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ISSN 2229-5054

International Journal of Drug Formulation & Research Nov.-Dec. 2010, Vol. 1 (iii) 134-166

International Journal of Drug Formulation & Research

OXADIAZOLE: A NEW PROFILE OF BIOLOGICAL ACTIVITIES. V.S.Kulkarni*, M.D.Lele1, B.B.Gavitre2, M.D.Patil2, K.R.Bobe2, D.T.Gaikwad 2 *,2 P.S.P.S.S, Indira Institute of Pharmacy, Sadavali (Devrukh), Dist-Ratanagiri, Maharashtra415804
1

Bharathi College of Pharmacy, Bharathinagara (Mandya), Karnataka-571422

Abstract: Compounds containing 1,3,4-oxadiazole nucleus find unique place in medicinal chemistry and play significant role as, they are associated with immense biological activity. The small and simple 1,3,4-oxadiazole nucleus is present in compounds involved in research aimed at evaluating new products that posses interesting pharmacological properties like antipanosonal, antibacterial, fungicidal, herbicidal, antitumour, anti-inflammatory, anti T.B, diuretic, hypoglycemic, anticonvulsant and analgesic. 2,5-disubstituted-1,3,4-oxadiazole derivatives have attracted considerable attention owing to their effective biological activity and extensive use. Potent review focus on oxadiazole with potential activities that are now in development. Keywords: heteroatom.
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1,3,4-oxadiazole,

biological

activity,

2,5-disubstituted-1,3,4-oxadiazole,

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International Journal of Drug Formulation & Research Nov.-Dec. 2010, Vol. 1 (iii) 134-166

1. Introduction: 1,3,4-oxadiazole is pseudo heteroatom ring containing three heteroatom represented by following canonical forms.

Ring nitrogen is easily protonated and protonated 1,3,4-oxadiazole is resistant to further electrophilic attack. Any nucleophilic attack at the ring site is difficult because all the three heteroatom bear free lone pair of electrons. Because of this typical electronic composition and movement of electronic charge to the neighboring atoms, 1,3,4-oxadiazole ring is known for various types of transformation and ring isomerisation. Generally, 2,5-disubstituted-1,3,4oxadiazole derivatives tend to be stable, particularly 2,5-diaryl-1,3,4-oxadiazoles are more stable than the corresponding 2,5-dialkyl derivatives. Oxadiazoles are monocyclic ring system with multiple applications. Although 1,3,4-oxadiazole ring system was known in 1880, proper studies regarding its chemistry, structure, physical properties and application of its various derivatives started from 1950. Rhone-Poulenc Co.1 has patented oxadiazon, a commercial herbicide which have 1,3,4-oxadiazoles moiety in its structure.

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International Journal of Drug Formulation & Research Nov.-Dec. 2010, Vol. 1 (iii) 134-166
CH3 O CH3 Cl H3C H3C N O

N Cl OH

After that oxadiazole derivatives have been studied extensively and found to have diverse chemical reactivity and broad spectrum of biological activities. Zareef et al2 have described the synthesis of new benzene sulphonamide bearing 2,5-disubstituted-1,3,4-oxadiazole moiety and screened for anti HIV activity. Abdel-Rehman and Holla3 synthesized 1,3,4-oxadiazole derivative possessing anticancer activity. Given below is brief account of various alterations conducted on oxadiazole ring and their associated biological activity. 2. Biological activity: Oxadiazoles are important class of heterocyclic compounds, found in many potent biologically active molecules. It has been noticed continuously over the years that interesting biological activities were associated oxadiazole derivatives. Recently the applications of oxadiazole were found in drug development and used as like anti-HIV2, antitumour3, antipanosonal, antibacterial7, fungicidal19 , antihypertensive27, anti-T.B.32, anti-inflammatory42, analgesic43, diuretic48, antimiotic52,

anticonvulsant53 and herbicidal62. A brief review of oxadiazole associated with large number of biological activities is presented below. 2.1 Antitumour activity:

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A series of potent and selective antitumour agents mostly from substituted oxadiazole were developed and examined, in vitro, their antitumour activity in ovarian, breast, lung, renal and colon carcinoma human cell lines. Aboraira et al4 synthesized 5-2-(hydroxyl-phenyl)-3-substituted-2,3-dihydro-1,3,4oxadiazol-2thione derivatives [1] which are promising anticancer agent. Mannish base having free carboxylic moiety (d), (e), (f) have high activity but less than that of chloro substitute (b) is most promising anticancer agent. Holla et al3 reported a set of 2-chloro-1,4-bis-(5-substituted-1,3,4-oxadiazol-2-ylmethyleneoxy)phenylene derivatives [2] possessing anticancer activity. Compounds (a) and (b) show significant activity against cell lines with G 150 values<100m concentration. Loetchutinat et al5 presented a series of 5-aryl-3-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-(3H)thiones [3]. They act as P-glycoprotein inhibitors. All compounds show antiproliferation activity in K562 and showed more potent antiproliferation of K562/Adr.highly expressing Pglycoprotein. Ruel et al6 reported 5-isopropyl-6-5(methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo-[2,3B]pyridine-5-yl)-pyrrolo-[2,1-F][1,2,4]-triazin-4-amine (BMS-645737) [4] which are VEGFR-2 inhibitor and acts as promising anticancer agent.

