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International Bulletin of Drug Research., 2(1): 132-146
PROGRESS IN THE PHARMACOLOGICAL POTENTIAL OF
OXADIAZOLES: A REVIEW
SADAF J. GILANI٭1
, MOHAMMAD T. ZZAMAN1, K. NAGARAJAN
1,
RICHA GOEL2, ALKA ARORA
3
___________________________________________________________________________
ABSTRACT
Heterocyclic compounds are indispensable structural units for both the chemists and the
biochemists. 1,3,4-Oxadiazole derivatives have been extensively studied owing to their wide
spectrum of biological activities. The present review article covers the active compounds
having oxadiazole ring with fused heterocycles which possess interesting biological activities
such as anti-inflammatory, analgesic, antimicrobial, anti-convulsant, anti-proliferative, anti-
mycobacterial, anti-protozoal, anti-diabetic, anthelmintics and MAO enzyme inhibitors.
Results of various derivatives of different oxadiazole and their substitutions with diverse
biological activities are reviewed in present article.
KEY WORDS
1,3,4-oxadiazole derivatives, biological activities
AFFILIATION
1Department of Pharmaceutical Chemistry, KIET School of Pharmacy, Ghaziabad, U.P.-
201206-India
2Department of Pharmacognosy and Phytochemistry, KIET School of Pharmacy, Ghaziabad,
U.P.-201206-India
3Department of Pharmaceutics, Innovative College of Pharmacy, Greater Noida, U.P. - India
*Address for correspondence:
E-mail: [email protected]
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INTRODUCTION
Oxadiazoles are five membered ring system containing two carbon atoms, two
nitrogen atoms and one oxygen atom. Depending upon the position of N-atom in the
heterocyclic ring, oxadiazoles may be divided into four types.
(1) (2) (3) (4)
Of all the possible isomers, 1, 3, 4-oxadiazole has been found to posses appreciable
biological activities [1-5]
. The 1, 3, 4-oxadiazole isomer of oxadiazole series and its dihydro
derivatives provide a bulk of literature on oxadiazole. A glance at the standard reference
work shows that more studies have been carried out on the 1, 3, 4-oxadiazole than all other
isomers combined. Therefore, a considerable research has been focused on this nucleus.
Oxadiazole is a very weak base due to the inductive effect of the extra heteroatom.
The replacement of two –CH= groups in furan by two pyridine type nitrogen (-N=) reduces
aromaticity of resulting oxadiazole ring to such an extent that the oxadiazole ring exhibit
character of conjugated diene. The electrophillic substitutions in oxadiazole ring are
extremely difficult at the carbon atom because of the relatively low electron density on the
carbon atom which can be attributed to electron withdrawal effect of the pyridine type
nitrogen atom. However the attack of electrophiles occurs at nitrogen, if oxadiazole ring is
substituted with electron-releasing groups. Oxadiazole ring is generally resistant to
nucleophilic attack. Halogen-substituted oxadiazole, however undergo nucleophilic
substitution with replacement of halogen atom by nucleophiles. Literature survey reveals that
the oxadiazoles undergoes number of reactions such as electrophilic substitution,
nucleophilic substitution, thermal and photochemical [6]
. This has been exploited in the
preparation of oxadiazole therapeutic molecules for various applications. In this view an
attempt has been made to review the biological activities of oxadiazoles.
PREPARATION OF OXADIAZOLES
Thiosemicarbazides
2-Amino-5-substituted-1,3,4-oxadiazoles (1) can be conveniently prepared from 1-
benzoyl-thiosemicarbazide by cyclization with lead oxide[7]
.
(1)
Scheme 1
Thiosemicarbazides are also cyclised in the presence of mercuric oxide to give 2-
amino-5-substituted-1,3,4-oxadiazole (2) [8]
.
(2)
Scheme 2
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Hydrazines
Hydrazones are oxidatively cyclized by lead tetraacetate [9]
to give the corresponding
disubstituted -1,3,4-oxadiazole (3).
(3)
Scheme 3
Acid Hydrazides
Acid hydrazides are cyclized with carbon disulfide in the presence of pyridine or
alkali hydroxide to give 2-mercapto-1,3,4-oxadiazole (4) [10]
.
(4)
Scheme 4
Aryl acid hydrazides are cyclized with ortho-esters to give 2-aryl-1,3,4-oxadiazole (5)
[11].
