrazides for their anti-mycobacterial activity against Mycobacterium tuberculosis and Mycobacterium avium. Five compounds showed moderate activity against Mycobacterium tuberculosis.4-chloro,2-bromo-,4-bromo-,3-fluoro- and 2,6-dichloro benzylidene derivatives. The compounds studied had rather low activity against Mycobacterium avium.

[R]

[S]

Other activities exhibited by 1,3,4-Thiadiazole Derivatives :

Supuran and co-workers^31-34 have shown that a number of 5-amino-1,3,4-thiadiazole-2-sulfonamides as well as their complexes with Zn(II) or Cu(II), have strong carbonic anhydrase inhibitory properties. Several of the most active inhibitors have a lower intra-occular pressure, thus considered as potentially active anti-glaucoma drugs.

Scozzafava and Supuran³⁵ have also shown that aryl-sulfonyl(ureido)-phenylalanyl-alanyl-5-amino-2-mercapto-1,3,4-thiadiazolesare effective metalloprotease inhibitors.

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Received on 18.01.2013 Modified on 04.02.2013

Asian J. Research Chem. 6(3): March 2013; Page 272-277