-
Molecules 2012, 17, 1-x manuscripts;
doi:10.3390/molecules170x0000x
molecules ISSN 1420-3049
www.mdpi.com/journal/molecules
Review
Approaches of Synthesis and Pharmacological Activity of
1,3,4-
Oxadiazole: a Review of the Literature 2000-2012.
Cledualdo Soares de Oliveira 1, Bruno Freitas Lira
1, Jos Maria Barbosa-Filho
2 and Petrnio
Filgueiras de Athayde-Filho 1,
*
1 Department of Chemistry, Federal University of Paraba,
58051-900, Joo Pessoa-PB, Brazil; E-
Mails: [email protected] (C.S.O.);
[email protected] (B.F.L.); 2
Laboratory of Pharmaceutical Technology, Federal University of
Paraba, 58051-900, Joo Pessoa-
PB, Brazil; E-Mails: [email protected] (J.M.B.-F.)
* Author to whom correspondence should be addressed;
[email protected];
Tel.: +55-83-3216-7937
Received: / Accepted: / Published:
Abstract: This review provides readers with an overview of the
main synthetic methodologies
used in the synthesis of 1,3,4-oxadiazole derivatives, also
covering the broad spectrum of
pharmacological activities reported in the literature over the
past twelve years.
Keywords: 1,3,4-Oxadiazole, Synthesis Methods; Pharmacological
Activity.
1. Introduction
1,3,4-oxadiazole (1) is a heterocyclic compound containing an
oxygen atom and two nitrogen atoms
on a five-membered ring, and they can be considered derivatives
of furan by substitution of two groups
methylene (=CH) by two nitrogens type pyridine (-N =) [1,2]. Are
known three isomers of 1,3,4-
oxadiazole, namely: 1,2,4-oxadiazole (2), 1,2,3-oxadiazole (3)
and 1,2,5-oxadiazole (4) (Figure 1).
However, the isomers 1,3,4-oxadiazole and 1,2,4-oxadiazole are
more known and widely studied by
researchers because they have many properties chemical and
biological important.
OPEN ACCESS
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Molecules 2012, 17
2
Figure 1. Isomers of oxadiazole.
NN
O1
2
34
5
1 2 3 4
N
ON
1
2
34
5
N
ON
1
2
34
5 NO
N
1
2
34
5
Among the class of heterocyclic compounds, 1,3,4-oxadiazole is
an important motifs of
construction for the development of new drugs since compounds
containing this unit have a broad
spectrum of biological activities such as antibacterial,
antifungal, analgesic, anti-inflammatory,
antiviral, anticancer, antihypertensive, anticonvulsant,
antidiabetic and furthermore have attracted
interest in medicinal chemistry as surrogates (bioisosteres) of
carboxylic acids, esters and
carboxamides [2]. In fact, the ability of heterocyclic compounds
1,3,4-oxadiazole have of undergo
various chemical reactions have made of these compounds
important privileged structures for the
construction of molecules with enormous biological potential.
Examples of drugs containing the 1,3,4-
oxadiazol unit currently used in clinical medicine are:
Raltegravir (1), an antiretroviral drug [3] and
Zibotentan (2) an anticancer agent [4] (Figure 2).
Figure 2. Structures of Raltegravir e Zibotentan, drugs that are
in late stage clinical development.
NN
O
N
S
HN
O
O
N
N
O
6
NN
OO
HN
N
N
O
OH
O
HN
F
5
The synthesis of novel 1,3,4-oxadiazole derivatives and
investigation of the behavior of their
chemical and biological properties have gained greater
importance in the last two decades. In fact, in
recent years the number of scientific studies with these
compounds has increased considerably.
Considering only the period from 2002 to 2012, the Scifinder
Scholar database records 2577 references
with the word 1,3,4-oxadiazole as input, demonstrating the
relevance of such compounds for the
chemistry of heterocyclic compounds. The Figure 3 shows the
number of publications over the past
twelve years involving 1,3,4-oxadiazole. The graph is not
totally linear, there is a decrease of 2002
(169 articles) to 2003 (146 articles) and then a gradual
increase from 2003 to 2006 (219 articles).
Again there is a small decline of 2006 to 2007 (214 articles),
an increase from 2007 to 2011 (319
articles) [5].
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Molecules 2012, 17
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Figure 3. Number of publications in the last twelve years
involving 1,3,4-oxadiazole.
Therefore, taking into account the importance of these compounds
to the chemistry of heterocyclic
compounds and also for medicinal chemistry, we decided in this
review to present what are the main
approaches of synthesis used to obtain of these important
heterocyclic nucleus, as well as presenting a
broad spectrum of pharmacological activities of these compounds
that were reported in the literature
over the past twelve years.
2. Methods of synthesis of
2,5-disubstituted-1,3,4-oxadiazoles
2.1. Methods of synthesis of
5-substituted-2-amino-1,3,4-oxadiazole
Some methods reported in the literature for the preparation of
5-substituted-2-amino-1,3,4-
oxadiazole (7) is outlined in Scheme (1). The methods a and b
uses the acylhydrazide intermediate (8),
readily prepared from the corresponding ester and hydrazine
hydrate, which can react with cyanogen
bromide (14) or di(benzotriazol-1-yl)metanoimina (23).
Dehydration of acylsemicarbazide (9) also has
been extensively used in the synthesis of (7), although more
stringent conditions are necessary (method
c). Finally the acylthiosemicarbazide intermediates (11) and
(12) have been used in different routes to
obtain the desired heterocyclic through oxidative cyclization
reactions with iodine at elevated
temperatures or with derivatives of carbodiimides (methods e and
f). Furthermore, semicarbazones
(10) being versatile intermediates can easily be cyclized to the
corresponding 1,3,4-oxadiazole
(method d).
95 120
169 146 149
190 219 214
229 254
307 319
166
0
50
100
150
200
250
300
350
200020012002200320042005200620072008 209 201020112012
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Molecules 2012, 17
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Scheme 1. Retrosynthetic analysis of
5-substituted-2-amino-1,3,4-oxadiazole.
NN
OR NH2
a
N
Br
H2NNH
R
O
H2N
S
NH
HN R
O
NH
Bt Bt
H2NNH
R
Ob
H2N
O
NH
HN R
O
c
H2N
S
N
HN R
O
e
f
H2N
O
NH
N R
d
7
8
9
10
11
12
13
14
Using the approach (a) of the Scheme 1, Patel and Patel [6]
synthesized the compounds 5-aryl-2-
amino-1,3,4-oxadiazole (15) with yields of 62 to 70%. Compounds
(15) were used as intermediates in
the synthesis of novel derivatives of quinazolinones (Entry a,
Scheme 2). Kerimov and co-workers [7]
synthesized a new series of 2-amino-1,3,4-oxadiazoles (17)
carrying a benzimidazole moiety from the
reaction between
2-(2-(4-substitutedphenyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide
(16) and
cyanogen bromide, in which were obtained 33-60 % yield (Entry b,
Scheme 2).
Scheme 2. 5-aryl-2-amino-1,3,4-oxadiazole obtained from
acylhydrazides and cyanogen bromide.
NN
O NH2
15
NH
O
NH2
R
CNBr
MeOHR
R = 2-Cl, 4-Cl
N
N
CH2CONHNH2
R
CNBr/EtOH
60-70 oC, 6 hN
N
R
O
NNNH2
R = H, Cl, OMe, OCH2Ph 33-60 %1716
a)
b)
Katritzky and co-workers [8] have prepared the compounds
5-aryl-2-amino-1,3,4-oxadiazole (18)
(Scheme 3) in excellent yields from the reaction between
di(benzotriazol-1-yl)metanoimina (13) and
arylhydrazides (8) using the approach (b) of the Scheme 1.
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Molecules 2012, 17
5
Scheme 3. 5-aryl-2-amino-1,3,4-oxadiazole obtained from
acylhydrazides and di(benzotriazol-1-
il)metanoimina.
