Article / Review Article

"1, 3, 4-Thiadiazoles: An Overview"

Dhanapal Visagaperumal*, Jayakumar Ramalingam, Vineeth Chandy

Department of Pharmaceutical Chemistry, T John College of Pharmacy, India

*Corresponding author: Dhanapal Visagaperumal, Department of Pharmaceutical Chemistry, T John College of Pharmacy, Bangalore, India. Tel: +91990896316; Email: chemistryvishak@gmail.com and vishak_dr@yahoo.co.in

Received Date: 12 January, 2018; Accepted Date: 26 January, 2018; Published Date: 01 February, 2018

1.       Abstract

Many of the pharmaceutically important compounds possessed 1,3,4-thiadiazoles as its heterocyclic moiety. They have shown many of the activities like anti-inflammatory, anticonvulsant, antimicrobial, anticancer, antihypertensive. In this review some of the recent work done on the moiety with their activity was given.

2.       Keywords: Biological Activities; 1,3,4-Thiadiazoles

  1. Introduction

A large number of biologically active compounds were having heterocyclic moieties and the molecular framework of the compounds determines the biological activity. Heterocyclic nucleus containing nitrogen atoms were having a special interest because they are in an important class of natural and non-natural products, many of them exhibits usual biological synthesis. Thiadiazoles had an important place in the drug industries. Among that, 1,3,4-thiadiazoles have wide uses in many fields. In the earlier days, they were used in the pharmaceutical area as an antibacterial with known sulphonamides. Then, in later days some of them were used as antitumour, anti-inflammatory agents, pesticides, dyes, lubricants and analytical agents.

1, 3, 4-thiadiazole derivatives is possessing biological activities probably conferred because of strong aromaticity of the ring system, that leads to great in vivo stability and generally, a lack of toxicities for higher vertebrates, including humans. When different functional groups are attached to nucleus it may interact with biological receptors and produce an outstanding property. 1,3,4- Thiadiazoles exhibits various biological activities and find a great use in the fields of pharmaceuticals, acetazolamide, the first non-mercurial diuretic drug [1-4], antitumor agents [5], agrochemicals [6]. Some antibacterial sulphonamides which are not used clinically but possessed historical [7] importance. However, this molecules Thiadiazoles (e.g. 1,3,4-thiadiazoles) exhibit a number of extremely interesting spectroscopic properties, which are also worth mentioning. One of the very interesting spectroscopic properties of Thiadiazoles is the dual fluorescence effect (which can hardly be associated with the ESIPT or TICT effects) [8-11]. Herewith a brief account of various alterations done on the Thiadiazoles nucleus and their biological activities was given.  

    1. Biological Activities

  1. Antimicrobial activity

A.A. Aly, et al. [12] had synthesized a variety of heterocyclic compounds from 2-amino Thiadiazoles like 3-[5-(3-chlorobenzo[b]thiophen-2-yl)-1,3,4-thiadiazol-2-yl]-2-arylthiazolidin-4-ones 1, 1-[5-(3-chlorobenzo[b]thiophen-2-yl)-1,3,4-thiadiazol-2-yl]-3-phenyldihydropyrimidine-2,4,6-trione 2, N-(4,5-dihydro-1H-imidazol-2-yl)-5-(3-chlorobenzo[b]thiophen-2-yl)-1,3,4-thiadiazol-2-ylamine 3, N-[5-(3-chlorobenzo[b]thiophen-2-yl)-1,3,4-thiadiazol-2-yl]-1H benzo[d]imidazol-2-ylamine 4. The compounds were screened for antibacterial activity against Bacillus cereus, Escherichia coli and for antifungal activity against Aspergillus niger and Penicillium notatum. All the compounds have shown a remarkable activity towards the selected strains.