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R = 1-morpholine
N N OH O S R

a) -NH-C6H4-(2-Cl), b) -NH-C 6H 4-(3-Cl), c) -NH-C6H4-(4-Cl), d)-NH-C 6H 4-(2-COOH), e) -NH- C 6H 4-(4-COOH), f) -NH-C6H3-(2-OH-4-COOH)


R N N O O

O N O N

a) R = 2 ,4 -dich lo ro -C 6 H 3 - O C H 2 , b ) R = 4-C l-C 6 H 4 N H -C H 2


OH X Y Ar HS O N N Z

Ar

X=H, Z=H but the Y varies as H, OCH 3 , CH 3, Cl, Br


R2 NH N R5 R6 HN N N N H

R4

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2.2 Antimicrobial activity: Antimicrobial activity has been exhaustively studied for oxadiazole over the years. It shows wide spectrum of chemotherapeutic activity and considerable amount of work has been done on synthesis of new potent antibacterial, antifungal, anti T.B. acting oxadiazoles. 2.2.1 Antibacterial activity: Mulvad et al7 reported a series of new oxadiazole [1,3,5]-triazine, triazolo and thidiazolo-1,3,4oxadiazole derivatives[5] that posses antibacterial activity. R1 may be H or CH3 but R2 and R3 =H remains as it is. All the compounds show good activity towards S. aureus and S. typhi. Montgomery et al8 synthesized Benzyl phenyl ether with oxadiazole[6] that act as inhibitor of bacterial phenylalanyl t-RNA synthatase. X=CH and R=NH2 is most active against

Streptrococcus pneumoniae (SP) and Haemophilus influenza. R changing from H to CH3 or C2H5 increases activity towards SP. Mogilaiah et al9 prepared new 1,3,4-oxadiazolyl-1,8-napthyridine[7] possessing antibacterial activity. (b) is most potent among all. (a) and (c) also show good activity. Dabhi et al10 synthesized 2-mercapto/carboxy-methylthio-5-(3'-arylamino-sulfophenyl)1,3,4oxadiazole [8]. Compounds (a) and (b) show good antibacterial activity. (c), (d), (e) show good antifungal activity. Ates O. and coworkers11 reported a series of some 5-aryl-2-[(N,N-disubstituted thiocarbamoylthio) acylamine]-1,3,4-oxadiazoles[9] and screened them for antimicrobial activity. Most of compounds

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showing good activity. Sangapure et al12 synthesized some 1,3,4-oxadiazole derivatives that posses antibacterial and antifungal activity. Oxadiazole coupled with Benzofuran show moderate activity towards S. aureus. Mahadevan et al13 synthesized Naptho-[2,1-b]-furo-oxadiazolyl derivatives[10] possessing antimicrobial, anti-inflammatory, anthelmentic, analgesic and diuretic activity. (a) and (b): good antimicrobial activity. (b) and (c): anthelmentic and analgesic activity. Compounds are not showing diuretic activity. Hui et al14 reported new derivatives of 1,3,4-oxadiazole of 5-methylisoxazole [11] possessing antibacterial activity. Compounds posses good antibacterial activity. Shetgiri et al15 prepared a series of 1,3,4-oxadiazole derivatives that posses antibacterial activity. They showed good antibacterial activity. Nagalakshmi et al16 synthesized 2,5- disubstituted1,3,4-oxadiazole [12] that posses antimicrobial and anti-inflammatory. Compound (b) and (f) show good anti inflammatory activity with standard. (a) and (g) shows good activity towards B. substilis. (a), (h), (i): good activity toward S. aureus. (e): shows good antifungal activity toward Candida albicans. Jain et al17 synthesized 2-[5-(aryl)-[1,3,4]-oxadiazol-2-ylsulfonyl-alkanoic acid [13] that posses antibacterial activity. Compound containing 2,4-dichloro moiety (a) and (b) are most active compounds showing antibacterial activity against gram (+ve) as well as gram (-ve). Danawade et al18 reported a series of 1-substituted-5-methoxy-3-(5-mercapto-1,3,4-oxadiazol-2yl)methoxy-2-methylindole [14] possessing antibacterial activity. (a), (b), (c) show good activity

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towards E. coli. (a) and (c)- moderately active towards B. cirroflagellolus. (a): highly active towards penicillium.

R3 R2 O OH O N OH N N

HS N OH O R3 OH N N N O

R1

R3 R2 O OH O NH OH N N S NH2

R2 R1

R1

5
R N N O

Cl O X

O N N N O N

O CH3 CH 3 Ar

a) Ar= p -CH 3-C6 H4, b) Ar= p-Cl- C 6 H4 , c) Ar= NO2 -C 6 H4


R NH O 2S N N SX O

8
a) R = 2 -C H 3 -O -C 6 H 4 , X = H /C H 2 C O O H , b) R = 4 -C H 3 -O -C 6 H 4 , X = H c) R = 3 -C H 3 -C 6 H 4 , X = H /C H 2 C O O H , e) R = -C H 2 - C 6 H 4 , X = H /C H 2 C O O H d ) R = 3 -C l-C 6 H 4 , X = H / C H 2 C O O H

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N O O N N NH R O NH S N O R1 S

