INTRODUCTION

Oxadiazole are one memberd ring structure having the large numer importance. Since 1880 the class of 1,3,4,-oxadiazole was reported for its properties but its derivetives and pharmacological active derivetives was strated to synthesis from 1950. Since then a diversified reaction, various derivetives are used to obtain an oxadiazole having novel pharmacological activity. The oxadiazole chemistry has been developed extensively and is still developing. Presently there are a number of drugs used clinically, which comprise oxadiazole moiety in association with various heterocyclic rings. 2,5-disubstituted-1,3,4-oxadiazole derivatives have attracted considerable attention owing to their effective biological activity and extensive use.

1,3,4-OXADIAZOLES OF PHARMACOLOGICAL IMPORTANCE

The synthesis of 2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles and tested for the anticonvulsant activity. Among the series compound (1) shows moderate anticonvulsant activity.^[1]

A facile synthesis of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles was carried out and the compounds were then evaluated for their anti-HBV activity.^[2] The compound (2) was able to inhibit the expression of the viral antigens. The inhibition of virion production was comparable to that of lamivudine and EC50 values of 1.63 and 2.96 M were obtained for compound(2) and lamivudine, respectively.

Various series of 1,3,4 oxadiazole moieties as benzodiazepine receptor agonist. Out of all compounds, compound (3) shows mild anticonvulsant activity.^[3]

Some new fluorine containing 1,3,4 oxadiazole derivatives and screened them for antibacterial and anticancer activities. Among the series, compound (4) has more active against breast cancer MFC-7 and compound (5) shows promising antibacterial activity as compare to standard drugs.^[4]

Novel oxadiazole and oxadiazoline analogues have been synthesized by using cotton pellets-induced granuloma method having anti-inflammatory activity.^[5]Structure-activity relationships among the synthesized oxadiazole and oxadiazolides analogues indicates that the hydroxy, nitro, or chloro group in the aromatic ring is responsible for imparting significant antiinflammatory activity to the oxadiazole and oxadiazoline nucleus.

3-acetyl-2 substituted phenyl-5 substituted 1,3,4 oxadiazole derivatives were synthesized and screened for their anti-proliferative activities. Among them, compound (11) and (12) were highly effective against PC3 cells with IC₅₀ 1.2 &1.7 mM respectively.^[6]

The number of 1,2,4 triazole, 1,3,4 oxadiazole derivatives and screened for antiinflammatory and antibacterial activities.^[7] These compounds show good antiinflammatory activity. Among the all compounds, the compound (13) shows 72.34% anti-inflammatory activity.

New series of bis-1,3,4 oxadiazoles were prepared and evaluated for the antibacterial, antifungal and genotoxic activity.^[8] All compounds shows promising antibacterial and antifungal activities against S. aureuss and B. subtilis.

Novel symmetrical and asymmetrical 2,5-disubstituted 1,3,4-oxadiazoles have been synthesized by a facile and mild method with high yield. It was found that the fluorine was easy substituted by hydrazine in polyhalogen-substituted aroyl hydrazine. The preliminary bioassay tests show that two of the compounds (18) and (19) exhibited a significant insecticidal activity on armyworm, Leucania separata Walker.

Another series of 1,3,4-oxadiazole compounds which are analog of fenametes ( NSAID drugs ) were prepared and evaluated for in-vitro Inhibition of Cyclooxygenase and 5-Lipoxygenase Activities.^[9] Off the initial set of 1,3,4-oxadiazoles only those with an exocyclic sulfur at C-2 are potent balanced dual inhibitors. 1,3,4-0xadiazole-2-thiones (20) inhibit both CO and 5-LO activities at micromolar concentrations.

Analgesic and ulcerogenicity studies of novel S-Substituted phenacyl 1,3,4-oxadiazole-2-thiol and Schiff bases of Diclofenac acid as non-ulcerogenic derivatives all the related compounds show promising activities.^[10]

A series of substituted 1,3,4-oxadiazole derivatives were synthesized as antiinflammatory agents. The cyclodesulfurization of the corresponding thiosemicarbazides with the presence of I₂/NaOH used to get objective compounds.^[11] The investigation of antiinflamatory activity was carried out on histamine induced edema on rat abdomen which shows the inhibitory effect of oxadiazole derivatives, (22) and (23) proved to be more potent antiinflammatory agents at 200 mg/kg dose.