                               

                         

2-[1-(3-nitrobenzoylamino)-3-(methylthio)]-propyl-5-(substituted amino)-1,3,4-thiadiazoles 5 were prepared by Lenuta profire, et al. [13]. All the compounds were tested for antimicrobial activities against Staphylococcus aureus, Bacillus antracis, Bacillus cereus, Sarcina lutea, Escherichia coli. On MIC determination, only the compound containing R=4-CH3 C6H4 had showed good activity at low concentration upon Bacillus aureus and Bacillus cereus. They were also investigated for toxicities and were found to have less toxicity.

       

H.S Joshi, et al. [14] had synthesized a series of 2-(3’-chloro-5’-phenoxy-benzo[b]thiophen-2’-yl)-5-arylamino-1,3,4-thiadiazoles 6 and tested their antimicrobial activity. They found that when R=4-Cl C6H4 and R=4-CH3 C6H4, the compound showed good activity against Escherichia coli and R=3-Cl C6H4, 4-Cl C6H4 they showed good activity against Bacillus megaterium and with R=C6H5 and R=2-NO2 C6H4 it showed good activity against Staphylococcus aureus. When the compound possessed R=C6H5, 3-Cl C6H4, 4-Cl C6H4 a good activity against Aspergillus niger was found. All the other compounds have shown mild activity against other organisms.

Some 2-aryl-5-(6’-chloro-1’,3’-benzothiazol-2-yl-amino)-1,3,4-thiadiazoles 7 were screened for antibacterial activity against E coli, Staphylococcus aureus, Pseudomonas aeruginosa and for antifungal activity against Aspergillus niger, Candida albicans by Mohd Amir, et al. [15]. Acetoxy phenyl derivative showed potent activity against Staphylococcus aureus and when R=2-naphthylmethyl, it showed good activity against E. Coli and with R=2,4-dichlorophenyl containing compound showed significant activity against bacterial strains. When R=2-aminophenyl and R=2, 4-dichloro phenoxy methyl gave good antifungal activity against Aspergillus niger and Candida albicans respectively.  

P. Mishra et al. [16] prepared some new 2-methyl-3-(1,3,4-thiadiazoyl)-4-(3H) quinazolinones 8 and screened them for them in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, E Coli and Candida albicans, Aspergillus niger, Curvularia lunata for antifungal activity. All the compounds have shown mild to moderate activity. They also determined MIC for the synthesized compounds and found that they had better fungi toxic than bacteriotoxic. Compound with 4-Cl C6H4 had a potent antibacterial and antifungal activity.

Sheena Shashikanth, et al. [17] prepared few 2-(2-aroylaryloxy) methyl-5-N-phenylamino-1,3,4-thiadiazoles 9 and found some active compounds when screened them against Bacillus cereus, Staphylococcus aureus, E coli for antibacterial and Penicillium nigricans, Aspergillus fumigatus, Fusarium solani for antifungal activity. The chloro substitution has shown good activity.

A series of 2,5-disubstituted 1,3,4-thiadiazoles 10 were synthesized by H. Rajak, etal. [18] and found a mild to moderate antimicrobial activity when screened against Staphylococcus aureus, Bacillus aureus, Proteus mirabilis, Pseudomonas aeruginosa and for antifungal activity against Aspergillus niger and Candida albicans. The compound with 4-NO2 C6H4 substituent found to be more active compound, showing a broad spectrum of activity.

Various 1,3,4-thiadiazole derivatives 11 were synthesized by A. Shafiee, et al. [19] and found to be active against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Bacillus subtilis, Clostridium difficile, Aspergillus niger and Cryptococcus neoformans. They found that most of the compounds were active against Bacillus subtilis and Clostridium difficile. 2-butylamino-5-[(4-nitro-1H-imidazol-1-yl) methyl]-1,3,4-thiadiazole had shown good activity against most organisms.

Zi yi Zhang, et al. [20] had synthesized some derivatives of 1,3,4-thiadiazole 13 and screened the compounds for in vitro antibacterial activity at 100 ppm concentration against E coli, Staphylococcus aureus, Pseudomonas aeruginosa and the unsubstituted and 4-Cl substituted compound were found to have moderate active compounds and others were inactive against Staphylococcus aureus.