HN
N
NN
NN
N
+R1 N
H
O
NH2
HN
N
N
N
O
N
NH2R1 + 2
THF
3-6 hrefluxo
138
18
R1 = Ph, 4-t-BuC6H4, 4-NH2C6H4, 4-OHC6H4, 4-NO2C6H4, 3-NO2C6H4,
4-ClC6H4, 2-ClC6H4, 4-Pyridyl, EtO
The oxidative cyclization of semicarbazones (19) with bromine in
acetic acid is one of the
approaches more used for the preparation of
5-substituted-1,3,4-oxadiazol-2-amino (20) (Entry a,
Scheme 4) [9,10]. The electrocyclization of semicarbazones (21)
to the corresponding 5-aryl-2-amino-
1,3,4-oxadiazole (22) has emerged as an alternative method
(Entry b, Scheme 4) [11,12].
Scheme 4. 5-substituted-1,3,4-oxadiazol-2-amino from of
cyclization reaction of semicarbazones.
AcOH/AcO-Na+
Br2/AcOH
N
O
N
NH2R
R
N
HN NH2
O
R = H, 4-Cl, 4-NO2, 4-Me, 4-OH, 4-F, 4-OMe, 2-Cl, 3-Cl, 4-NH2,
4-N(CH3)2
19 20
MeCN, 3 h, rt
NN
O NH2R
80-90 %
R N
HN NH2
O
LiClO4
R = C6H5, 4-Cl-C6H4, 4-MeO-C6H4, 3-NO2-C6H4, 4-OH-C6H4, CH3
22
a)
b)
21
Another interesting approach to the synthesis of
5-substituted-2-amino-1,3,4-oxadiazol is
cyclization reaction of acylthiosemicarbazides using iodine as
oxidizing agent. In this regard, El-Sayed
and co-workers [13] reported the synthesis of
5-((naphthalen-2-yloxy)methyl)-N-phenyl-1,3,4-
oxadiazol-2-amine (24) in 62 % yield, by heating of compound
(23) in ethanol in presence of sodium
hydroxide and iodine in potassium iodide (Scheme 5).
Scheme 5. Synthesis of 1,3,4-oxadiazole-2-amino from of
cyclization reaction of
acylthiosemicarbazide with iodine.
ONH
OHN
HN
O
Ph
EtOH, NaOH
I2/KI
reflux, 2 h, 62 %
NN
O NH
PhO
23 24
Rivera and co-workers [14] reported that
1,3-dibromo-5,5-dimethylhydantoin is an oxidizing agent
effective for reactions of cyclization of acylthiosemicarbazide.
Compounds (25) were cyclized to the
corresponding 5-aryl-2-amino-1,3,4-oxadiazole (26) in excellent
yield (Scheme 6). The main
advantage of this method is that the reagents used are
commercially cheap and safe to work.
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Molecules 2012, 17
6
Furthermore, it is applicable to large scale synthesis where the
use of other oxidizing agents cannot be
used.
Scheme 6. Synthesis of 5-aryl-2-amino-1,3,4-oxadiazole from
acylthiosemicarbazide and 1,3-
dibromo-5,5-dimethylhydantoin.
Ar N
ONN
OAr NH2
N NH2
S
NaOH (5 N), KI
H2O, i-PrOH
1,3-dibromo-5,5-dimethylhydantoin
Ar = Ph, 4-ClC6H4, 4-MeOC6H4
2625
H
H
We have seen that 5-aryl(alkyl)-2-amino-1,3,4-oxadiazoles can be
prepared by cyclization of
derivatives of semicarbazides and thiosemicarbazides, and this
requires reagents usually such as POCl3
or H2SO4. Alternatively, reagents that activate the carbonyl
group has been used. Accordingly, Dolman
and co-workers [15] reported a new method of synthesis of
5-aryl(alkyl)-2-amino-1,3,4-oxadiazole
(28) from acylsemicarbazide (27) (X=O) and
acylthiosemicarbazides (27) (X=S) mediated by tosyl
chloride. Yields of 97-99% were obtained when used
thiosemicarbazides derivatives which were more
reactive than those of semicarbazide (Scheme 7).
Scheme 7. Synthesis of 5-aryl-2-amino-1,3,4-oxadiazole from
acylthiosemicarbazide and tosyl
chloride.
R N
O NN
OR NN N
X
TsCl (1.2 equiv)Py (2.1 equiv)
THF, 65-70 oC
R, R1 = alquil, aril
28
27
H
H
R1
HR1
H
X = O, S
2.2. Methods of synthesis of
5-substituted-1,3,4-oxadiazole-2-thiol
The main route for the synthesis of
5-substituted-1,3,4-oxadiazole-2-thiol(thione) (29) involves
first
the reaction between acylhydrazides (8) and carbon disulfide in
an alcoholic solution basic followed by
acidification of the mixture reaction (Scheme 8). A large number
of 1,3,4-oxadiazole derivatives
prepared by this route have been reported in recent years. It is
known the existence of tautomerism
thiol-thione in compounds (29) and one of the tautomeric forms
usually predominates [16].
Scheme 8. Synthesis of
5-substituted-1,3,4-oxadiazole-2-thiol.
NN
OR SH
29
R NH
O
NH2
1) EtOH, KOH
CS2
2) H3O+
8
NHN
OR S
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Molecules 2012, 17
7
The compounds (30) [17], (31) [18], (32) [19], (33) [20], (34)
[21], (35) [22], (36) [23], (37) [24],
(38) [16] and (39) [25] (Figure 4) are just some of many
compounds of this class prepared using the
synthetic route of the Scheme 8.
Figure 4. 5-aryl-1,3,4-oxadiazole-2-thiol obtained by reaction
of acylhydrazide with carbon disulfide.
NH
Cl Cl
N N
OSH
30
N
NO2N
R
N N
O SH
R = H, CH3
31
O
R
32
O
NNSH
R
R = H, Cl, F
NN
O
H
SR
R1
33
R = H, CH3
R1 = SCH3, CH2CH(CH3)2NN
O SH
34N
N
O
NN
O S
35
H
S
Cl
NN
O SH
36R
R = 2-CF3, 2,3,4-tri-F, 2-F, 2,6-di-F
2,6-di-Cl, 2-MeO, 2-Me, 2-Br, 2-Cl-6-F
NN
O SHS
N
N37
NN
OSH
38O N
N
N
N
CH3
H3C
S O
NN
SH
39
2.3. Methods of synthesis of
2,5-diaryl(alkyl)-1,3,4-oxadiazole
Several synthetic methods have been reported in the literature
for the preparation of 2,5-diaryl
(alkyl)-1,3,4-oxadiazoles (40) symmetrical and asymmetrical
(Scheme 9). One of the most popular
methods involve the cyclodehydration of 1,2-diacylhydrazine (41)
using phosphorous oxychloride
(POCl3) as a dehydrating agent, approach c of the Scheme 9.
Other dehydrating agents commonly used
are sulfuric acid, phosphoric acid, trifluoroacetic acid,
phosphorus pentachloride, phosphorus
pentoxide, thionyl chloride and reagents milder as, carbodiimide
derivatives, TsCl/pyridine,
trimethylsilyl chloride, Ph3O/Tf2O, PPh3/CX4 (X = Cl, Br, I) and
Burgess reagent. Other routes
important to obtain 2,5-diaryl(alkyl)-1,3,4-oxadiazole
symmetrical (R = R1) or asymmetric (R R1) (40) are the reactions of
acylhydrazide (8) and carboxylic acids aromatic (42) (approach a),
the
oxidative cyclization of acylhydrazones (45) (approach b) and
the reaction of tetrazoles (43) with acid
chlorides (44) in the presence of pyridine, approach d (Scheme
9).
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Molecules 2012, 17
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Scheme 9. Retrosynthetic analysis of
2,5-diaryl(alkyl)-1,3,4-oxadiazole.
