A mini review on pharmacological activities of oxadiazole and thiadiazole compounds

70

A mini review on pharmacological activities of oxadiazole and thiadiazolecompounds

M. Asif

*

(a)Department of pharmacy, GRD (PG) IMT, Dehradun, India

*Corresponding author. E-mail :aasif321@gmail.com

Received 05 May 2014, Revised 04 June 2014, Accepted 06 June 2014.

Abstract

In the last few years, heterocyclic compounds have attracted strong interest and a lot of work has been done on oxadiazole and thiadiazole ring. Oxadiazole and thiadiazole a five member heterocyclic nucleus has attracted a wide attention of the chemist in search for the new therapeutic agents. Various different oxadiazole and thiadiazole compounds have been prepared and possess useful pharmacological activities.

Both oxadiazole and thiadiazole derivatives possess a wide range of pharmacological activities such as anticancer, anticonvulsant, antimicrobial, anti-inflammatory, antioxidant, antitubercular, antimalarial, antinociceptive etc. This review contains various pharmacological activities of oxadiazole and thiadiazole derivatives and it is the milestone for the new research towards oxadiazole and thiadiazole moiety.

Key words: Heterocyclic compounds, oxadiazole, thiadiazole, biological activities.

1. Introduction

Heterocyclic compounds are cyclic compounds with at least two different elements as ring member atoms. They are the counterparts of homocyclic compounds, which have only ring atoms from the same element. Heterocyclic compounds contain one or more hetero atoms other than carbon within the ring structure, such as sulfur, oxygen or nitrogen. Non-carbon atoms which replace carbon atoms in ring system are called heteroatoms. Oxadiazole and thiadiazole and its derivatives possess a great significance in medicinal chemistry and numerous heterocyclic compounds containing oxadiazole and thiadiazole with different biological activities can be synthesized from them [1-8]. Oxadiazole and thiadiazole is a five membered, heterocyclic ring containing two carbon and three heteroatoms (N,S,O) atoms. It forms a pair of isomeric chemical compounds. Oxadiazole and thiadiazole is considered to be the most useful component, widely used in research purpose as a building block for complex chemical compounds such as pharmaceutical drugs. Oxadiazole and thiadiazole is a basic aromatic heterocycle and its derivatives posses a wide variety of pharmacological activity such as antifungal, anticancer, anticonvulsant,

71 antimicrobial, anti-inflammatory, antioxidant, anti-tubercular, anti-malarial, analgesic. The modifications in oxadiazole and thiadiazole ring systems by substitution with different groups at different position in the ring that can be made on it to different biological activities as well as enhance its pharmacological effect of previous prepared compounds [9-16]. Nitrogen containing heterocyclic systems has been attracting increasing interest over the past decade because of their utility in various applications, especially chemotherapy. That’s why the search for new biological active agent is one of the most challenging tasks to the medicinal chemist. In recent years, the chemistry of five member heterocyclic derivatives has received considerable attention owing to their synthetic and effective biological importance. The oxadiazole, a heterocyclic nucleus having a five member ring containing one oxygen and two nitrogen atoms, in older literature it was referred as furadiazoles which attracted wide attention of chemist for preparation of different biological active drugs. Biological activities of oxadiazole are due to the presence of -N=C-O linkage. There are four possible isomers of oxadiazole depending on the position of nitrogen atom in the ring namely 1,2,3-oxadiazole (1a) 1,2,4-oxadiazole (1b), 1,2,5-oxadiazole (1c), and 1,3,4- oxadiazole (1d). Out of these 1,3,4-oxadiazoles are found to be most potent biologically [17-24]. A large number of 1,3,4-oxadiazole derivatives have been found to exhibit various biological activities such as anti-Inflammatory, antimicrobial, anticancer, anticonvulsant, antihypertensive etc.