(5)
Scheme 5
BIOLOGICAL PROFILE
Oxadizoles possess various biological activities which are given hereunder:
Anti-inflammatory activity
Burbuliene et al [12]
synthesized and evaluated 5-[(2-disubstitutedamino-6-methyl-
pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-2-thiones for their in vivo anti-
inflammatory activity. Compound (6) was found to be more active than standard ibuprofen.
In search of novel compounds, Kumar et al [13]
also synthesized a series of substituted 1,3,4-
oxadiazole/thiadiazole and 1,2,4-triazole derivatives (7) by cyclisation of carboxylic group of
biphenyl-4-yloxy acetic acid in various reaction conditions. The target compounds was
pharmacologically evaluated for their anti-inflammatory potential. Khan [14]
and Saxena et al [15]
synthesized 2-(coumarin-3-yl)-5-aryl-1,3,4-oxadiazole derivatives (8) and 5-[2-ydroxy
phenyl]-1,3,4-oxadiazole-2(3H) thione (9) respectively. All the oxadiazole derivatives were
evaluated for their ability to inhibit carrageenan induced rat paw edema and showed good to
moderate anti-inflammatory activity.
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(6) (7) X= O, S
R= Substituted phenyl
(8) (9)
Analgesic activity
Jayashankar et al [16]
synthesized a series of novel ether-linked bis (heterocycle)s (10)
via [3 + 2]-cycloaddition reaction of nitrile oxide with allyl alcohol followed by
intramolecular 1,3-diploar cycloaddition reaction of nitrile imine with carbonyl group and
showed good analgesic activity. Bhandari et al [17]
synthesized and screened a series of S-
substituted phenacyl 1,3,4-oxadiazoles (11) derived from 2-[(2,6-dichloroanilino) phenyl]
acetic acid (diclofenac acid). These compounds were tested in vivo for their analgesic
activity. Eight new compounds, out of 18, were found to have significant analgesic activity in
the acetic acid induced writhing model with no ulcerogenicity. Gilani et al [18]
synthesized a
series of 1,3,4-oxadiazole (12a–g) derivatives of isoniazid in satisfactory yield and
pharmacologically evaluated for their analgesic activity by known experimental models.
Further, Akhter et al [19]
reported synthesis and analgesic activity of various aroylpropionic
acid derivatives containing 1,3,4-oxadiazole nucleus (13a-i). The study showed that the
cyclization of carboxylic group of aroylpropionic acids into an oxadiazole nucleus resulted in
compounds having good analgesic effects with reduced gastric irritation.
(10) (11)
R = substituted acetophenones
(12) (13a-i)
R = a: C6H5 R = H, 4-CH3, 2,4-(CH3)2
b: 2-C6H4Cl R’ = [H; 2-Cl; 4-Cl; 4-NO2]
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c: 2,4-C6H3Cl2
d: 2-C6H4CH3
e: 2-C6H4OCOCH3
f: OC6H5(phenoxy)
g: 4-C6H4NO2]
Antimicrobial activity
Chandrakantha et al [20]
synthesized a new series of 1,3,4-oxadiazoles bearing 2-
flouro-4-methoxy phenyl moiety (14) and their antimicrobial studies were performed. Few of
the compounds showed significant antimicrobial activity. Joshi et al [21]
synthesized a novel
series of compounds (15) derived from 5-substituted-2-thiol-1,3,4-oxadiazoles. Compounds
were evaluated for their preliminary in vitro antibacterial activity against some gram-positive
and gram-negative bacteria. Some compounds showed very good antibacterial activity. Liu et
al also [22]
synthesized a series of novel sulfoxide derivatives containing 1,3,4-oxadiazole
moiety and evaluated their antifungal activity. The bioassay results showed that the
compound (16) possess high antifungal activity. El-eman et al [23]
synthesized 5-(1-
adamantyl)-2-substituted thio-1,3,4-oxadiazole. All the synthesized compounds were tested
for in vitro activities against certain strains of gram positive and gram negative bacteria and
the yeast like pathogenic fungus Candida albicans. Compound (17) was found as the most
active derivatives particularly against gram positive bacteria.
(14) (15)
R= Substituted acid R = C6H5; 2,6-Cl2-C6H3
(16) (17)
Anticonvulsant activity
Lankau et al [24]
synthesized a series of 3- and 5-aryl-1,2,4-oxadiazole derivatives and
evaluated their anticonvulsant activity in a variety of models. These 1,2,4-oxadiazoles exhibit
considerable activity in both pentylenetetrazole (PTZ) and maximal electroshock seizure
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(MES) models. Compound (18) was protective in the PTZ model in rats with an oral ED50 of
25.5 mg/kg and in the MES model in rats with an oral ED50 of 14.6 mg/kg. Neurotoxicity
(rotarod) was observed with an ED50 of 335 mg/kg. Gilani et al [25]
synthesized a series of
isoniazid incorporated derivatives of 1,3,4-oxadiazoles (19a-h) and found that all the
compounds were active in MES and a majority of compounds were active in ScPTZ test.