NN
OR R1
a
H2NNH
R
O
bd
c
40
8R1
O
OH
R
O
NH
N R1
R
O
NH
HN R1
O
NN
NH
NR
R1
O
Cl
42
45
41
43
44
The asymmetrical compounds
5-(2,4-dichloro-5-flurophenyl)-2-(aryl)-1,3,4-oxadiazole (47)
were
prepared in two steps (Scheme 10) by Zheng and co-workers [26]
refluxing the corresponding
diacylhydrazine (46) with phosphorus oxychloride (POCl3). When
it is not intended to isolate the
intermediate diacylhydrazine, generally it is used the one-pot
reaction of a carboxylic acid with
acylhydrazide and POCl3 as dehydrating agent (see approach a,
Scheme 9). In this sense, Amir and
Kumar [27] reported the synthesis of novel derivatives of
2,5-disubstituted-1,3,4-oxadiazole (49)
beginning with the anti-inflammatory drug ibuprofen as starting
material (Scheme 11). The phosphorus
oxychloride (POCl3) was used as dehydrating agent in the
reaction of acylhydrazide (48) with some
substituted aromatic carboxylic acids.
Scheme 10. Synthesis of asymmetrical
2-(2,4-dichloro-5-fluorophenyl)-5-aryl-1,3,4-oxadiazoles.
NH
O
NH2
Cl
Cl
F
Cl
O
Rn
THF, 0 oC
NH
OHN
Cl
Cl
F
O
Rn
N
O
NCl
Cl
F
Rn
POCl3
Reflux2-3 h
Rn = 2,3,4,5-tetrafluoro (93 %), 2,4,5-trifluoro (94 %),
2,6-difluoro (96 %), 2-chloro (96 %), 2-chloro-4,5-difluoro (93
%)
46 47
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Molecules 2012, 17
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Scheme 11. Synthesis of 2,5-dissubstituted-1,3,4-oxadiazole
derivatives of ibuprofeno.
NN
OR
NHNH2
O
POCl3
reflux 49
R = 4-Cl, 4- NH2
48
+
R
HO
O
OH
O
Ibuprofen
EtOH
H2SO4
O
O
NH2NH2
EtOH
Other dehydrating agent normally used for the dehydration of
diacylhydrazines is thionyl chloride,
the scheme (12) outlines some examples.
Scheme 12. Cyclization of diacylhydrazine with thionyl chloride.
50 [28], 51 [29] and 52 [30].
O
HN
N
O
NH
OR SOCl2
NN
ON
O
R
R = Ph, 4-EtOC6H4, 4-PhOC6H4, 4-ClC6H427-33%
50CHCl3reflux, 20 h
O
HN
NH
O
N
SOCl2
NN
O N
72 %
51Pyridine
HO
HO
C5H11
NH
OHN
O
OH
SOCl2
Py
C5H11
O
NN
OH
77 %
52
The use of POCl3 requires great care because it is very toxic
and corrosive. Therefore, other
reagents softer and easier to work than POCl3 have arisen in
recent years. For example, Bostrom and
co-workers [2] synthesized the compounds
2,5-disubstituted-1,3,4-oxadiazole (54) by
cyclodehydration of diacylhydrazine (53) using
triphenylphosphine oxide (3 equivalents) and triflic
anhydride (1.5 equivalents), obtaining 26-96 % of yield (Scheme
13).
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Molecules 2012, 17
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Scheme 13. cyclodehydration of diacylhydrazine using
triphenylphosphine oxide and triflic anhydride.
R1
O
NH
HN R2
O
Ph3PO (3 equiv)
Tf2O (1.5 equiv)
CH2Cl2, 0 oC to rt
NN
O R2R1R1 N
H
O
NH2
R2COCl (1.1 equiv)
TEA (1.5 equiv)
CH2Cl2, r.t
R1 = Ph, 3-pyridyl, n-propyl, 5-bromothiophenyl-2-yl,
p-chlorophenyl, 4-hydroxyphenyl
R2 = Ph, Et, p-tolyl, p-chlorophenyl, benzyl, 3-pyridyl,
iso-propryl, N,N-dimethyl-4-aminophenyl
26-96 %
5453
Nagendra and co-workers [31] reported the synthesis of novel
orthogonally protected 1,3,4-
oxadiazole (56) tethered dipeptide mimetics by cyclodehydration
reaction of diacylhydrazine (55)
using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) (EDC) as
dehydration agents, obtaining 70-
92% of yield (Scheme 14).
Scheme 14. Cyclodehydration reaction of diacylhydrazine using
EDC.
Pg1HN
HN
O
NH2
R1
Pg2HNF
O
+CH2Cl2, rt
30 min Pg1HN
HN
O
NH
R1 O
NHPg2
R2
R2
O
N NPg1HN
R1
NHPg2
R2
Pg1HN
HN
O
NH
R1 O
NHPg2
R2
EDC/TEA
DCMreflux, 3h
Pg1 = Boc or Z group; Pg2 = BOC, Z or Fmoc group 70-92%
55
55 56
Li and co-workers [32] reported that silica-supported
dichlorophosphate is an efficient
cyclodehydrant for the synthesis of 2,5-disubstituted
1,3,4-oxadiazoles (58) from 1,2-diacylhydrazines
in solvent-free medium under microwave irradiation. This
protocol was suitable to the synthesis of
alkyl, aryl and heterocyclyl substituted symmetrical and
unsymmetrical 1,3,4-oxadiazoles, and has
advantages of no corrosion, no environmental pollution,
accelerated rate, high yield and simple work-
up procedure (Scheme 15).
Scheme 15. Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from
1,2-diacylhydrazines and silica-
supported dichlorophosphate.
HNR1
O
NH
R2
ON
O
N
R1 R2
O2Si O PCl2
O
neat, MW, 2 min76-95 %
R1, R2 = aryl, alkyl, heterocyclyl
57
58
Sharma and co-workers [33] developed a simple and general method
for the synthesis of 1,3,4-
oxadiazoles (59) from diacylhydrazines using inexpensive ZrCl4
as catalyst. Additional advantages
over the existing methods include higher yields, shorter
reaction times, and a simple experimental
procedure, which makes it a useful process for the synthesis of
1,3,4-oxadiazoles (Scheme 16).
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Molecules 2012, 17
11
Scheme 16. Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from
1,2-diacylhydrazines and
zirconium(IV) chloride.
HNAr
O
NH
Ar1
ON
O
N
Ar Ar1
59
10 mol% ZrCl4
CH2Cl2, rt
2-3 h, 71-88%
Yang and Shi [34] reported halogen effects in Robinson-Gabriel
type reaction of cyclopropane-
carboxylic acid N`-substituted-hydrazides with PPh3/CX4 (X = Cl,
Br, I) as dehydration agents
resulting in formation of 1,3,4-oxadiazole (60) (Scheme 17).
Scheme 17. Effects of halogen in formation of
1,3,4-oxadiazole.
R NH
OHN
O
2 PPh3, CCl4
MeCN, reflux
NN
OR
R = m,m-Me2C6H3, C6H5, p-BuOC6H4 benzyl, naphtlalen-2-yl,
tridecyl
80-97%
60
Pouliot and co-workers [35] reported the use of
diethylaminodifluorosulfinium tetrafluoroborate
([Et2NSF2]BF4), XtalFluor-E, as a new cyclodehydration agent for
the preparation of 1,3,4-oxadiazoles
(61) from 1,2-diacylhydrazines (Scheme 18).
Scheme 18. Preparation of 1,3,4-oxadiazoles from
1,2-diacylhydrazines using XtalFluor-E.
HNR1
O
NH
R2
O XtalFluor-E (1.5 equiv)AcOH (0 or 1.5 equiv)
DCE (0.1 M), 90 oC, 12 h
N
O
N
R2R1
61
Li and Dickson [36] developed a mild and convenient one-pot
protocol for the synthesis of 1,3,4-
oxadiazoles (62) from carboxylic acids and hydrazides using HATU
as coupling agent and Burgess
reagent as dehydrating agent, (Scheme 19).