  1. Antitubercular activity

H.S. Joshi, et al. [14] had synthesized a series of 2-(3’-chloro-5’-phenoxy-benzo[b]thiophen-2’-yl)-5-arylamino-1,3,4-thiadiazoles 6 and tested for antitubercular activity and found that p-methoxy derivative showed good inhibition at 0.25μg/ml than other compounds. Shashikant R Pattan et al [21] prepared some of N’-substituted-N’-[5-(4-nitrophenyl)-[1,3,4] thiadiazol-2-yl]-methanediamines 14 and screened for antitubercular activity. Most of the compounds have shown significant activity.

2 - (3’, 5’ - dichlorobenzo[b]thiophen - 2’ -yl) - 5 - arylamino - 1,3,4 - Thiadiazoles 15 were synthesized by H.S. Joshi and K.M. Thaker [22]. They had evaluated all the synthesized compounds and found that the compound with nitro phenyl shown good inhibition against Mycobacterium tuberculosis H37Rv with 98% inhibition among all compounds. The compounds for antitubercular activity were conducted on organism at 6.25 μg/ml in primary screening and those that have shown >90% inhibitions were compared with standard at 0.25 μg/ml.


  1. Anti-inflammatory activity

Rajesh Sharma, et al. [23] synthesized a series of diaryl substituted 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives 16 and evaluated for anti-inflammatory activity using Carrageenean induced rat paw oedema method. The compound with R=SO2NH2, R1=SO2Cl showed highest selective COX-2 inhibitory activity. Some of the compounds have shown both COX-1 and COX-2 inhibition and some with only on COX-1. They found that some compounds have shown non selective COX inhibitors.

K.M. Basavaraja, et al. [24] prepared few 2-[3-substituted-2-thione-1,3,4-thiadiazole-5-yl] amino bezothiazoles 17 and found a high significant anti-inflammatory activity when R’=diphenylamino, R’=morpholino, R’=diethylamino group.

Some new substituted thiadiazolothieno-pyrimidinones 18 were prepared by Amit Kumar Das et al. [25] and found to have some active compounds when evaluated for anti-inflammatory activity. Some thiadiazolopyrimidinones (R= o-methoxy, m-methoxy, p-methoxy, o-methyl, m-methyl, p-methyl, p-amino, p-chloro) were synthesized. Among these, p-methoxy, o-methyl, m-methyl, p-chloro showed activity after 3 h and o-methoxy, m-methoxy had shown after 2 h from time of administration. p-Amino has shown least activity.

S.K.Srivastava, et al.[26] synthesized new carbazolyl-thiadiazol-2-oxo-azetidines 19 and evaluated their anti-inflammatory activity. Only the compound with Ar=2-Cl C6H4 had shown good activity when compared to other derivatives and all the other compounds have given mild to moderate activity.

B. Gopal Krishna, et al. [27] worked on the synthesis of 5-(2-substituted benzoxazol-5-yl)-2-methyl thio/ benzylthio/ arylamino carbonyl methylthio-1,3,4-thiadiazoles 20 and studied their anti-inflammatory activity. They found that only compound with R=CH2 C6H5 has shown 65.39% inhibition of edema.

A new series of compounds containing 3-alkyl/aryl-6-(1-chloro-3,4-dihydronaphth-2-yl)-5,6-dihydro-s-triazolo[3,4-b] [1,3,4] thiadiazoles 21 were synthesized by Rajive gupta, et al. [28]. They had evaluated their compounds for anti-inflammatory activity and found that all compounds showed mild anti-inflammatory activity of about 3- 12% against acute Carrageenean-induced oedema in rat paw method.

E. Palaska, et al. [29] prepared few derivatives of 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-thadiazoles. They had evaluated the compounds for anti-inflammatory activity and ulcerogenic activities. None of the compounds showed significant side effects.