9
HN

H3C

N O

N R

10

a)R=C 6H 5, b)R=4-Cl- C 6H 5, c)R=4-NO 2- C6 H 5


O N O H 3C N N O N H S C H 3 H 3C O N N H 3C O N N O N H S

11
H3C O O N

N H

Ar N

12 a) 4-NO2-C6H4, b) C6H5-CONH-C6H4, c) 2-NO2-C6H4-NH-C6H4, d)2,4-(OH)2-C6H3,


e)2,4-C6H3-NH-C6H4, f)3,5-NO2-C6H3, g)4-OH-C6H4, h)4-CH3-C6H4, i) 3-NH2-C6H4
Ar O S N N R

13

OH O

a) Ar= 2,4-dic hlo ro-C 6 H 3 , R = C H 3 , b) A r= 2,4-d ic hlo ro-C 6 H 3 , R = H


H 3C O N N SH O

14

N R

CH 3

a)R=furfuryl, b)R=Phenyl, c)R= p -tolyl

2.2.2 Antifungal:

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Kidwai et al19 prepared a series of 3,4-thidiazolyl-substituted-1,3,4-oxadiazole [15]using Microwave showing antifungal activity. Compound with R= 4-CH3 or R= 2-Cl show good activity and Hall A et al20 reported some novel 1,3,4-oxadiazole [16] as a EP1 receptor antagonists. Misra et al21 reported a series of 1,2,4-triazolo and thidiazolo[3,2-b]-1,3,4oxadiazole with thiones [17] as possible antifungal agent. Compound (a) Ar= C6H5, Ar = 2OCH3-C6H4 and (b) Ar= C6H5, Ar = 4-OCH3- C6H4 show better antifungal activity. (c) Ar= H, Ar = 2-OCH3- C6H4 also show good antifungal activity. (d) Ar= H, Ar = 4-OCH3-C6H4 it show good activity among all synthesized compounds. Dutta et al22 synthesized 2,5-disubstituted-1,3,4-oxadiazole [18] and screened for antifungal activity. But compounds are not showing antifungal activity and Li Y and coworkers23 synthesized stereo selective, (E)-(Methoxyimino)-benzenacetate derivatives containing 1,3,4-oxadiazole ring [19] and tested compounds exhibited more potent fungicidal activities against R.Solani. Song B et al24 prepared novel sulfone derivatives contain trimethoxy phenyl substituted 1,3,4oxadiazole [20] and thiadiazole moiety and screened for antifungal activity. Most of compounds showing good activity. Frank et al25 reported a series of 1,3,4-oxadiazoles [21] carrying imidazole moiety possessing antibacterial and antifungal activity. Changing R by H or CH3 and changing R by p-tolyl, panisyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl or by 3,4-methylenedioxyphenyl, all compounds show good antibacterial and antifungal activity. Fuloria et al26 synthesized some 1,3,4-oxadiazole derivatives [22] from

phenylpropionohydrazides having good antimicrobial activity.

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Kambale et al27 synthesized 5-methyl-3-[p-(6'aryl2'thioxo1',2',5',6'-tetrahydropyrimidin-4'-yl)phenyl]3H-2-oxo-4-1,3,4-oxadizole [23] that posses antibacterial, antifungal, anti-inflammatory and anticonvulsant activity. (a) to (d) compounds show good antibacterial activity towards S. aureus and P. aurigenosa and antifungal activity towards Aspergilus flavus and Fusarium oxysporium. They also posses anti-inflammatory and anticonvulsant activity. Cl and Br substituted compounds b and d have more antibacterial activity than (a) and (c). Agarwal et al28 prepared a series of 2'-aryl/aryoxymethyl-spiro [cyclohexane1,5'-[5H]-[1,3,4]oxadiazolo-[3,2-c] thiazole [24] act as fungicidal. (e) is most active towards A. niger and H. oryzae. Khare et al29 synthesized 6-aryl-2-(-D-glucopyronosyl)-3-oxo-2,3-dihydro-1,3,4

oxadiazolo[3,2-B]1,2,4,6-thiatriazine-1,1-dioxide [25] that posses fungicidal activity. (b), (c), (e) - posses fungicidal activity towards Cephalosporium sacchari and Colletotrichum fallatum. Bhovi et al30 reported a new series of 2-methyl-3-ethoxycarbonyl-1-oxadiazolyl-amino-carbonyl methyl-indole [26] having antimicrobial and antifungal activity. (a) Posses highest antibacterial activity towards Micrococcus and E. coli. (b) Showed weak activity towards E. coli and

moderate activity towards Micrococcus. (a) and (b) showed moderate activity towards penicillium. (a): moderate activity towards A. niger but (b) has weak activity. Singh et al31 prepared new derivatives 1,3,4-oxadiazolo[3,2-a]-5-triazine-5,7-thiones and dithiones analogues [27] which act as potential antifungal agent. (I.a), (I.b), (II.a), (II.b) are most potent antifungal agent.