Scheme 19. Synthesis of 1,3,4-oxadiazoles from carboxylic acids
and hydrazides using HATU and
Burgess reagent.
R OH
O
H2NNH
O1. HATU, DIEA
2. Burgess ReagentTHF, r.t., 1-3 hours
N
O
N
R+
62
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Molecules 2012, 17
12
MeO O2N
OMe CH3
CH3
NC
O
O
N
Cl
H3C
Cl
SBr
H2NCl
NH
SH3C
O O
R =
Another method to the one pot synthesis of
2,5-disubstituted-1,3,4-oxadiazole (63) from
benzohydrazide and carboxylic acid was reported by Rajapakse
[37] using the coupling agent 1,1'-
carbonyldiimidazole (CDI) and triphenylphosphyne as dehydrating
agent (Scheme 20).
Scheme 20. Synthesis of 2,5-dissubstituted-1,3,4-oxadiazole
using CDI and triphenylphosphyne.
Ph NH
O
NH2HO R
O
+CDI
Ph3, CBr4CH2Cl2
O
NN
Ph R
NBn Ph
NHBocPh
23-73%
R =
63
In 2006, Kangani and co-workers [38] described a one-pot direct
synthesis of 1,3,4-oxadiazoles (64)
in excellent yields from carboxylic acids (1 equiv) and
benzohydrazide (2.2 equiv) using Deoxo-Fluor
reagent (Scheme 21).
Scheme 21. Synthesis of 1,3,4-oxadiazoles using Deoxo-Fluor.
R OH
O
H2N
HN
O
iPr2NEt, 0 oC
Deoxo-Fluor
CH2Cl2, 2-3 h
NN
OR+
Carboxylic acid = palmitic acid, linoleic acid, elaidic acid,
benzoic acid, p-toluic acid, p-nitrobenzoic acid
79-94 %
64
A convenient, one pot procedure was reported for the synthesis
of a variety of 2,5-disubstituted-
1,3,4-oxadiazoles (65) by condensing monoarylhydrazides with
acid chlorides in HMPA solvent under
the microwave heating. The yields obtained were good to
excellent and the process was rapid and does
not needed any added acid catalyst or dehydrating reagent
(Scheme 22) [39].
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Molecules 2012, 17
13
Scheme 22. Synthesis of 2,5-disubstituted-1,3,4-oxadiazoles
using microwave heating.
R NH
O
NH2 +Cl R1
O 1) HMPA, 1h, rt
2) MW, 40 Sec
N
O
N
R1R
R = Ph, 4-NO2Ph, 4-MeOPh, 4-pyridyl
R1 = Ph, 2-furyl, CH2Ph, CH3, 2-propyl,
2-thienyl, 4-NO2Ph, 4-MeOP
45-95 %
65
In approach b (see Scheme 10), N-acylhydrazones usually suffer
oxidative cyclization under the
action of oxidizing agents such as Br2, HgO, KMnO4 and acetic
anhydride. Other oxidizing agents
milder have emerged in recent years such as, ammonium cerium
nitrate, Cu(OTf)2, chloramine-T,
trichloroisocyanuric acid or hypervalent iodines. For example,
the reaction of N-acylhydrazones (66)
treated with acetic anhydride under reflux conditions yielded
the compound (67) in good yield
(Scheme 23) [40].
Scheme 23. Synthesis of 1,3,4-oxadiazolines from
N-acylhydrazones using acetic anhydride.
O
NH
NN
S
(CH3CO)2O
reflux, 4h
NN
OR
67
R = NO2, Cl, Br, OH, OCH3, CH3
R
O
66
N
S
In 2006, Dabiri and co-workers [41] reported a new procedure for
the synthesis of disubstituted
oxadiazoles (68) through the one-pot reaction of benzohydrazide
and para substituted aromatic
aldehydes in the presence of ammonium cerium nitrate (CAN) and
dichloromethane as solvent
(Scheme 24).
Scheme 24. Synthesis of 2,5-diaryl-1,3,4-oxadiazole from
benzohydrazide and aromatic aldehydes.
NN
OR
NAC (1 mmol)
reflux, CH2Cl2 11 h
+
R
H
O
NHNH2
O
R = H, NO2, Cl, OCH3, CH3
68
A direct access to symmetrical and unsymmetrical
2,5-disubstituted-1,3,4-oxadiazoles (70) has been
accomplished through an imine C-H functionalization of
N-arylidenearoylhydrazide (69) using a
catalytic quantity of Cu(OTf)2 was related by GUIN and
co-workers [42] (Scheme 25).
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14
Scheme 25. Synthesis of 1,3,4-oxadiazole from
N-arylidenearoylhydrazide and Cu(OTf)2.
Ar N
HN
O
Cu(OTf)2 (10 mol %)
O2 (air), Cs2CO3, DMF
110 oC, 12-24 h
NN
OAr
Ar = Ph, 4-MeC6H4, 4-t-BuC6H4, 4-OMeC6H4, 3,4-diOMeC6H3,
4-BuOC6H4, 4-FC6H4,
3-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-AcOC6H4, 2-pyridyl, 2-furyl,
2-thienyl
54-93 %
69 70
Li and He [43] synthetized the compound
2-(anthracen-9-yl)-5-(p-tolyl)-1,3,4-oxadiazole (72) with
75,4 % yield from oxidative cyclization of N-acylhydrazone (71)
using chloramine-T, (Entry a,
Scheme 26). Gaonkar and co-workers [44] also reported the
synthesis of 1,3,4-disubstituted oxadiazole
(74) from the oxidative cyclization of N-acylhydrazones (73)
with chloramine-T under microwave
irradiation, (Entry b, Scheme 26).
Scheme 26. Oxidative cyclization of N-acylhydrazone using
chloramine-T.
NH
O
NChloramine-T
EtOH, ref, 4h
NN
O
75,4%71
72a)
N NO
NNH
R
O
Microwave20-50 min
Chloramine-T
80-100 oC
NN
O R
O
N
N
R = phenyl, 2-flurophenyl, 3-flurophenyl, 4-flurophenyl,
2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-furanyl,
2-thiophene, 3-pyridinyl, 4-pyridinyl, 2-hydroxyphenyl,
4-hydroxyphenyl, 4-bromophenyl, 6-hydroxynaphthalenyl,
2-methyl-1,3-thyazolyl, 4-methoxyphenyl, 2,4-dichlorophenyl,
2,4-diflurophenyl, 4-nitrophenyl
73 74
b)
Pore and co-workers [45] developed an efficient method for the
one-pot synthesis of unsymmetrical
2,5-disubstituted 1,3,4-oxadiazoles (75) using
trichloroisocyanuric acid (TCCA) at ambient
temperature. The main advantage of this method is the mild
nature of the synthesis and short reaction
time (Scheme 27).
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Molecules 2012, 17
15
Scheme 27. Synthesis of 1,3,4-oxadiazole using
trichloroisocyanuric acid (TCCA).
R NH
O
NH2 +R1
O
H
N N
N
Cl
O
Cl
O
Cl
O
TCCA
EtOH, rt15-20 min
NN
OR R1
R = Ph, 4-ClC6H4, 4-OCH3C6H4, 4-CH3C6H4R1 = Ph, 4-OCH3C6H4,
4-ClC6H4, 4-CH3C6H4
Yield (75-85%)
75
Pardeshi and co-workers [46] using a mixture of
N-chlorosuccinimide and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) oxidatively cyclizes
structurally diverse acylhydrazone (76),
thereby providing an efficient and convenient method for the
synthesis of various 2,5-disubstituted
1,3,4-oxadiazoles (77). The salient features of this method are
mild reaction conditions, short reaction
time, excellent yields, and simple workup procedure (Scheme
28).
Scheme 28. Oxidative cyclization of acyl hydrazone using
N-chlorosuccinimide and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU).