1,2,3-oxadiazole 1,2,4-oxadiazole 1,2,5-oxadiazole 1,3,4-oxadiazole Structures of oxadiazole isomers

1,2,3-thiadiazole 1,2,4-thiadiazole 1,2,5-thiadiazole 1,2,4-thiadiazole

Structures of thiadiazole isomers

The 1,3,4-thiadiazole moiety have been widely used by the medicinal chemist in the past to explore its biological activities. Many drugs containing thiadiazole nucleus are available in the market such as acetazolamide, methazolamide, sulfamethazole, etc. Thiadiazole can act as the bio-isosteric replacement of the thiazole moiety. So it acts like third and fourth generation cephalosporins, hence can be used in antibiotic preparations. There are several isomers of thiadiazole, that is 1,2,3-Thiadiazole (2a), 1,2,4- Thiadiazole (2b), 1,2,5-Thiadiazole (2c) and 1,3,4-Thiadiazole (2d). 1,3,4-Thiadiazole is the isomer of thiadiazole series. A review of standard reference works shows that more studies have been carried out on the 1,3,4- Thiadiazole than all the other isomers combined. Members of this ring system have found diverse applications such as pharmaceuticals, oxidation inhibitors, cyanide dyes, and metal complexing agents.

72

2. Pharmacological activities of five membered heterocycles

2.1. Antimicrobial and Antifungal Activity:

Antimicrobial activity of some compounds showed potent activity against many microorganisms. The compounds prepare belongs to 1-(5-phenylamino-[1,3,4]thiadiazole-2-yl)methyl‐5‐oxo‐[1,2,4]triazole (1) derivatives [25]. The antimicrobial activity of some compounds against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Salmonella typhi used to investigate the antibacterial activities. The 5,5’-(5- nitrobenzene-1,3-diyl)bis(1,3,4-oxadiazole-2-thiol)azo dye, coupled with quinoline, and napthols which are biologically active molecules possessing safer antimicrobial activity. Compound (2a, 2c and 2d) showed significant antimicrobial activity when compared to other compounds. Specifically, compound 2a and 2b having methoxy, halogen and electron donating atom was more efficient than other compounds but less potent than standard drug ampicillin [26].

N N

N O S

N N NH

NH₂

O N N

SH

N N R N N

O HS

2a R=

N HO

1 HO

O HN

HO

O HN CH₃

HO

O HN CH₃

Cl

2b 2c 2d

Two series of 2-alkylthio-5-aryl-1,3,4-oxadiazole 3(aryl = 2-hydroxyphenyl, 5-bromofuryl and alkyl = H, CH2CH3, CH2(CH2)2CH3, CH2Ph, CH2CO2CH2CH3, CH2CO2H) were were examined against two bacterial strains, Gram negative (E. coli) and Gram positive (S. aureus), and against pathogenic fungi Aspergillus niger. The minimum inhibitory concentration (MIC) was determined for compounds against two bacterial strains. LD50 values for some selected compounds have showed a good antimicrobial activity [27]. A series ofs oxadiazole was evaluated against Mycobacterium Tuberculosis. Compound 3- {2-furyl[4-(4-{2-furyl[5-(2-naphthyloxymethyl)-2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3yl]methyl

amino}phenylsulfonyl) anilino]methyl}-5-(2-naphthyloxymethyl)-2,3-dihydro-1,3,4oxadiazole-2-thione 4 have shown best activity against M. Tuberculosis and isoniazide resistant M. Tuberculosis [28]. The 1,3,4-oxadiazole derivatives (5a-d) for their in-vitro antibacterial activity against Gram-positive: S.

aureus, B. subtilis and Pseudomonas aeruginosa) and Gram-negative: E. coli [29].