In plants a trans-cinnamate 4-hydroylase (a cytochromeP450) from Populus kitakamiensis, which was expressed in yeast. A series of 5-aryl-1,3,4-oxadiazole-2-thiols were synthesized Inhibitors for plant defense mechanism. The thiol group is shown important for stronger activity with structural activity studies. Of the compounds tested, 5-(3- fluorophenyl)-1,3,4-oxadiazole-2-thiol (24) was the most active.^[12]

The Anti-inflammatory activity were tested for compound (25) the compound were synthesized having a group of 1,3,4-oxadiazoles derived from 2-[(2,6-dichloroanilino) phenyl] acetic acid. The anti-inflammatory activities of these compounds were carried out in vivo it shows the comparable activity with standard diclofenac and also tested for their analgesic, ulcerogenic and lipid peroxidation activities.^[6]

4-(5-Substituted-1,3,4-oxadiazol-2-yl)pyridine derivatives were synthesized and evaluated for their in vitro antimycobacterial activity, compounds showed an exciting activity in opposition to Mycobacterium tuberculosis H37Rv and five clinical isolates (drug-sensitive and resistant strains).^[13] Compound (26) [4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine] having more 10 fold activity compared to isoniazid, 20 fold more active compared to streptomycin, and 28 fold more potent than ethambutol against drug-resistant strain CIBIN 112.

A series of pyrazolyl-1,3,4-oxadiazoles and evaluated for their antiviral potential. Out of all synthesized compounds, the compound (28) shows promising antiviral activity.

THEORETICAL AND SYNTHESIS OF 1, 3, 4 OXADIAZOLES

A novel method of making 2-amino, 5-substituted-1,3,4-oxadiazoles (29); and more particularly, to an improved method for making such compounds which possesses important advantages over prior known procedures were given. ^[14]

The synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from acids and acyl hydrazides with the use of one pot method was carried out.^[15] Acid activation with CDI, followed by combination with the desired acylhydrazide and dryness in the same pot among Ph3P and CBr4 affords the equivalent 1,3,4-oxadiazoles in superior yield. To presents the scope of the acid and acylhydrazide components.

Numbers of 2,5-disubstituted-1,3,4-oxadiazoles have been synthesized by oxidation of 1-aroyl-2-arylidene hydrazines with potassium permanganate on the surface of a solid mineral support as well as in mixtures of acetone and water under microwave irradiation. ^[16]

Some of the steroidal diacyl hydrazines and their 1,3,4-oxadiazole derivatives were prepared.^[17] The reactions were carried out in the presence of a palladium catalyst, a base and acetic or benzoic hydrazide as the nucleophilic reagent. The corresponding N-acetamido-carbamoyl or N-benzamido-carbamoyl derivatives were obtained in high yields. Some of these derivatives served as starting materials for the synthesis of new steroidal 1,3,4-oxadiazole compounds.

By reacting the acylthio-semicarbazide intermediate were sysnthesised by reacting an acid chloride with thiosemicarbazide. Cyclizationvia desulfurization using 1,3-dibromo-5,5-dimethylhyd-antoin as the primary oxidant, in the presence of potassium iodide, which gives a variety of oxadiazoles in goodyields. The main advantage to this approach is that the reagents used are commercially inexpensive and safe to handle.^[18]

(33)

Synthesis of 2-Substituted 5- trifluoromethyl 1,3,4-oxadiazoles. The reaction is presumed to proceed through acylation of the tetrazole ring followed by thermolysis of the arising N-acyltetrazole with nitrogen elimination and the formation of an oxadiazole ring. The employment of trifluoroacetic anhydride permits performing complete conversion of 5-substituted tetrazoles into the corresponding 2-substituted 5-trifluoromethyl-1,3,4-oxadiazoles at 20–25°C. The reaction occurred with a vigorous nitrogen evolution and without starring.^[19]

Synthesis and characterization of piperidine or morpholine 5- (4- pyridinyl)- 1,3,4 oxadiazole-2-thiol were explored influences of the ratio of reactants on the course of the reaction were determined.

2,5-Disubstituted 1,3,4-oxadiazoles have been synthesized by oxidation of 1-aroyl-2-arylidene hydrazines with potassium permanganate on the surface of a solid mineral support as well as in mixtures of acetone and water under microwave irradiation. ^[17]

The microwave- assisted synthesis of 2,5 disubstituted-1,3,4 oxadiazoles and were structurally characterized by 1H-NMR, IR, UV and elemental analysis.^[20]

Antimicrobial Oxadiazoles:

From 1-and/or 2-naphthol Six new 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-thione, 2-amino-5-(1-/2-naphthyloxymethyl)-1,3,4- oxadiazole, 5-(1-/ 2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one derivatives have been synthesized. ^[21] The antimicrobial properties of the compounds were investigated against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, Candida albicans, C krusei and C. parapsilosis using microbroth dilution method.

Number of novel 5-aryl-2-[(N,N-disubstituted thiocarbamoylthio)acylamino]-1,3,4-oxadiazole derivatives were synthesized.^[22] All compounds were tested for antimicrobial activity agaist Staphylococcus aureus and Staphylococcus epidermidis.the compound (42) and (43) shows better activity.