Ar NH
O
N
MDC30-60 min
NN
OAr Ar1
Ar = Ph, 4-NO2C6H4, 4-OCH3C6H4, 4-CH3C6H4, 3,5-(CF3)C6H3Ar1 =
Ph, 4-OCH3C6H4, 4-ClC6H4, 4-CH3C6H4, 4-pyridyl
Yield (55-85%)
Ar1N-chlrosuccinimide/DBU
7677
Dobrot and co-workers [47] reported the synthesis of
2,5-disubstituted-1,3,4-oxadiazoles (79)
conveniently prepared by oxidative cyclization of
N-acylhydrazone (78) promoted by an excess of
Dess-Martin periodinane under mild conditions (Scheme 29).
Scheme 29. Oxidative cyclization of N-acylhydrazone using
Dess-Martin periodinane.
R N
O
N
H
R1
H
NN
OR R1
O
I
O
OAcOAc
AcO
DMP
DMF or CH2Cl2rt, 17-92 %
R = Ph, 4-ClC6H4, 4-NO2C6H4, 2-furyl, 4-pyridyl,
3-chloro-benzo[b]thien-2-yl
R1 = Ph, 4-MeOC6H6, 4-BrC6H4, 2-furyl, 2-thienyl, 4-pyridyl,
3-thienyl, 3-NO2C6H4Pr, i-pr, 2-NO2C6H4, 3-MeO-4-BnOC6H3,
78 79
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16
Polshettiwar and Varma [48] reported a novel one-pot
solvent-free synthesis of 1,3,4-oxadiazoles
(82) by condensation of benzohydrazide (80) and
triethylorthoalkanates (81) under microwave
irradiations and catalyzed efficiently by solid supported
NafionNR50 and phosphorus pentasulfide in
alumina (P4S10/Al2O3) with excellent yields (Scheme 30).
Scheme 30. Nafion catalized 1,3,4-oxadiazole synthesis.
NH
O
NH2
R1
+
O O
R2 ONafionNR50
MW, 80 oC, 10 min
NN
O R2
R1
R1 = H, F, OMe; R2 = H, Et, Ph
80-90 %80
8281
Kudelko and Zieliski [49] developed an easy and efficient method
to synthesize 5-substituted-2-styryl-1,3,4-oxadiazoles (85) from
cinnamic acid hydrazide (83) and commercially available
triethyl
orthoesters (84). This method has the advantage of providing the
desired products rapidly and in high
yields which makes it a useful addition to the existing
synthetic procedures (Scheme 30).
Scheme 30. Reaction of cinnamic acid hydrazide with triethyl
orthoesters.
Ph NH
O
NH2 + R
O
OO
method A and B
AcOH
NN
O RPh
R = H, Me, Et, Ph83 84
85
Cui and co-workers [50] reported the synthesis of various
-keto-1,3,4-oxadiazole derivatives through a sequential
intermolecular dehydrochlorination/intramolecular aza-Wittig
reaction of
carboxylic acids and imidoyl chloride intermediates, which were
generated by isocyanide-Nef reaction
of acyl chlorides and (N-isocyanimine)triphenylphosphorane in
CH2Cl2 at room temperature (Scheme
31).
Scheme 31. Synthesis -keto-1,3,4-oxadiazole .
R1 Cl
OCN-N=PPh3
CH2Cl2, rt, 2 h R1
O N
Cl
N
PPh3R2COOH, Et3N
CH2Cl2, rt, 8 h
NN
O R2
O
R1
R1 = C6H5, 4-ClC6H4, 4-MeC6H4, C6H5CH2R2 = C6H5, 2NO2C6H4,
4-MeC6H4, 2-BrC6H4 CH3, 2-furyl, vinyl, isopropenyl
Isolated yield 36-69%
86
Ramazani and Rezaei [51] developed a novel and efficient method
for the synthesis of 2,5-
disubstituted-1,3,4-oxadiazole (88) from four components and
involving a one-pot procedure for the
condensation reaction between
(N-isocyanimino)triphenylphosphorane (87), a secondary amine, a
carboxylic acid and an aromatic aldehyde in CH2Cl2 to room
temperature, thus yielding, high yields
(Scheme 32).
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Molecules 2012, 17
17
Scheme 32. Synthesis of 1,3,4-oxadiazole dissubstituted from
four components in one-pot procedure.
H
O
Ph NH
R
+
OH
O
R1
+N N
(Ph)3P
CCH2Cl2
rt, 2h
NN
OR1
N
Ph
PhR
8788
R = CH3, CH2Ph, R1 = H, F, Br, Cl, I
Although less popular than the other methods mentioned above,
the Huisgen reaction (reaction of 5-
aryl/acyltetrazole with acid chloride or acid anhydride) is
widely used for the synthesis of various 2,5-
disubstituted-1,3,4-oxadiazoles. Some interesting examples are
reported below.
The reaction of tetrazole (89) with chloroacetyl chloride (90)
gave the disubstituted oxadiazole (91)
(Entry a, Scheme 33) [52]. The reflux of
4-methoxyphenyltetrazole (92) with 4-tert-Butylbenzoyl
chloride for 2 hours afforded
2-(4-tert-Butylphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (93) in
96
% yield (Entry b, Scheme 33) [53]. Similarly, the compounds (95,
Entry c) [54] and (98, Entry d) [55]
were obtained in excellent yield treating the intermediate (94)
and (97) with acid chlorides (Scheme
33). In general the tetrazole intermediate can be obtained by
reaction of arylnitrile with ammonium
chloride and sodium azide.
Huisgein reaction also proceeds well with acid anhydride in
place of acid chlorides, as demonstrated
by Efimova and co-workers [56], that synthesized
1,3,4-oxadiazole compounds (100) and (101) by
acylation of a series of 5-aryl(hetaryl)tetrazoles (99) with
acetic and benzoic anhydrides under
microwave irradiation (Entry e, Scheme 33) (see also Reichart
and Kappe [57]).
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Molecules 2012, 17
18
Scheme 33. Synthesis of 1,3,4-oxadiazole from of Huisgein
reaction.
HN
N
N
N
R
+Cl
O
Clo-xileno
30-40 oC
N
O
NCl
R89 90 91
R = H, Cl, NO2, OEt,
MeO
N N
NHN Cl
O
pyridine, 2 h 96 %
NN
OMeO
92 93
a)
CN
F
X NH4Cl, NaN3
DMF, 105 oC
66-78 % F
XN
N
NHNNN
OF
XY
YY
Y
Cl
O
Y
Y
Y = H, Me, i-Pr, t-Bu
X = H, Me
Py, reflux, overnight47-85 % 98
N
N N
NHNCl
O
pyridine, reflux, 2 h, 90 %
NN
ON
9594
96 97
b)
c)
d)
N N
N
HNR
N
O
N
R
N
O
N
BzR
Ac2O
Bz2O
R = 4-MeOC6H4, Ph, 4-BrC6H4, 4-O2NC4H4, pyridin-2-yl,
pyridin-3-yl
99
10073-87 %
10173-96 %
e)
3. Pharmacological Activity of 1,3,4-Oxadiazole
3.1. Antimicrobial activity
During the last decades the rapid emergence of drug resistance
in the treatment of infectious
diseases in the world emphasizes the need for new antimicrobial
agents which are safer and more
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Molecules 2012, 17
19
efficient. Many researchers have reported in recent years that
the core compounds containing 1,3,4-
oxadiazole have excellent antimicrobial activity.
In this sense, de Oliveira and co-workers [58] recently reported
the synthesis and antistaphylococcal
activity of 1,3,4-oxadiazolines (102) against some strains of
Staphylococcus aureus resistant to
methicillin and amino glycosides (MARSA) and strains that encode
efflux proteins (multidrug
resistance drugs - MDR). Compounds (102) showed efficient
anti-staphylococcal activity with 4g/mL to 32g/mL, being that all
the compounds were 2-8 times more active than the standard drug
chloramphenicol (Figure 5).