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X R O N N O S O N S N S N CH3 H3C

N N O

15 R -4CH3 or R -2-Cl

16

CH3

Ar N

O N N N Ar1 S

17
S O Cl N Cl N R O H 3C N O CH3 O O

N N

18 R is C 6 H 5 , 2C l-C 6 H 4 or - (C H 2 ) 2 -C 6 H 5
H 3C H 3C O H 3C O S O
N NH N N O NO 2 R R2

19
R

O N N O

20
H 3C

21

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O N S HN R N HB HA

O CH3 N

23
a) R = C 6 H 5, b ) R = p -B r-C 6 H 4, c) R = p -C H 3 -C 6 H 4, d ) R = p -C l-C 6 H 4
R

N N O

24 a) R=H, b) R=2-Cl, c) R=2-C H 3, d) R=4-CH 3, e) R=3-CH 3-4-Cl


R

O N N N O

S O OH

HO

OH OH

25

a ) R = H , b ) R = 4 - C l , c )R = 2 - C l, d ) R = 4 - F , e ) R = 4 - O C H 3 , f) R = 4 - N ( C H 3 ) 2 , g ) R = 4 - N O 2

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O R CH3 N N NH O S CH3

26
a) R=OH

b) R=OCH 3

S N R1

N N S

O R N

O N R1

N N S

O R N

(I)

27

(II)

I.a) R=4-OCH 3-C6H 4, R1= C6H5, I.b) R=4-OCH 3-C6H 4, R1=2-CH 3-C6H 4 II.a) R=4-OCH3 -C 6H4, R1= C6H5, II.b) R=4-OCH 3-C6H4, R1=2- CH 3-C6H4

2.2.3 Anti T.B.: Navarrete-vazquez G et al32 prepared a set of 4-(5-substituted-1,3,4-oxadiazol-2-yl)-pyridines [28] and evaluated for their antimycobacterial potential against M. tuberculosis. Shaharyar M et al33 prepared oxadiazole mannish bases[29] and evaluated for antimycobacterial activity towards M. tuberculosis and resistant M .tuberculosis. Grazia Mamolo M et al34 synthesized 3H-1,3,4-oxadiazol-2-thione and 2-one [30] derivatives and tested for their in vitro antimycobacterial activity towards Mycobacterium tuberculosis. Szarka Z and Horvath J35 reported a new set of some steroidal 1,3,4-oxadiazole derivatives [31]and screened them for anti-inflammatory, antibacterial, tuberculostic and antimicrobial activity.

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Ali et al36 synthesized oxadiazole Mannisch base [32] that posses antimycobacterial activity. R1=C6H5 and R2=furfuryl is most promising towards M. tuberculosis H37RV and INH resistant M. tuberculosis. R1=4-NO2-C6H5 and R2=furfuryl compound also show better activity. Vasoya et al37 prepared a new series of acetyl oxadiazole bearing Benzo[b] thiophene nucleus [33] as potent biological active agent. (a), (e), (f) are prominent anti T.B. activity. (e), (b), (c): good antifungal activity. (d) has good antibacterial activity towards E. coli and S. aureus, and Holla et al38 synthesized 1,3,4oxadiazole derivatives [34] possessing anti T.B. activity. Guniz Kucukguzed S and colleagues39 prepared and characterized some novel 1,3,4-oxadiazoles [35] and some related compounds and screened them towards Mycobacterium tuberculosis. Krasovskii A.N et al40 synthesized 5-aryl (het-aryl)-1,3,4-oxadiazol-2-thiones [36] and their derivatives and screened for antimicrobial and tuberculostic activity and Islam et al41 synthesized novel oxadiazole derivatives having antibacterial activity.

N N N O

28
O S S O N N R1 R2 NH R1 O S N N

Ar

Ar may be 2-NO2C6H4 or 4-pyridyl


O

NH

29

R2

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N N O O S N N X X= H 3C N CH3 N N X O

30
O

O CH3 N CH3 O N

31
S O N R1 N NH R2 O S O NH R2 N R1 N S O

32
R1 is C6H5 or 4-NO2-C6H5, and R2=furfuryl
Cl O N S O NH

33

a) 4-Cl-C6H4 , b) 4-OH-C 6H4, c) 4-OH-3-OCH3 -C6H3, d) 3,4-( OCH3 )2-C6H3, e) 2,3,4-( OCH3 )3-C6H2, f) 3-OC6H5-C6 H4

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O O H3C NH O N N N H
R' S O N R N N NH R'' O

35

36

R=3-BrC6H4, R= C6H5, R=4-NO2- C6H 4

2.3 Anti-inflammatory: Large number of oxadiazole derivatives were evaluated for Anti-inflammatory and found to posses significant activity. 2,5-disubstituted-1,3,4-oxadiazole show good Anti-inflammatory activity. 2-bromophenyl-5-phenyl-1,3,4-oxadiazole show very good activity. Hussein et al42 synthesized 2-[3-(4-bromophenyl) propan-3-one]-5-(substituted phenyl)-1,3,4oxadiazole having anti-inflammatory and analgesic activity. Compound (a) and (b) are showing anti-inflammatory activity more than that of standard drug acetyl salicylic acid (63.2%). Also compounds show maximum analgesic activity. These compounds tested for ulcerogenic activity but they show less activity than standard indomethacin. Except comp. (c) no one shows nitrofurazone like activity towards E. coli. Bhandari S.V. and his group43 reported [38] novel S- substituted-phenyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac and evaluated for anti-inflammatory, analgesic and ulcerogenicity activity.