73 N

O N

S R R'

O N N

S

O HN S

O O

NH N O

N S

O O O

3 4

O N N OH

S R

5a= 5b= ^O5c=

O

CH₃5d=^H2N

A series of 1, 3, 4-oxadiazole 6 derivatives were screened for antibacterial and antifungal activity against S. aureus (G+ve), E. coli (G-ve),Vibrio cholera (G-ve), Klebsilla pneumonie (G-ve), P. aureginosa (G- ve), B. substillis (G+ve), Caryne bacterium (G+ve), Status albus (G+ve), Bacillus lintus (G+ve), S. typhi etc. whereas antifungal activity was screened by fungus Streptomyces griseus, Monoscus rubrum, Candida albicans etc [30]. The 1,2,4-oxadiazole-pyranopyridine/chromene hybrid heterocycles in moderate yields. In vitro screening of these compounds against M. tuberculosis H37Rv disclosed that the 1,2,4-oxadiazole pyranopyridine hybrids display enhanced activity relative to the 1,2,4- oxadiazolechromene hybrids. Some compounds weres more potent than the standard drug ethambutol and ciprofloxacin. Only one compound 7, was found to be the most potent in the library, being 1.2, 15.2, and 24.6 times more active than isoniazid, ciprofloxacin, and ethambutol respectively. However, all the compounds were less active than rifampicin [31].

N N O R' HN

R ^X

Ar' O

NH₂

N O N

Ar' Ar' 6 7

A series of Bis-[thiadiazol-2-yl-tetrahydro-2Hpyrazolo[3,4-d][1,3]thiazole] methanes. The compounds 8 were evaluated for their antibacterial activity against Gram-positive bacteria viz. B. subtilis, S. aureus and Micrococcus luteus and Gram-negative bacteria viz. Proteus vulgaris, Salmonella typhimurium and E.

coli [32]. A series of 1,3,4-thiadiazole-2-amines were evaluated for the antibacterial and antifungal activity against S. aureus, B. subtilis, E. coli, P. aeruginossa, Saccharomyces cerevisiae, C. albicans, A.

niger. Ciprofloxacin and Gresiofluvin were used as standard drug for the antibacterial and antifungal activity. Some compounds 9 have showed the better antibacterial activity and antifungal activity compared with the standard drug [33].

74 O

O CH₃ N

N S

H₃C

N N S N

N S

S

N N Ar'

R Ar'

Ar' R

Ar'

N S

N (CH₂)n

N N S

H₂N NH₂

8 9

A novel ethylene bridged benzisoxazolyl imidazo[2,1-b][1,3,4]-thiadiazoles were tested as antibacterial agent. Some compounds (10a-c, 11a-b, 12a-b) showed moderate to good bacterial inhibition. The high attributed to the activity is presence of electron withdrawing chloro-and bromo functional groups as comparable to that of standard [34]. The invitro anti-Helicobacter pylori activity of N-[5-(5-nitro-2- heteroaryl)-1,3,4-thiadiazol-2-yl] thiomorpholines 13 and some related compounds. They found that nitrofuran analog containing thiomorpholine S, S-dioxide moiety was the most potent compound tested [35].

N N

S N

O N

R

N N

S N

O N

R

Br

10a R=Cl, 10b R=Br, 10c R=3 Coumarinyl 11a R=Cl; 11b, R=NO2

N N

S N

O N

R

NCS

O2N O

S N N

N S

O O

12a R=Cl, 12b, R=OMe 13

A series of 7-[4-(5-amino-1,3,4-thiadiazole-2-sulfonyl)]-1-piperazinylfluoroquinolonic derivatives. The compounds 14 were evaluated for their in vitro antibacterial activity against some Gram positive and Gram-negative bacteria. The antibacterial N-sulfonylfluoroquinolones indicated that all the compounds showed better activity against Gram-positive bacteria S. Aureus [36].

75 N N

S

S N O

O

N

N

H₂N O

OH O

R R₂

R1

R3

R₄

F

14 R =C3H5, C2H5; R1= H, NHCOCH3, NH2; R3 = H, F, OCH3; R4=H, CH3

Schiff’s bases as new ligands, the synthesized ligands and their corresponding metal (II) complexes (15) were screened in vitro for their antibacterial activity against four Gram-positive (E.coli, P. aeruginosa, S.typhi & S.flexeneri) and two Gram-positive (B.subtilis & S.aureus) bacterial strains by the agar-well diffusion method. It was concluded that the ligands act as tridentate (NNO donor) forming octahedral complexes with Co (II), Cu (II), Ni (II) and Zn (II) ions. These complexes are more effective antibacterial agents than the parent ligands [37].