A series of new derivatives of 5-(1-/2-
naphthyloxymethyl)-1,3,4-oxadiazol-2(3H)-thione (R=SH),
5-(1-/2-naphthyloxymethyl)-1,3,4- oxadiazole-2-amino (R=NH2) and
5-(1-/2-naphthyloxymethyl)-
1,3,4-oxadiazol-2(3H)-ones (R=OH) (103) [59] were synthesized
and their antimicrobial activity were
evaluated, all compounds were active against S. aureus, E. coli,
P. aeruginosa, C. albicans and C.
parapsilosis at a minimum concentration of 64-256 mg/mL (Figure
5).
Patel and Patel [6] verified the antibacterial activity of a
series of derivatives containing the 1,3,4-
oxadiazole nucleus against two Gram-positive bacteria (S. aureus
MTCC 96 and S. pyogenes MTCC
442) and two Gram-negative bacteria (E. coli MTCC 443 and P.
aeruginosa MTCC 1688) using as
drug standard Ampicillin. Studies with Gram-positive bacteria
Staphylococcus aureus shown that the
compounds 4-[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]benzenamine
(104) and 3-{[5-(2-
chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2-{2-[2,6-dichlorophenyl)amino]benzyl}-6
iodoquinazolin-4(3H)-one (105) were 2 and 5 fold more potent
than ampicillin, respectively (Figure 5).
The compounds 2,5-disubstituted oxadiazoles (106) (Figure 5)
containing the acetyl group in
position 3 of the ring oxadiazole were synthesized and evaluated
against two strains of bacteria S.
aureus and P. aeruginosa and against two species of fungi C.
albicans and A. flavus by disk diffusion
method. Ampicillin and Fluconazole were used as standard drug
for the antibacterial and antifungal
activity, respectively. All compounds showed activity equipotent
to ampicillin and fluconazole [60].
The antibacterial and antifungal activity of
2-(5-amino-1,3,4-oxadiazol-2-yl)-4-bromophenol (107)
and 5-(3,5-dibromophenyl)-1,3,4-oxadiazol-2-amino (108) was
investigated against two strains of
Gram-positive bacteria Streptococcus aureus, Bacillus subtilis
and two strains of Gram-negative
bacterial Klebsiella pneumoniae and Escherichia coli and two
fungal species Aspergillus Niger and C.
Pannical which exhibited activity approximately equal to the
standards drugs Streptomycin and
Griseofulvin, respectively, [61] (Figure 5).
Sangshetti and co-workers [62] investigated the antifungal
activity of a number of disubstituted
oxadiazoles (109) (Figure 5) containing the unit triazole at
position 5 of the oxadiazole anel against
different species of fungi such as Candida albicans, Fusarium
oxysporum, Aspergillus flavus,
Aspergillus Nger e Cryptococcus neoformans. Miconazole e
Fluconazole were used as standard for
the comparison of antifungal activity. It was observed that the
compounds containing the group methyl
sulfone (R = SO2CH3) attached to the nitrogen of the piperidine
ring and the groups Cl or OH (R1)
exhibited better pharmacological profile, being equipotent to
miconazole drug against some fungi
species.
The compounds (110) e (111) were 2 and 4 fold more potent than
the Furacin drug in the evaluation
of antibacterial activity against E. coli, P. aeruginosa,
respectively. While the compounds (112) and
(113) were 2 fold more potent than the drug fluconazole in
testing antifungal activity against C.
albicans [63] (Figure 5). Other compounds with antibacterial
activity are: 114 [64], 115 [65], 116
[66], 117 [13], 118 [67], 119 [24], 120 [68], 121 [69] e 122
[70] (Figure 5).
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Molecules 2012, 17
20
Figure 5. Disubstituted-1,3,4-oxadiazole with antibacterial and
antifungal activity.
NN
O NH2
OH NN
O NH2
Br
Br Br107 108
NN
O
110
F
MeO
BrNN
O
F
MeO
FF
F111
NN
O
112
F
MeO
Br
Cl
O
N N
ON
MeO
F
113
102
103
OO
NN
R
R = SH, NH2, OH
N
O
N
O
O
NO2
R
R = H, Me, NO2, Cl, OMe
NN
OH2N
Cl
104 N
N
O
HN
Cl
Cl
I O
NN
Cl
NN
O
O
106R
R = N(CH3)2, Cl, H, OH
NN
O
NN
N
N
R
R1
109
R = H, Me, et, Boc, 4-Cl-
C6H4CO
COCH3, C6H6CO. SO2CH3R1 = H, Cl, OH, OCH3, NO2,
Me
OMe
O
O
NN
O
R1
R
114
N
COOH
R1
O
F
R2N
NO
N NAr
R
115
NN
O O
NN
ArAr116
ON
NNS
Ac
O
NN
O
R
117
N
O
N
SR
R1
118
N
O
N
SS
N
N O
R
119
N
O
N
S
HN
O
120O
O
S
N
R
N
O
N
S
121O
N
NN
O
N
ON
N
R
N
N
O
O
NN
N
O
F
122
105
2-(2-naphthyloxymethyl)-5-phenoxymethyl-1,3,4-oxadiazole
compounds (123) in minimum
inhibitory concentration of 6,25 g/ml [71] (Figure 6). The
antimycobacterial activity was also studied
by Kumar and co-workers [40] for a series of disubstituted
oxadiazoles (124) containing the unit
thiazole against Mycobacterium tuberculosis H37RV, in that the
derivative containing the group Cl
exhibited excellent inhibition at a minimum inhibitory
concentration of 4 g/mL, (Figure 6).
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Molecules 2012, 17
21
Yoshida and co-workers [72] described the synthesis and
optimization of the anti-Helicobacter
pylori activity of a novel series of cephem derivatives.
Compound 125 exhibited Helicobacter pylori
(13001 and FP1757) activity at a minimum inhibitory
concentration of 0.1 g/mL. BAKAL and GATTANI [73] investigated the
anti-tubercular activity of a series of 2,5-disubstituted
oxadiazole
against M. tuberculosis H337Rv. Compound 126 with MIC50 = 0.04
0.01M was comparable with Isoniazid drug. Compound 127 was 7.3-fold
against Mycobacterium tuberculosis H37Rv and 10.3-fold
against INH resistant Mycobacterium tuberculosis more active
than isoniazid (Figure 6) [74].
Figure 6. 1,3,4-oxadiazole with antimycobacterial activity
SHN
N O
O
NH
NO
N N
O
S SO O
O O
127
O
N
O
N
O
123
NN
OR
124
N
S
R = H, Cl, NO2, Me, OH, OMe
N
S
COOHO
HN
S
O
125
O
NN
NN
O SCl
Cl
Cl
126
3.2. Anticonvulsant activity
A few novel
3-[5-(4-substituted)-phenyl-1,3,4-oxadiazole-2-yl]-2-styrylquinazoline-4(3H)-ones
oxadiazole (128) were synthesized and their anticonvulsant
activity were evaluated by Kashaw and co-
workers [75], (Figure 7). New derivatives of
2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazole
(129) were designed and synthesized as new anticonvulsant
agents. In this study, the authors found that
the introduction of an amino group at the 2-position of the
1,3,4-oxadiazole ring, and a fluorine
substituent at the para position of the benzylthio group
improves the anticonvulsant activity [76],
(Figure 7).
Rajak and co-workers [77] synthesized some semicarbazones
containing the unit 1,3,4-oxadiazole
and the anticonvulsant potential of these new compounds (130)
was evaluation in three model of test
(MES), (scPTZ) and (scSTY), being most compounds showed activity
in all three models, (Figure 7).
Other compounds with anticonvulsant activity are: 131 [78], 132
[79], 133 [80], 134 [76], 135 [81],
136 [82], 137 [83], (Figure 7)
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Molecules 2012, 17
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Figure 7. 1,3,4-oxadiazoles with anticonvulsant activity.