With the use of distinct aromatic aldehydes the synthesis of some Schiff bases of 2-amino-5-aryl-1,3,4-oxadiazoles have been carried out .^[23] The antibacterial properties of the compounds were investigated against and using the broth dilution method and the antifungal screening of the compounds were carried out using Aspergillus niger (MTCC-1344) and Candida albicans (MTCC-227) using the broth dilution method. With use of broth dilution method the antibacterial activity of compound were carried against Bacillus subtilis (MTCC-619), Proteus mirabilis (MTCC-425), Staphylococcus aureus (MTCC-96), Pseudomonas aeruginosa (MTCC-424), and antifungal screening were carried out with Aspirgillus niger and candida albicans.

Some isoniazid based 1,3,4-oxadiazole derivatives and tested for their antibacterial activity against Escherichiacoli and Staphylococcus aureus. The compound (47) shows good antibacterial activity with 72.50 % inhibition.^[24]

A series of 2-(4-nitro-1-imidazolylmethyl)-1,3,4-oxadiazole derivatives were synthesized and tested for their antimicrobial activity. Some of the tested compounds were active against Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Clostridium difficile, Aspergillus niger and Cryptococcus neoformans by using disc diffusion method. All compounds shows comparable activity related to reference drug cefotaxime against S. aureus. Out of all, the compound (48) shows better activity specially against C. difficile.^[25]

A series of novel 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles were synthesized and they are tested for in vitro activities against Gram-positive and Gram-negative bacteria and also for activity against Candida albicans.^[26] Some derivetives shows the good or moderate activity against Gram-positive bacteria Bacillus subtilis.

However, compounds (49) and (50) displayed marked antifungal activity against C. albicans.

A series of novel 2-{4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}-5-substituted-1,3,4-oxadiazoles were synthesized and evaluated for their antimicrobial activity and were compared with standard drugs.^[27] The compounds demonstrated potent to weak antimicrobial activity. Out of the compounds studied, compound (51) showed significant inhibition. The minimum inhibitory concentration of the compounds was in the range of 8–26 μg ml–1 against bacteria and 8–24 μg ml–1 against fungi. These compounds are a novel class of potent antimicrobial agents.

2,5-disubstituted 1,3,4-oxadiazoles and screened for their antimicrobial activity.^[4] All these compounds show significant antibacterial activity when compared with standard drug ofloxacin against S.aureus and E. Coli.

A series of hydrazide hydrazones and 1,3,4-oxadiazolines of 4-fluorobenzoic acid hydrazide were prepared and evaluated as potential antimicrobial agents and were tested for their antibacterial and antifungal activities against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans.^[28] From these compounds, 4-fluorobenzoic acid [(5-nitro-2-furanyl) methylene] hydrazide (53) showed equal activity with ceftriaxone against S. aureus. In addition, the MIC values of compounds for the same strain were in the range of those reported for ceftriaxone.

A series of novel 2,5-disubstituted-1,3,4-oxadiazoles have been synthesized from long-chain alkanoic and alkenoic acids. These compounds are tested for antibacterial activity against two gram-positive and two gram-negative bacteria during in vitro studies, and also have shown inhibitory activity against five strains of fungus. So, these are known as the potential agents in therapeuticas.

New series of 2-[[-(4-substitutedbenzoyloxy)-phenylacetyl or methylacetyl]amino]-5-(4-methoxyphenyl)-1,3,4-oxadiazoles were obtained by condensation of 2-[(-chloro-phenylacetyl or -bromopropionyl)amino]-5-(4-methoxy phenyl)-1,3,4-oxadiazoles with sodium salts of 4-substituted benzoic acids. ^[29] The antibacterial activities of the novel compounds against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumonia ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri and Proteus mirabilis and antifungal activity against Candida albicans ATCC 10231 were tested using disk diffusion method. Compound (55) found to be active against S. aureus ATCC 6538 (MIC, 78g ml−1,) and compound (56) against S. epidermidis ATCC 12228 (MIC, 156 _g ml−1).^[30]

Synthesized 5-aryl-2-amino-1,3,4-oxadiazoles (58) and 2-(2,5-dihydroxyphenylthio)-5-aryl-1,3,4-oxadiazoles (59) by treating 2-mercapto-5-substituted-1,3,4-oxadiazoles with primary and secondary amine in absolute ethanol and p-benzoquinone in anhydrous xylene respectively.

Where, R1= H, R₂ = C₆H₅

During the present investigation the method due to B and also method due to has been employed for the synthesis of 5-{2-[(substituted phenyl)amino]ethyl}-1,3,4-oxadiazole-2-thiol derivatives. Due to diversified nature of 2,5-disubstituted 1,3,4-oxadiazole, we thought of preparing new series of oxadiazole derivatives with the enhanced biological activity.

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Received on 30.06.2012 Modified on 20.07.2012

Asian J. Research Chem. 5(8): August, 2012; Page 1084-1091