N S

N

R R'

X N S

N R

N

X N

N R N

M

Cl₂

Schiff’s base 15 M = Co(II), Cu(II), Ni(II) or Zn(II) X=O/S/N Structural formula of the investigated metal complexes

Several 3,6-Disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-Thiadiazole and their dihydro analogues (16) tested for their antibacterial, antifungal, anti-inflammatory and analgesic activities. The antimicrobial results showed that some of the compounds are active against both Gram-positive and Gramnegative bacteria.

Compounds also showed good inhibition of growth of the yeast-like Candida albicans and the fungi Aspergillus niger [38].

N N N

N S

Ar' R

16 R=2-Chloro -methoxy phenyl, 3,4-Dimethoxybenzyl, 2-Methyl-3-Furanyl Ar'=2–phenyl-4-quinolinyl, 2-methy-4-quinolinyl, 4 Quinolinyl

6 -Dihydroxy- 4-piperydinyl, 5-methoxy-3-indolyl methyl

Some new series 1,3,4-thiadiazoles 17 and further evaluated antimicrobial Activity [39]. The metal chelates of 5-[4-Chlorophenyl (1,3,4)thiadiazol-2-ylaminomethylene]-8-hydroxy quinoline 18,

76 characterized and evaluated its anti-microbial activity [40]. The 3-(substituted phenoxymethy)-6- phenyl/substitutedphenoxymethyl-1,2,4-triazolo(3,4-B)-thiadiazole derivatives 19 were screened for their in-vitro antimicrobial activity and exhibited equipotent antibacterial and antifungal activity at MIC of 1 g/mL when compared with standard drug respectively. They showed comparable anti-TB activity against M. tuberculosis at MIC of 0.50 g/mL, when compared with standard drug Rifampin and Isoniazid which showed MIC of 0.25 g/ml. All the newly synthesized compounds were screened for their antibacterial activity against S. aureus, E. coli, P. vulgaris, K. pneumonia and showed better activities [41,42].

N

O S

N N R

N OH HN N N Cl S

N N N

N S

R₁ O

R 17 18 19

2.2 Anticonvulsant activity

A series of new 2-substituted-5-[2-(2-fluorophenoxy) phenyl]-1,3,4-oxadiazoles (20a-f) has been synthesized and screened for their anticonvulsant activities. Compound (20a) shows considerable anticonvulsant activity both in PTZ and MES models [43]. A series of five membered heterocyclics were tested as anticonvulsion agent. Compounds (21) 2-(4-chlorophenyl) amino-5-(4-pyridyl)-1, 3, 4- thiadiazole and (22) 2-(4-chlorophenyl) amino-5-(4-pyridyl)-1, 3, 4oxadiazole showed potent activity [44].

O X N N

R

F 20a-f

X R 20a O NH2

20b O SH 20c O SCH3

20d O OH 20e N SH 20f N OEt

N X

N N H N

Cl

21X=S 22X=O

Compounds 1-(5-aryl-1, 3, 4-thiadiazol-2-yl) urea 23 were screened for their anticonvulsant activity by subcutaneous Pentylenetetrazol Method (PTZ) induced convulsion method. Some of the compounds exhibited prominent anticonvulsant activity [45]. A series of new 3-[5-substituted phenyl-1,3,4- thiadiazol-2-yl]-2-styryl quinazoline-4(3H)-ones 24a-c were evaluated for anticonvulsant activity .Compounds were examined in the maximal electroshock (MES) insduced seizures and scPTZ-induced seizure models. Compound showed good anticonvulsant activity in the test models [46].