N
N
O
O
NN
R
R1128 129
S
ON
N
R
R1
N
O
N
NH
NH
ON
R
O
R1
130
O
NN
NN
S
O
Br
131
O
NN
NH2
O
F
137
N
O
O
NH
NN
O
NH
NH
S
132
RN
O
N
NH
NH
ON
R133
N
O
N
NH2
S
R
134O
Cl
ON
N
O
O
X
135
X = 19F, 18F
N
N
SEt
O
NN
S
NH
R
136
3.3. Anti-inflammatory activity
The anti-inflammatory activity of a series of oxadiazoles
derivatives of the Ibuprofen drug
containing the unit arylpiperazine at 3-position of the
oxadiazole anel (138) was investigated by
Manjunatha and co-workers [20] using the method of paw edema
induced by carrageenin and having
sodium diclofenac as a reference drug. Compounds containing the
groups 4-Cl, 4-NO2, 4-F and 3-Cl
were more active than the sodium diclofenac, whereas the
compounds with the groups 4-MeO and 2-
EtO showed low activity (Figure 8).
The compounds (139) were synthesized from the anti-inflammatory
drug fenbufen and evaluated
for their anti-inflammatory activities by the method of induced
paw edema and sodium diclofenac and
fenbufen were standard drug. The compounds containing the groups
4-Cl, 4-NO2, 4-F e 4-MeO were
equipotent to fenbufen and the compound with the group
3,4-di-MeO was more potent than the
Fenbufen and equipotent to sodium diclofenac [84], (Figure
8).
The compounds 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazole
(140) displayed strong dose
dependent inhibition of carrageenan-induced edema producing more
than 50% inhibition at a
concentration of 60 mg/kg. The compound with the group
3,4-di-MeO was more potent than the
standard drug indomethacina [85], (Figure 8). Burbuliene and
co-workers [86] also investigated the
anti-inflammatory activity of
5-[(2-disubstituteddiamino-6-methyl-pyrimidin-4-yl)
sulphanylmethyl]-
3H-1,3,4-oxadiazol-2-thione derivatives (141), was found that
some derivatives were more potent than
ibuprofen, (Figure 8). Other compounds with anti-inflammatory
activity: 142 [87], 143 [88], 144 [89],
145 [90], 146 [91], 147 [92], 148 [93] and 149 [94], (Figure
8).
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Molecules 2012, 17
23
Figure 8. 1,3,4-oxadiazole with anti-inflammatory activity.
N N
OR
R = 4-Cl, 3,4-di-MeO
140
NN
O SS
H
NN
R''R'N 141
NN
O S
N NR
138
R = 4-Cl, 4-NO2, 4-F,
4-MeO, 2-EtO, 3-Cl
N
O
N
139O
R
R = H, 4-Cl, 4-NO2, 4-F, 4-OCH3, 3,4-di-MeO
N
N
O
NS
O
SNN
O
N
Br
Cl
142
OH
ON
N
FFN
HCH3143
O
O
NNH3C
OCH3
144 MeO
MeO
MeOON
O O
NN
Cl
Cl
145
NN
O
O
146
N
N
Cl
Cl
NO
SO
NN
N
147
N
OO
O2N
NN
OSO
R148
N
NN
S O
O
F
O
NN
Br
149
3.4. Analgesic activity
The compound
5-(2-(2,6-dichlorophenylamino)benzyl)-N-(4-fluorophenyl)-2-amino-1,3,4-
oxadiazole (150) in evaluation of its analgesic activity was
more potent than the sodium diclofenac
drug with an analgesic activity maximal of (81,86%) [27],
(Figure 9). The compound (151) contained
the 2,4-dichlorophenyl group, present at the second position on
oxadiazole ring, showed the maximum
activity (70.37 1.67%), equivalent to that of the standard drug
ibuprofen (73.52 1.00%) [95],
(Figure 9). Compounds 138, 139, 144, 146, 147, 148 of the Figure
8, also display analgesic activity.
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Molecules 2012, 17
24
Compound (139) with the group R = 4-F showed a maximal analgesic
activity (72.52%) and its
activity has been better than the drugs sodium diclofenac (70.32
%) and fenbufen (54.1%) [84].
Figure 9. 1,3,4-oxadiazole with analgesic activity.
NN
ON
ClCl
N
O
N
NH
150
HN
Cl
Cl
F
151
3.5. Antitumor activity
Savariz and co-workers [96] synthesized and evaluated the
antitumor activity in vitro of new
Mannich bases, among the compounds studied the compound (152)
showed a potent activity against
melanoma cell lines (UACC-62) and lung (NCI-460) with GI50 value
of 0.88 and 1.01 mmol/L,
respectively, (Figure 10). LIU and co-workers [97] synthesized
and reported the anti-proliferative and
EGFR inhibition of a series of 2-(benzylthio)-5-aryloxadiazole
derivatives, compound (153) shows the
most potent biological activity (IC50 = 1.09 M for MCF-7 and
IC50 = 1.51 M for EGFR) (Figure 10). Ouyang and co-workers [98] and
Tuma and co-workers [99] synthesized various 1,3,4-oxadiazoles
derivatives and were evaluated as to their ability to inhibit
tubulin polymerization and block the mitotic
division of tumor cells. The compounds (154) and (155) exhibited
potent activity. In the studies in
vitro, compound (154) in nanomolar concentrations causes the
mitotic division interrupt in breast
carcinoma and squamous cell tumors, including multi-drug
resistant cells. In the studies in vivo,
compound (155) had a desirable pharmacokinetic profile with
appropriate plasma levels after oral
administration and had a significantly higher efficiency than
paclitaxel taxane (Figure 10).
The antiproliferative effects of 24 new compounds
2,5-diaryl-2,3-dihydro-1,3,4-oxadiazolines (157)
(Type I) and (158) (Type II) analogous to combretastatin-A4
(156) were evaluated in murine L1210
leukemia cells (Figure 10). Furthermore, the compounds were also
evaluated in murine B16 melanoma
cells. Combretastatin-A4 is the most potent natural
combretastatines, and early studies showed that it
inhibits the polymerization of tubulin and proliferation of
murine and human cancer cells. The
compound of type I with the groups R1=R2=R4=R5=H e R3=Br was the
more potente with IC50 of 0.6
0.7 M, while the compound of type II with groups R1=R5=H e
R2=R3=R4=OCH3 was the more potent with IC50 of 0.5 0.06 M. However,
these compounds were substantially less potent than the compound
(156) which has IC50 entre 0.003 M for L1210 cells [100]. Other
compounds with antitumor activity: 159 [101], 160 [102] and 161
[103].
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Molecules 2012, 17
25
Figure 10. 1,3,4-oxadiazole with antitumor activity.
N NO
NNNH
H
S
N
152
O
NN
S
NH2
153
N
O
N
NH
NNH
O
O
N
N
O
N
NH
NH
O
O
N
154
155
MeO
MeO OMe
OH
OMe
156
N
O
NMeO
MeO
MeO
157
O
R1R2
R3
R4R5
N
O
N
MeO
O
R1R2
R3
R4R5
158
O
O
O
NNS
159, IC50 = 1.27 0.05 MTelomerase Activity.
N
O
NCN
N
NSPh
H
O
160
hepatocellular carcinoma HepG2
IC50 = 12.4 g/mlF
F
F
NN
O
NN
S
F F
161, cytotoxic agent
IC50 = 15.54 M in MCF-7 cells
3.6. Antiviral activity
On October 16, 2007, the US Food and Drug Administration (FDA)
approved raltegravir (162,
Figure 11) for treatment of human immunodeficiency virus (HIV)-1
infection in combination with
other antiretroviral agents in treatment-experienced adult
patients who have evidence of viral
replication and HIV-1 strains resistant to multiple
antiretroviral agents. Raltegravir is first in a novel
class of antiretroviral drugs known as integrase inhibitors
[104].