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Burbuliene

et

al44

synthesized

5-{(2-disubstitutedamino-6-methyl-pyrimidin-4-yl)-

sulfanylmethyl-3H-1,3,4-oxadiazole-2-thiones [39] and tested these compounds as anti-inflammatory agents. Waghale et al45 synthesized 2-(3-methyl-7-substituted-2-oxoquinoxalin-yl)-5-(aryl)-1,3,4 oxadiazole[40] possessing anti inflammatory and analgesic activity. II(a), II(b), III(a), III(b) maximum anti-inflammatory activity. III(a) 7-methyl quinoxaline was found to posses maximum activity than unsubstituted quinoxaline. III(a) to III(e) show good analgesic activity. 4-OCH3 and 3,4,5-(OCH3)3 in aromatic ring significantly increases analgesic activity III(a) to III(e). Mahfouz N N, Omar F A and Rahman M A46 reported same series of substituted 1,3,4oxadiazole derivatives[41] and screened them for anti-inflammatory activity. Amir et al47 prepared some 1,3,4-oxadiazole [42] derivative possessing potent anti inflammatory action. Compounds 1 and 2 show maximum anti inflammatory action. These groups when replaced by 4-aminophenyl or 4-nitrophenyl, it will minimize activity. In case ulcerogenic activity, compound with R=2-acetoxyphenyl shows maximum activity. Sudha et al48 synthesized 5-(4-aroyl)-aryloxy methyl-2-thio1,3,4-oxadiazole [43] and screened for their antibacterial, antifungal, anti-inflammatory and diuretic activity. Compounds a and d show good antibacterial, antifungal, anti-inflammatory and diuretic activity. All compounds also show good diuretic activity. Saxena et al49 prepared a new series of 1,3,4-oxadiazole thiones [44]which act as anti- inflammatory. R= 3-NO2 and R= 3-Cl show maximum activity. Wang X et al50 reported synthesis of substituted 1,3,4-oxadiazoles [45] under microwave irradiation and screened for anti-inflammatory, anticancer and antifungal activity.

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R Br O N N

37 a) R= -C6H5-Cl, b) R= - C6H4-(OCH3)2, c) R= -C6H5-F

O NH Cl N S N Cl O

38
H3C O NH S

N N R1 N R2

39
N Ar O O N N SH O R N O N N S R1

O R N O

CH3

CH3

CH3

(I)

40

(II)

(III)

II a) R 1=R=CH 3, II b) R=-CH3 , R 1=-C 2H5, III a) Ar=4-OCH 3-C 6H 4, R= CH 3, III b) Ar=3,4,5-(OCH3)3-C 6H4, R= CH3, III d) Ar=4-OCH3-C 6H 4, R= H,
R N O NH R1 N

III c) Ar=3,4,5-(OCH3)3 -C 6 H4, R= H, III e) 3,4,5-(OCH3)3-C 6H4, R= Cl

41

R=Pyridyl and R1=Phenyl


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Cl Cl Cl O O N SH Cl Cl N O O N R

42 1

Cl

2
R1 R N N O HS

43

a) R=R 1=H, b)R=CH3, R 1=H c) R=H , R 1 =C l d) R=C H3, R 1=Cl


H N Ar= Ar O
O

Cl

44
R N Ar O N N N R

45 Ar=pyridyl and R=substituted phenyl

2.4 Antimiotic: No. of derivatives evaluated for antimiotic activity and found to posses antimiotic activity by some derivatives.
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Ouyang X et al51synthesized a novel class of oxadiazole derivatives [46] and evaluated for their antimiotic agents. Lokanatha Rai K M and Linganna N52 reported that alkylated 2-amino-1,3,4oxadiazole derivatives [47] have good antimiotic activity.
O NH O N N N NH O

46
N

R O N N N Br

47 R =phen yl
Br

2.5 Anticonvulsant: Zarghi A and coworkers53 designed and synthesized a series of new 2-substituted-5-(2benzylthiophenyl)-1,3,4-oxadiazoles[48] and tested them for possible anticonvulsant activity. Demina M M and Larina L I54 synthesized 5-trimethylsilylethynyl-1,3,4-oxadiazoles using of phosphoryl chloride. Compounds showing good anticonvulsant activity. Reynaud et al55 synthesized 1,3,4-oxadiazole [50] by new route some of derivative show sedative and antidepressant activity. Compound (a) is very sedative; (b) is anxiolytic and antidepressant. Zarghi et al56 synthesized 2-substituted-5-[2-(2-halobenzyloxy)-phenyl]-1,3,4-oxadiazole[51] that posses anticonvulsant activity. Compounds showing anticonvulsant activity in MES and PTZ models.
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N O S N CH3 NH2 H3C Si CH3 O R N N

49

48

F
R' N O N R

50
a. R= C 6 H 5 N, R=CF 3 -C 6 H 5 , b. R=NH 2 -C 6 H 5, R=CF3 -C 6 H 5

O N N

O R

51
X

2.6 Antiviral: Zareef M et al2 synthesized new benzensulfonamides bearing the 2,5-disubstituted-1,3,4oxadiazole [52] moiety and screened for anti-HIV and antifungal activity.
R O O HS N N 52 Z NH S O