Zarghi et al [26]
synthesized new 1,3,4-oxadiazoles (20) as anticonvulsant agents.
Electroshock and pentylenetetrazole-induced lethal convulsion test showed that the induction
of an amino group in position 2 of 1,3,4-oxadiazole ring had the best anticonvulsant activity.
Zarghi et al [27]
synthesized a series of new 2-substituted-5-(benzyloxyphenyl)-1,3,4-
oxadiazoles (21) and evaluated their anticonvulsant activity both in PTZ and MES models.
They proposed that anticonvulsant effect was mediated through benzodiazepine receptors
mechanism. Almasirad et al [28]
synthesized a new series of 2-substituted-5-[2-(2-
fluorophenoxy) phenyl]-1,3,4-oxadiazoles and screened for their anticonvulsant activity.
Compound (22) showed considerable anticonvulsant activity both in PTZ and MES models.
The effect was supposed to be mediated by the benzodiazepine receptors and other unknown
mechanism, respectively.
(18) (19a-h)
R = a: 2-C6H5Cl
(20) b: 4-C6H5Cl
c: 2-C6H5OH
d: 3-C6H5OH
e: 4- C6H5OCH3
f: 4- C6H5F
g: 2-C6H5NO2
h: 4- C6H5N(CH3)2
(21) (22)
Anti‐proliferative activity
Ouyang et al [29]
synthesized derivatives of oxadiazoles and evaluated their ability to
inhibit tubulin polymerization and to arrest mitotic division of tumor cells. Among the
synthesized compounds, 23 showed potent activity. Padmavathi et al[30]
synthesized a new
class of 1,3,4-oxadiazoles from acid hydrazides on treatment with different carboxylic acids
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in the presence of phosphorus oxychloride. Compound 24 exhibited maximum cytotoxicity.
Aboraia et al[31]
synthesized a series of 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-
oxadiazole-2-thione derivatives and 13 of them were selected by the National Cancer
Institute (NCI) and 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
25 and 26 proved to be the active members in this study compared to 5-fluorouracil and
cyclophosphamide as reference drugs, respectively. Compounds 25 and 26 were identified as
promising lead compounds. Gudipati et al [32]
synthesized a series of 5- or 7-substituted 3-{4-
(5-mercapto-1,3,4-oxadiazol-2-yl)phenylimino}-indolin-2-one by treating 5-(4-
aminophenyl)-1,3,4-oxadiazole-2-thiol with different isatin derivatives. All the synthesized
derivatives were screened for anticancer activity against HeLa cancer cell lines using MTT
assay. All the synthetic compounds produced a dose dependant inhibition of growth of the
cells. The IC50 values of all the synthetic test compounds were found between 10.64 and
33.62 μM. The potency (IC50 values) of anticancer activity of compounds 27 was comparable
with that of known anticancer agent, cisplatin. Among the synthesized 2-indolinones,
compounds 27 with halogen atom (electron withdrawing groups) at C5 position showed the
most potent activity. These results indicate that C5 substituted derivatives may be useful
leads for anticancer drug development in the future. Kumar et al [33]
developed a facile,
convenient and high yielding method and synthesized a series of novel 5-(3’-indolyl)-2-
(substituted)-1,3,4-oxadiazoles from readily available starting materials and screened for
their in vitro anticancer activity against various human cancer cell lines. Compounds 28a,
28b and 28c exhibited potent cytotoxicity (IC50~1 lM) and selectivity against human cancer
cell lines.
(23) (24)
(25) (26)
(27) (28)
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R1 R2 R
F H a 4-pyridyl
Cl H b 3-pyridyl
Br H c 4-BnO-3-CH3OC6H3
Anti-mycobacterial activity
Mallikarjuna[34]
and Joshi et al [35]
synthesized a series of 4-isopropylthiazole-2-
carbohydrazide analogs, derived clubbed oxadiazole-thiazole derivatives(29) and 4-pyrrol-1-
yl benzoic acid hydrazide analogs (30). The synthesized compounds were evaluated for their
preliminary in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain
by broth dilution assay method. Some compounds showed very good anti-tubercular activity.