77 N

S N

NH NH₂ O R

23 _N

N

Ar' S N N

R

O 24a = R =C6H5; Ar =4-ClC6H4

24b = R = 3-Cl C6H4; Ar=4-Cl C6H4

24c = R = 4-Cl C6H4; Ar=Pyridyl

2.3. Anti-inflammatory and analgesics

The 2,5-Disubstituted 1,3,4-oxadiazole derivatives 25 and 26 were tested for their anti-inflammatory activity determined by rat paw oedema method. These compound gives good response for anti- inflammatory activity for this activity and indomethacine was used as standard drug. Compound [3- Chloro-N-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazole-2yl]benzamide and [4-Nitro-N-[5-(4-Nitro-phenyl)- [1,3,4] oxadiazole-2yl] benzamide have greater anti-inflammatory activity [47].

N O H N

N

Cl O Cl

N O H N

N

O₂N O NO₂

25 26

A series of novel ether-linked bis (heterocycle)s compounds 27a-b were screened for anti-inflammatory and analgesic activities against ibuprofen and aspirin [48]. A series of oxadiazole derivatives 28 of ibuprofen which contains the arylpiperazine unit at position 3 of the oxadiazole ring as well as they investigate the Anti-inflammatory activity using paw edema induced by carrageenan with sodium Diclofenac as the reference. Compounds containing 4-Cl, 4-NO2, 4-F and 3-Cl groups were more active than sodium diclofenac, whereas compounds with 4-MeO and 2-EtO groups showed less activity [49].

N N O O O

N

R R'

N O

N

N N

S H3C

CH₃ H3C

R

27a -R, R' =3-O2NC6H4 28 R = 4-Cl , 4-NO2,4F, 4MeO, 2-EtO, 3-Cl 27b -R, R' =2,4-Cl2 C6H3

Some 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives 29 and 30 by cyclisation of 4- amino-5-[1-(6-methoxy-2-naphthyl)ethyl]-3-mercapto-(4H)-1,2,4-triazole with various substituted aromatic acids and aryl/alkyl isothiocyanates, through a single step reaction. All compounds were screened for anti-inflammatory activity [50].

78 O

CH₃

CH₃

N N N

N S

R

O CH₃

CH₃

N N N

N S

R'HN 29 30

A series of spiro-thioxanthene and spiro-xanthene-9’2-[1,3,4]thiadiazole derivatives. Some compounds 31 and 32 were tested for anti-inflammatory and analgesic activities comparable to ibuprofen [51] Various substituted thiadiazoles 33 were screened for anti-inflammatory activity by winter et al method with standard drug (Diclofenac Sodium). However, Compounds have shown promising anti-inflammatory activity [52].

X N N S R

Ar

N S

N

NH R O Ar

31 X = S; 32 X = O 33

2.4. Anticancer activity

A series 3,6-disubstituted triazolo[3,4-b]thiadiazole derivatives 34 and 35 were evaluated for their cytotoxic activity against a panel of 60 human cancer cell lines and some of them demonstrated inhibitory effects on the growth of a wide range of cancer cell lines generally at 10-5 M level and in some cases at 10-7 M concentrations. Compounds and maintained the highest growth inhibition [53].

N N N

N S

NH₂ O

Cl

N N N

N O S

Cl

S N HO

NH₂

34 35

Some 2,6-dimethyl-N’-substituted phenylmethylene imidazo[2,1-b][1,3,4]thiadiazole-5-carbohydrazides 34 were evaluated as anticancer in the 3-cell line, one dose in vitro primary cytotoxicity assay the evaluation against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10- fold dilutions. 2,6-Dimethyl-N’-(2-hydroxyphenyl methylidene) imidazo[2,1b][1,3,4]thiadiazole-5-carbo

79 hydrazide showed the most favorable cytotoxicity [54]. The coumarin ring system into oxadiazole moiety to explore the possibilities of some altered biological action, the series of compounds 35 bearing 1,3,4–

oxadiazole moiety with substitution in the 2 and 5 position. The cytotoxicity activity of compounds was tested by MTT assay and the Compounds show good activity on MCF-7 cell lines. Some compounds showed significant activity [55].