R is CH 3 or Cl and Z is - (CH 2 )3

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2.7 Miscellaneous: Zareef M et al57 synthesized 4-substituted-1-aroyl-thiosemicarbazides and their cyclization to mercaptotriazoles and aminothidiazoles. [53] moieties and investigated for carbonic anhydrase inhibitors. Meyer E and Joseph A C58 synthesized of new 1,3,4-oxadiazoles derivatives [54] as potential nonpeptide angiotensin II receptor antagonists. Khan et al59synthesized 2, 5-disubstituted-1,3,4oxadiazole having Tyrosinase inhibitory activity. Compound 3e exhibit more potent inhibition activity against enzyme Tyrosinase which is more potent than standard potent inhibitor Lmimosine, 3j showing less potent activity but other 3-substituted compound show good inhibition activity. In case of 4a to 4m Bromine replaced by Phenyl ring decreases potency. Shaban et al60 synthesized some 1,3,4-oxadiazole and bis 1,3,4oxadiazole that posses nematocidal, insecticidal and herbicidal activity. Wustrov et al61 synthesized series of oxadiazolone bioisosters [55] of pregabalin and gabapentin. Several were found to be exhibit similar potency for 2- subunit of voltage gated calcium channel. Hu et al62 synthesized arecoline derivative containing amino-5-triazole coupled oxadiazole [56] having potent vascular relaxing agonist taking direct effect on endothelial target for acetylcholine for treatment of cardiovascular disease. All compounds posses vascular relaxing activity comparable to arecoline (36.5%). Shehata et al63 synthesized mesoionic-1,3,4-oxadiazolo-[3,2-a]-pyrimidin-ones [57] as potential adenosine antagonist. These are stable when 6-position posses alkyl chain.

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R1 O O S N N R NH S O

53 R1= CH3 and R= - (CH2)3

CH 3

O OH O O

54

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N N O

55

NH2
CH3 N

N N

NH2

S O N N R

56

R m a y b e H , m e y h o x y , m e t h y l, C l o r B r g r o u p
O N O N N O CH 3 CH 3

57

2.3 Conclusions: Reviewed new class of 2,5-disubstituted-oxadizole has shown wide spectrum of biological activity. 2-bromophenyl-5-phenyl-1,3,4-oxadiazole show very good anti-inflammatory activity. In search of new antimiotic, 2-amino-1,3,4-oxadiazole showed good antimiotic activity. Thiazole attached to 1,3,4-oxadiazole show good antifungal activity. Oxadiazole show good antibacterial activity but more activity show when it is substituted with other nucleus like imidazole, indole, pyrimidine, triazole, thiazole etc.2-(2-napthyoxymethyl)-5-phenoxymethyl-1,,3,4-oxadizole

show good antimycobacterial activity. Biological profile of new class of oxadiazoles represents much progress with regard to older compound.
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2.4 References: 1. Rhone-Poulenc Ag company, SA Brit Pat. Reactions of carbon disulfide with Nnucleophiles. 1968, 1,110, 500: 1968. Chem. Abstr. 69; 52143-52158. 2. Zareef M, Iqbal R, Al-Masoudi NA, Zaidi JH, Arfan M, Shahzad SA. Synthesis of new benzenesulfonamides bearing the 2,5-disubstituted-1,3,4-oxadiazole moiety and screened for anti-HIV and antifungal activity. Synthetic Communications 2007;182:281-298 3. Holla S, Poojary KN, Bhat KS, Ashok M, Poojary B. Synthesis and Anticancer activity studies on some 2-chloro-1,4-bis-(5-substituted-1,3,4- oxadiazol-yl-methyleneoxy) phenylene derivative. Ind. J. Chem. 2005;44B:1669-1673. 4. Aboraia AS, Abdel-Rahman HM, Mahfouz NM, El-Gendy MA. Synthesis of 5-(2hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazol-2-thione derivatives which are promising anticancer agent. Bioorg. Med. Chem. 2006;14:1236-1246. 5. Loetchutinat C., Chau F., Mankhtkarn S. Syntheis of series of 5-aryl-3-(4hydroxyphenyl)-1,3,4-oxadiazol-2-(3H)-thiones as P-glycoprotein inhibitors. Chem. Pharm. Bull., 2003, 51(6), 728. 6. Ruel R, Thibeault C, Martel A. Synthesis of 5-isopropyl-6,5-(methyl-1,3,4-oxadiazol-2yl)-N-(2-methyl-1H-pyrrolo[2,3-B]pyridine-5-yl)-pyrrolo[2,1F] amine(BMS-645737) which are VEGFR inhibitor. 2008;18:2985-2989. 7. Mulvad V.V., and Chaskar A.C. Syntheis of series of new oxadiazole [1,3,5]-triazine, triazolo and thidiazolo-1,3,4-oxadiazole derivatives and screened for biological activity. Ind. J.of Chem., 2006, 45B, 1710.
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8. Montgomery JI, Toogood PL, Hutching KM. Discovery and SAR of benzyl phenyl ethers as inhibitor of bacterial phenylalanyl-tRNA synthatase. 2009;19:665. 9. Mogilaiah K, Vidya K. Synthesis and antibacterial activity of 1,3,4-oxadiazolyl-1,8naphthyridines.Ind. J. Chem. 2006;45B:1905-1909. 10. Dabhi TP, Shah VH, Parikh AR. Synthesis and biological evaluation of some new heterocyclic compounds. Ind. J. Pharm. Sci. 1992;54:98. 11. Ates O, Kocabalkanli A, Cesur N, Otuk G. Synthesis and antimicrobial activity of some 5-aryl-2-[(N,N-disubstituted-thiocarbamoylthio)acylamino]-1,3,4-oxadiazoles. IL Farmaco 1998;53:541-544. 12. Sangapure SS, Basawraj R. Synthesis and biological activities of Some 1,3,4-oxadiazole, thiadiazole, triazole and related compounds possessing benzofuran moiety Ind. J. Pharm. Sci. 2004;66(2):221-224. 13. Mahadevan SN, Murali KE, Chandrashekhar HR, Godavarthi A, Dhanaraj SA. Synthesis of some amino acids incorporated 4(3H)-quinazolinone as possible antiherpes viral agent. Ind. Drugs 2006;43(6):497-502. 14. Xin-ping Hui, Lin-Mei Zhang, Zi-yi Zhang. Synthesis of 1,3,4-oxadiazole derivatives and biological activity. Ind.J.Chem., 1999,38B,1066. 15. Shetgiri N.P., Nayak B.K.; Synthesis and biological activity of some new oxadiazole derivatives.Ind. J. of Chem., 2005, 44B,1267. 16. Nagalakshmi G. Synthesis, antimicrobial and anti-inflammatory activity of 2,5disubstituted-1,3,4-oxadiazoles. Ind. J. Pharm. Sci. 2008:70;49-55. Bioorg. Med. Chem. Lett.