  1. Antidiabetic activity

Shashikant R Pattan, et al. [30] worked on a few Thiadiazoles derivatives 14 and found some moderate to good active compounds when evaluated for antidiabetic activity. The compound with 4-carboxy-3-hydroxy phenyl amino has shown maximum antidiabetic activity than other derivatives. Some new series of 1,3,4-thiadiazoles 22 were synthesized and they were screened for antidiabetic activity by Shashikant R Pattan, et al. [31]. They had synthesized of about eight compounds of which the compound with R=piperidinyl had shown maximum antidiabetic activity and R=diphenylamino derivative showed moderate activity.


  1. Anticonvulsant activity

A. Foroumadi, et al. [32] reported some novel 2-amino-5-[4-chloro-2-(2-chlorophenoxy) phenyl]-1,3,4-thiadiazole derivatives 23 and studied their anticonvulsant activity using MES and PTZ method. They had synthesized four compounds of which the compound with R=C2H5 had shown good anticonvulsant activity by both methods. While R=CH3 has given the activity only with MES method

Bahar Ahmed, et al. [33] synthesized various compounds of 2-thiobenzyl-1,3,4-thiadiazoles 24 and studied their anticonvulsant activity and neurotoxicity test. They synthesized chlorobezylated imines and benzylated imines. Among these, chlorobenzylated imines have shown 100% protection towards MES induced hind limb extension method with fast recovery and without neurotoxicity whereas benzylated imines showed less protection than chlorobenzylated imines towards MES induced hind limb extension with slow recovery and without neurotoxicity.

Some of the new carbazolyl thiadiazol-2-oxo azetidines 19 had been synthesized by S.K.Srivastava, et al. [34]. They also studied for their anticonvulsant activity and found only the chloro derivatives had given good active compounds than other derivatives.

  1. Analgesic activity

A new series of 4-[5-chlorophenylamino)-1,3,4-thiadiazole-2-yl-sulphanyl]-benzene sulphonamide 16 were synthesized by Rajesh Sharma, et al. [35]. They had synthesized about 15 compounds and evaluated for analgesic activity using tail flick method. They found that compound with R=SO2NH2 and SO2Cl has shown a significant analgesic activity compared to Tramadol HCl. K.M. Basavaraja, et al. [24] prepared a series of 2-[3-substituted-2-thione-1,3,4-thiadiazole-5-yl] aminobenzothiazoles 17 and tested for analgesic activity by using Eddys hot plate method. They had synthesized eight compounds, among which the compound with chloro and morpholino substitution showed higher potency with faster onset of action.

  1. Anticancer activity  

Kemal Sancak, et al. [34] prepared a series of N-[5-({2-[(5-acetylamino-1,3,4-thiadiazole-2-yl) methoxy] substituted phenoxy} methyl)-1,3,4-thiadiazole-2-yl] acetamides 25, N-[5-({2-[(5-acetylamino-1,3,4-thiadiazole-2-yl)methoxy]substituted phenoxy}methyl)-1,3,4-thiadiazole-2-yl]benzamine 26, Ethyl-5-({2-[(4-{ethoxy carbonyl-5-({ethoxy carbonyl}imino)-4,5-dihydro-1,3,4-thiadiazole-2-yl) methoxy] substitutedphenoxy} methyl)-2-[(ethoxycarbonyl)imino]-2,3-dihydro-1,3,4-thiaiazole-3-carboxylate 27. All the new compounds were tested for cytostatic activity on tumor cell lines like breast cancer, on small cell lung cancer and CNS. The best activity was found with compounds containing acetyl an d ethoxy carbonyl groups.

  1. Antihypertensive activity

V. Alagarsamy, et al. [35] had synthesized few 2-substituted [1,3,4] Thiadiazoles [2,3-b] quinazolin-5(4H)-ones 28. The compounds were tested for in vivo antihypertensive activity. They found that compound containing R=NHCH2CH=CH2 has reduced BP significantly when compared to prazocin, the standard.