Further, Ahsan et al [36]
synthesized a series of 1,5-dimethyl-2-phenyl-4-{[(5-aryl-1,3,4-
oxadiazol-2-yl)methyl]amino}-1,2-dihydro-3H-pyrazol-3-one after molecular properties
prediction by Molinspiration and MolSoft software. Among the compounds synthesized,
compound (31) was found to be active with MICs, 0.78 μM and 1.52 μM against MTB and
INHR-TB, respectively.
(29) (30)
R R
a C6H5 C6H5
b 3,4,5 -(OCH3)3-C6H2 C6H5Cl2
c 4-N(CH3)2-C6H4
d 4-OH-C6H4
e 4-NO2-C6H4
f 2,3 -(Cl)2 - C6H3
(31)
Ar = 4-Pyridinyl-
Anti-protozoal
Ishii et al [37]
synthesized a series of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-
oxadiazole derivatives (32) and screened for their in vitro activity against Trypanosoma
cruzi. The bioactivity was expressed as fifty-percent inhibitory concentration (IC50) of
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parasite population growth for T. cruzi. A molecular modeling approach was performed to
establish qualitative relationships regarding the biological data and the compounds
physicochemical properties. The 5-(4-CO2CH3Ph) derivatives was the most active
compounds for T. cruzi (IC50 = 7.91 lM). Durust et al [38]
synthesized a series of novel
oxadiazolyl pyrrolo triazole diones (33a-k). These novel heterocyclic compounds were
investigated for their in vitro anti-protozoal activity and results found to be good.
(32) (33)
R = -C2H3O2 R = a:H
b:Cl
c:Br
d:F
e:CH3
f:I
g:NO2
h:OCH3
i:SCH3
j:CF3
k:N(CH3)2
Anti-diabetic
Shingalapur et al [39]
synthesized a series of 1,3,4-oxadiazoles 34(a–j) containing 2-
mercapto benzimidazole moiety and screened for in vivo antidiabetic activity using Oral
Glucose Tolerance Test (OGTT). Some of the compounds showed excellent antidiabetic
activity and also pharmacophore derived from active molecules suggested that presence of –
OH group was a common feature in all active compounds. Zou et al [40]
synthesized a series
of furoxan-based nitric oxide-releasing chrysin derivatives (35). Pharmacological assays
indicated that all chrysin derivatives exhibited in vitro inhibitory activities against aldose
reductase and advanced glycation end-product formation. Some chrysin derivatives were also
found to increase the glucose consumption of HepG2 cells. Furthermore, the compounds
released a low amount of NO in the presence of L-cysteine (range from 0.20% to 1.89%).
This hybrid furoxan-based NO donor chrysin derivatives offer a mutual prodrug design
concept for the development of therapeutic or preventive agents for vascular complications
due to diabetes.
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(34 a-j) (35)
R= Halogenated Aryl or Heterocyclic Ring
Anthelmintics
Bharathi et al [41]
synthesized 1,3,4-oxadiazole derivatives (36) by refluxing the
mixture of aldehyde with semicarbazide hydrochloride in ethanol using sodium acetate as a
catalyst. The newly synthesized compounds were tested for its anthelmintic activity. The
results showed that the synthesized compounds showed good activity.
(36)
R=C8H8O3, C9H10O3, C7H6O, C7H6O2, C7H5NO3, C9H
MAO enzyme inhibitors
Shaoyong et al [42]
synthesized a new series of 1,3,4-oxadiazole-3(2H)-carboxamide
derivatives (37) by direct heterocyclization reaction of substituted benzoylisocyanate with
various aroylhydrazones as novel monoamine oxidase inhibitors (MAOIs). The newly
synthesized compounds were evaluated for their MAO inhibitory activity by Kynuramine
Fluorimetric assay method. The preliminary results showed that most of the compounds have
moderate inhibitory activities toward MAO at the concentration of 10-5
–10-3
M providing a
novel class of lead compounds with potential MAO inhibitions for further optimization.
(37)
4. CONCLUSION
Oxadiazoles belongs to an important class of heterocyclic compounds and exhibits a
wide range of biological properties. Few methods for the synthesis of oxadiazole have been
reported. Thus by studying all the derivatives showing variety of activities it can be
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concluded that oxadiazole ring have been explored in past years and is still be used for future
development of new drugs against many more pathological conditions.
Acknowledgments
The authors are thankful to the Principal, KIET School of Pharmacy for motivation. Authors
are also thankful to KIET library and NISCAIR, New Delhi for providing the literature.
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