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17. Jain N, Pathak DP, Mishra P, Jain S. Synthesis and antibacterial studies of some 2-[5(Aryl)-[1,3,4]oxadiazol-2-yl-sulfanyl] alkanoic acids. J. Iran. Chem. Soc. 2009;6:77-81. 18. Donawade D.S., Raghu A.V., Gadaginamath G.S.; Synthesi of series of 1-substituted-5methoxy-3-(5-mercapto-1,3,4-oxadiazol-2-yl)methoxy-2-methylindole an screened for biological activity.Ind. J. of Chem., 2006, 45B, 689. 19. Kidwai M, Goel Y, Kumar P. Microwave assisted synthesis of new bioactive 1,3,4thidiazolyl substituted 1,3,4-oxadiazole. Ind. J. Pharm. Sci. 1998;60:396-398. 20. Hall A, Brown SH, Chowdhury A, Livermore DG, Ward Emma, Willay C. Synthesis of some novel 1,3,4-oxadiazole as EP1 receptor antagonist. Bioorg. Med. Chem. Lett. 2007;17:4450-4455. 21. Misra AI, Singh H, Yadav LDS, Misra JP. 1,2,4-triazolo and thiadiazol[3,2-b] 1,3,4oxadiazole with thiones as possible antifungal agent. Ind. J. Pharm. Sci. 1994;56(1):1-4. 22. Dutta MM, Goswami BM, Kataky JCS. Synthesis and antifungal activity of some new aroyl hydrazones and 2,5-disubstituted-1,3,4-oxadiazoles. J. Heterocycl. Chem. 1986;23:793-796. 23. Li M, Zhang XB, Tang BC, Zhang P, Tian W. Synthesis and characterization of 1,3,4oxadiazole derivative containing alkoxy chain with different length. 2007;846:55-64. 24. Song BA, Yang S, Bhadury PS, Lu P, Chen Z. Synthesis of novel sulfone derivatives containing trimethoxy phenyl substituted 1,3,4-oxadiazole and thiadiazole moiety and screened for antifungal activity.Bioorg. Med. Chem. 2007;15:3981-3989. 25. Frank PV, Kalluraya B. Synthesis of 1,3,4-oxadiazole carrying imidazole moiety. Ind. J. Chem. 2005;44B:1456-1459. J. Mol. Str.

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26. Fuloria N.K., Singh V., Shaharyar M., Ali Mohammad; Synthesis of 1,3,4-oxadiazole derivatives from phenylpropionohydrazides Molecules, 2009,14,1898. 27. Kambale RR, Sudha BS. Synthesis and pharmacological screening of 5-methyl-3-[P-(6'aryl-2'-thioxo-1',2',5',6'-tetrahydro-pyrimidin-4'-yl)-phenyl]-3H-2-oxo-D4-1,3,4oxadiazoles. Ind. J. Pharm. Sci. 2006;249-254. 28. Agarwal T, Tiwari N, Khan MH, Nizammudin. Synthesis of some 2'-aryl / aryoxymethylspiro [cyclohexane1,5'-[5H] [1,3,4]-oxadiazolo-[3,2-c]thiazole act as

fungicidal. Ind. J. Chem. 1994;33B:603-606. 29. Khare RK, Srivastava AK, Singh H. 6-aryl-2-(-D-glucopyronosyl)-3-oxo-2,3-dihydro1,3,4-oxadiazolo [3,2-B] 1,2,4,6-thiatriazine-1,1-dioxide activity. Ind. J. Chem. 2005;44B:163-166. 30. Bhovi MG, Gadaginamath GS. Chemoselective reaction of indole 1,3-dicarboxylates towards hydrazine hydrate: Bisheterocycles: Synthesis and antimicrobial activity of some new 2-methyl-3-ethoxycarbonyl-1-oxadiazolyl/thiazolidinonyl/pyrrolylthat posses fungicidal

aminocarbonylmethylindoles. Ind. J. Chem. 2005; 44B:1663-1668. 31. Singh H, Yadav LDS, Shukla KN, Drivedi R. Synthesis of new 1,3,4-oxadiazolo [3,2-a]s-triazine-5,7-dithiones and the dithionone analogues. Ind. J. Pharm. Sci. 1992;54:33-35. 32. Navarrete-Vazquez G, Molina-SalinasGM, Duarte-Fajardo ZV, Vargas-Villarreal J,