  1. Antiviral activity

V.K. Pandey, et al. [36] had synthesized few derivatives of 2-aryl-3-[5’-aralkyl-1’,3’,4’-thiadiazolyl-{2’(2”,4”-dipenyl-1”-oxo isoquinolinyl}]-4-oxo-3H-quinazolinones 29 and screened for antiviral activity against influenza virus. The compound with p-chlorophenyl group at 2nd position of quinazolone and methyl group at 5th position of thiadiazole ring showed maximum activity.

V.K. Pandey, et al. [37] prepared few derivatives of 1-(2’-diazo-5’-aralkyl-1’,3’,4’-thiadiazolyl)-6-methoxy[2,3-b] benzophenothiazines 30. They screened the compounds for antiviral activity against Japanese encephalitis (JEV) and Herpes Simplex Virus Type-I (HSV-I). They found that only one compound has shown activity against JEV upto 50% in vitro and also against HSV-I upto 8% in vitro. The compounds that had shown activity had phenyl group as its substitution.

  1. Antioxidant activity

A.S. Mundey, et al. [38] synthesized 5-(4-amino) substituted benzene sulphonamido-1,3,4-thiadiazol-2-sulphonamides 31 and screened their free radical scavenging activity by using 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) method. They found that the unsubstituted derivative has shown moderate activity.

B.K. Karale, et al. [39] had screened the antioxidant activity of some of the synthesized Thiadiazoles derivatives 32. They had evaluated using DPPH method and found only some active compounds among the synthesized derivatives.

Rajive gupta [28] synthesized a series of 3-alkyl/aryl-6-(1-chloro-3,4-dihydronaphth-2-yl)-5,6-dihydro-s-triazolo[3,4-b] [1,3,4] Thiadiazoles 21 and evaluated their antioxidant activity. They had evaluated against sodium nitroprusside induced nitric oxide production, measured by Griess reaction. Among all the synthesized compounds, only the compound containing the substituent like propyl, phenyl, 4-methylphenyl showed significant effect.

  1. Diuretic activity  

Few derivatives of some 1,3,4-thiadiazoles 33 were synthesized by Sanmati K Jaim [40] and also studied their diuretic action. They found that the compound having R=H with X=di-n-propyl/di-isopropyl amino substituent and compound with R=CH3 with X=pyrrolidino substituent showed good activity. The compound having R=CH3O, CH3 and X=2-pyrrolidino substituent showed moderate activity. From the results of compounds on diuretic activity it was found that di-iso propyl amino derivatives are more active than di-n-propyl amino derivatives.


  1. Plant growth regulators

Some of the 2,5-bismercapto-1,3,4-thiadiazole heterocyclic derivatives 34 were synthesized by Tai Bao Wei, et al. [41]. They evaluated the compounds for the plant growth promoters and found some active compounds. They evaluated on the wheat seeds and recorded the length of seedlings and roots by taking the concentration of compounds from 0.001 to 100 ppm. The compounds having the substituent like 2-chloro, 3-chloro and 4-methyl groups had good promoting effects.



  1. Conclusion

The literature reveals that 1,3,4-thiadiazoles has diverse biological potential, and the easy synthetic routes for synthesis have been attention of the chemists, pharmacologists and researchers. The anticancer and antiviral activities were the most encouraging activities for the pharmacists. Also the research on antitubercular activity has given positive results. In conclusion, a wide variety of biological activity of 1,3,4-thiadiazoles has been described.

  1. Acknowledgement

The authors are very much thankful to the Principal and the management of Bapatla Educational Society, Bapatla for the facilities provided in collecting the materials for this work.



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Citation: Visagaperumal D, Ramalingam J, Chandy V (2018) 1, 3, 4-Thiadiazoles: An Overview. Curr Res Bioorg Org Chem: CRBOC-103. DOI: 10.29011/CRBOC -101. 100003