S N N

N H₃C

CH₃ O

NH

N Ar

34 a-h

34a = C6H4

34b = 4-CH3 C6H4

34c = 2-HOC6H4

34d = 4-CH3O C 6H4

34e = 4-Br C6H4

34f = 4-Cl C 6H4 34g = 4-FC6H4

34h = 4-NO2C6H4

O O

N N O

R 35 R = substituted acids

A series of 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives 36 and 37 were evaluated for their in vitro anticancer activity. These compounds have been selected for a full anticancer screening against a 60-cell panel assay where they showed Non- selective broad spectrum and promising activity against all cancer cell lines. Compounds proved to be the active members in this study compared to 5-fluorouracil and Cyclophosphamide as reference drugs, respectively [56].

N O

N

Cl S

N O

N S

Cl 36 37

2.5. Antileishmanial activity

2,4-disubstituted1,3,4-thiadiazole derivatives were evaluated for invitro antileishmanial activity. Among these, compound 38 showed 73% in-vitro inhibition of promastigote of Leishmania donovani [57].

A series of 4-Amino-3-(4’-benzyloxyphenyl)-5-mercapto-1,2,4-triazole compounds 39-42 were screened for their antileishmanial activity against L. donovani. Compound showed maximum inhibition among all tested compounds [57]. A series of 3-aryl-5-thio cyanatomethyl-1,2,4-oxadiazoles 43 were tested against amastigotes of Leishmania donovani. In these 3-(4 chlorophenyl)-5-(thiocyanatomethyl)-1,2,4-oxadiazole showed more selectivity for L. donovani [58].

80 N

S N

N N

O₂N ^O

N N N

HN S

S 38 39

O

N N N

N S

NH

O

N N N

HN S

O 40 41

O

N N N

HN S

O

N N N

HN S

O 42 43

2.6. Antioxident activity:

Some disubstituted 1,3,4-oxadiazoles/thiadiazoles 44 are tested for antioxidant property by nitric oxide and DPPH methods. The results showed that the compounds with oxadiazole moiety showed high antioxidant property when compared with compounds having thiadiazole moieties in both methods at a 100 mM concentration. The benzyl series and exhibited greater antioxidant activity than aryl series [59].

Some 5-[(2-(substituted phenyl)-1H-benzimidazole-1-yl)methyl]-N-methyl-1,3,4-thiadiazole-2-amines 45 were tested for antioxidant properties, using various in vitro systems [60].

N S

N R' R

^S N N NH

N N

44 45

3. Discussion

Oxadiazoles and thiadiazoles have attracted considerable attention in the fields of medicine and agrochemical research as well as in materials science, due to their unique structures and properties.

Oxadiazole and thiadiazole and its derivatives belong to a class of exceptionally active compounds

81 possessing many pharmacological properties. Some of the derivatives of Oxadiazole and thiadiazole are also known to exhibit anticancer activity. Oxadiazoles and thiadiazoles have clinched much importance as they have also been investigated for their antibacterial, anticonvulsants, anti-inflammatory, anticancer, antitubercular, antimicrobial etc properties. Moreover, sulphur containing heterocycles represent an important group of sulphur compounds that are promising for use in practical applications [60-66]. There are number of oxadiazole and thiadiazole derivatives reported in this review possessing different biological activity comparable to clinically synthetic compounds. Oxadiazole and thiadiazole is a unique moiety that is responsible for various biological activities. This article highlighted research work of many researchers reported in literature for different pharmacological activities on synthesized oxadiazole and thiadiazole compounds. Thus many more modifications on oxadiazole and thiadiazole moiety can be possible and needs to be continued for the use of mankind. From the above discussions it may be concluded that the modifications in oxadiazole and thiadiazole moiety displayed valuable biological activities and these modifications can be utilized to develop potentially active agents for future investigations.

4. Conclusion

This review has presented comprehensive details of oxadiazole and thiadiazole analogues, compounds reported for particular pharmacological activity. More investigations must be carried out to evaluate more activities of oxadiazole and thiadiazole for many diseases whose treatment are difficult in the medical sciences. The modifications on oxadiazole and thiadiazole moiety for the formation of compounds with valuable biological activities, these modifications can be utilized as potent therapeutic agents in future.

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