Hernandez-Nunez E. Synthesis of 4-(5-substituted-1,3,4-oxadiazol-2-yl) pyridines and evaluated for their antimycobacterial potential. Bioorg. Med. Chem. 2007;15:5502-5508. 33. ShaharYar M, Siddiqui A, Ali M. Synthesis and antituberculostic activity of novel 1,3,4oxadiazole. J. Chinese Chem. Soc. 2007;54:5-9.

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34. Mamolo MG, Zampieri D, Vio L, Fermeglia M, Ferrone M, Pricl S, Scialino G, Banfi E. synthesis of 3H-1,3,4-oxadiazol-2-thione and 2-one derivatives and tested for their in vitro antimycobacterial activity. Bioorg. Med. Chem. 2005;13: 3797-3809. 35. Szarka Z, Skoda-Folde R, Horvath J, Tuba Z, Kollar L. Synthesis of some steroidal 1,3,4oxadiazole derivatives and their screening for anti-inflammatory, antibacterial and tuberculostic activity. Steroids 2002;67:581-586. 36. Ali MA, Shaharyar M. Oxadiazole Mannich base: their evalution for antimycobacterium activity. Bioorg. Med. Chem. Lett. 2007;17:3314-3316. 37. Vasoya L, Patel MR, Dobaria SV, Joshi HS. Facile synthesis of some new azetidinone and acetyl oxadiazole bearing benzo [b] thiophene nucleus as potent biological active agent. Ind. J. Chem. 2005;44B:405-409. 38. Holla SK. Synthesis and characterization of 1,3,4-thiadiazole and 1,3,4- oxadiazole derivatives containing 2-chloropyridin-5-yl-methyl moiety. Ind. J. Chem.

2004;43B:2170-2174. 39. Kucukguzel SG, Oruc EE, Rollas S, Sahin F, Ozbek A. Synthesis and characterization of some novel 1,3,4-oxadiazole and some related compounds and their screening against Mycobacterium tuberculosis. Euro. J. Med. Chem. 2002;37:197-206. 40. Krasovskii AN, Bulgakov AK, Andrushko AP, Krasovskii IA, Dyachenko AM, Bokun AA, Kravchenko NA, Demchenko AM. Synthesis of 5-aryl(hetaryl)-1,3,4-oxadiazol-2thiones and screened them for antimicrobial activity. Pharm. Chem. J. 2000;34:115-117. 41. Islam M., Siddiqui A.A., Rajesh R., Bakht A., Goyal S.; Synthesis and biological screening of some new oxadiazole derivatives. Acta Pol. Pharma.-Drug Research, 2008, 65,441.

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42. Hussein A, Ajmal M. Synthesis of novel 1,3,4-oxadiazole derivatives and their biological properties. Acta Pharm. 2009;59:223-233. 43. Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP, Mokale V. Synthesis of some novel S-substituted phenyl-1,3,4-oxadiazol-2-thiol and Schiff bases of diclofenac and evaluated for anti-inflammatory, analgesic and ulcerogenic activity. Bioorg. Med. Chem. 2008;16:1822-1831. 44. Burbuliene MM, Jakubkiene V, Mekuskiene G, Udrenaite E, Smicius R, Vainilavicius. Synthesis of 5-[(2-disubstitutedamino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-

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58. Meyer, E., Joussef, A.C., De Souza L.D.B.P, Synthesis of some new 1,3,4-oxadiazole derivatives as potential nonpeptide angiotensin II antagonist. Taylor and Francis Group., 2006, 36, 729-741. 59. Khan K.M., Shahzadi S.A., Ranil M., Ali M., Parveen, S., Anwar A., Voelter W.; Structure-activity relationship of tyrosinase inhibitory combinatorial library of 2,5disubstituted-1,3,4-oxadiazole. Lett. Org. Chem., 2006, 3, 286-288. 60. Shaban Moh., Nasar A.E., EL-Badary S.M.; synthesis of some 1,3,4-oxadiazole and bis 1,3,4oxadiazole that posses nematocidal, insecticidal and herbicidal activity. J. Isl. Acad. Sci.,1991, 4:3, 184. 61. Wustrow D.J., Belliotti T.R., Capiris T.; Oxadiazole bioisosters of pregabalin and gabapentin.Bioorg. Med. Chem. letters, 2009, 19,247. 62. Hu G.Q., Li Sheng, HUANG W.L., WANG Hai; Synthesis and bioactivity of arecoline containing amino-s-triazole coupled oxadiazole. Chinese Chem. Lett., 2006,17-19.

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