It seeking to identify most promising compounds that
raltegravir, Wang and co-workers [105]
design the synthesis of a series of raltegravir derivatives by
modifying the group 5-hydroxyl of
pyrimidine ring and evaluated for their anti-HIV activity. The
5-hydroxyl modification of raltegravir
derivatives significantly increased the anti-HIV activity, which
indicates that the hydroxyl may not be
indispensable for raltegravir. Compound 163 with subpicomole
IC50 value seemed to be the most
potent anti-HIV agents among all of the reported synthesized
compounds, so and thus emerged as new
potent anti-HIV agent (Figure 11).
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Molecules 2012, 17
26
Figure 11. Structures of raltegravir (162) and similar.
NN
OO
HN
N
N
O
OH
O
HN
F
162
NN
OO
HN
N
N
O
O
O
HN
F
163
Bz
The inhibitory activity of the compounds (164) and (165) (Figure
12) against the human
immunodeficiency virus type 1 (HIV-1) was determined using the
XTT assay on MT-4 cells. The
Compound (165) was the most active among the compounds tested,
producing 100%, 43% and 37%
reduction of viral replication at concentrations of 50, 10 and
2g/mL, respectively. On the other hand,
the compounds (164) with the groups R=4-F and 2-Br exhibited
mild producing antiviral activity more
than 10% inhibition of viral replication at concentrations of
2g/mL. All tested compounds were not
cytotoxic with CD50 > 100g/mL except the compound (165) whose
CD50 was 68g/mL [106].
Iqbal and co-workers [107] also reported the inhibitory activity
of compounds (166) and (167)
(Figure 12) against the human immunodeficiency virus type 1
(HIV-1) was determined using the XTT
assay on MT-4 cells. The compound (166) with the group R=Cl was
the most active among the
compounds tested with 62%, 21% and 14% reduction to a
concentration of 50, 25 and 5g/mL, respectively.
Figure 12. 1,3,4-oxadiazoles with inhibitory activity against
human immunodeficiency virus type 1
(HIV-1).
O
NN
S
H
R = H, 2-F, 4-F, 4-Cl, 2,Cl, 2-Br, 4-Br, 3-NO2,
4-NO2, 4-OCH3, 2-CN, 2-CF3, 2,5-F2
O
NN
S
NHR
164165
O
NN
SHR
SO
O
HN
O
NN
SHR
SO
O
H2N166 167
R = H, OCH3, Cl
Indinavir protease inhibitor is used as a component of
antiretroviral therapy for treating HIV
infection and AIDS. In this regard, Kim and co-workers [108]
have synthesized and evaluated the
protease inhibitory activity of a series of oxadiazoles (168)
analogous to indinavir, all compounds
prepared inhibited the enzyme with activity picomolar (IC50)
being more potent than the indinavir
(Figure 13).
Johns and co-workers [109] reported the antiviral activity by
inhibition of integration of viral DNA
of new containing derivatives containing the unit
1,3,4-oxadiazole in combination with a ring system
of 8-hydroxy-1,6-naphthyridine (169). Compound 170, containing a
5-methyl-1,3,4-oxadiazol-2-yl
group at the C2 Position of the quinoline ring, shows inhibitory
activity against the hepatitis C virus
NS3 protease [110], (Figure 13).
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Molecules 2012, 17
27
Figure 13. 1,3,4-oxadiazole with inhibitory activity against HIV
and hepatitis C virus.
O
O
N
H
NO
O
OH
HN
O
O
N
MeO
O
NN
170
IC50 = 12 nM
EC50 = 200 nM
N
N
R1 OH HN
O
N
NO
R2
O
O NH
CF3
OH
168
N
N
OH
O
NN
FR
169
3.7. Antihypertensive activity
Hypertension and other cardiovascular diseases are major causes
of morbidity and mortality
worldwide. Bankar and co-workers [111] reported the vasorelaxant
effect of the compound 4-(3-
acetyl-5-(pyridin-3-yl)-2,3-dihydro-1,3,4-oxadiazol-2-yl)phenyl
acetate (171, Figure 14) in rat aortic
rings by blocking the calcium channels L-type. Bankar and
co-workers [112] also investigated if the
correction of endothelial dysfunction is dependent on the
normalization of high blood pressure in
deoxycorticosterone acetate (DOCA- salt) and NG-nitro-L-arginine
(L-NNA) in hypertensive rats.
Compound (172) is a T type Ca2+
channel inhibitor with IC50 of 810 nM [113] (Figure 13).
Figure 14. Vasorelaxant activity of 1,3,4-oxadiazoles.
NN
O
O
NO
O
171
N N
O HN
OO
Cl
Cl 172
3.8. Enzyme inhibitors
Leukotrienes (LTs) are potent inflammatory lipid mediators
derived from arachidonic acid
metabolism and released from cells involved in inflammation. The
synthesis of all the LTs requires the
action of the enzyme 5-lipoxygenase (5-LO). Inhibition of 5-LO
reduces the production of both LTB4
and cysteinyl LTs (CysLTs) LTC4, LTD4 and LTE4. Therefore, the
5-LO inhibitors have therapeutic
potential for the treatment of inflammatory processes. Thus, a
new derivative oxadiazole p-
toluenesulfonate (173, Figure 15) containing an asymmetric
carbon was identified as a potent and
selective inhibitor of 5-lipoxygenase (5-LO) by Ducharme and
co-workers [114] and Gosselin and co-
workers [115].
Leung and co-workers [116] reported the discovery of a new class
of disubstituted oxadiazole (174,
Figure 15) of oleic acid derivatives with potent and selective
inhibition of fatty acid amide hydrolase.
Khan and co-workers [117] performed studies on the effects of
inhibition of the enzyme tyrosinase
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Molecules 2012, 17
28
with 19 compounds 2,5-disubstituted-1,3,4-oxadiazole, the
compound 3-(5-(4-bromophenyl)-1,3,4-
oxadiazol-2-yl) pyridine (175) with IC50 = 2,18M was more potent
than the standard L-Mimosine
(IC50 = 3,68 M) (Figure 15).
Tomi and co-workers [118] reported a study with the compound
bis-1,3,4-oxadiazole (176)
containing a glycine unit on the transferase activity of some
enzymes such as: GOT, GPT and -GT in serum. Compound (176) showed
activation in the activity of GOT and GPT and inhibitory effects
on
the activity of -GT, (Figure 15).
Figure 15. 1,3,4-oxadiazole with inhibitory activity of
enzymes.
O
N N
OR
174
NN
OS
N N
O
NH
O
OMe
MeO
176
NN
OHO CF3
NH H
O O
F
SO3
173MK-0633 p-toluenosulfonato
NN
O
NBr
175
Maccioni and co-workers [119] synthesized a set of
3-acetyl-2,5-diaryl-2,3-dihydro-1,3,4-
oxadiazoles and tested as inhibitors against human monoamine
oxidase (MAO) A and B isoforms.
None of the tested compounds show a significant inhibitory
ability toward the MAO-A. On the other
hand, several compounds were identified as selective MAO-B
inhibitors. Some of the tested
compounds exhibit interesting biological properties with IC50
toward the B isoform of the enzyme
ranging from micromolar to nanomolar values and that the
compounds (177) were more active at
inhibiting MAO-B at nanomolar concentration (Figure 16).
The study of optimization of the central heterocycle of
-ketoheterocycle inhibitors of fatty acid amide hydrolase realized
by GARFUNKLE and co-workers [120], led to identification of the
most
potent inhibitors (178). The 5-aminopyrimidinone
R-keto-1,3,4-oxadiazole (ONO-6818) is
representative of orally active nonpeptidic reversible
inhibitors of Human Neutrophil Elastase (HNE)
with potent Ki values in the nanomolar range (Figure 16)
[121,122]. Selective human Granzyme B
inhibitors that inhibit CTL mediated apoptosis (179) [123].
Compounds (180) (EC50 = 3.7 nM),
featuring an oxadiazole demonstrated balanced potency and PK
profiles. In addition, this molecule
exhibited potent oral in vivo efficacy in potentiating the
cytotoxic agent temozolomide in a B16F10
murine melanoma model [124], (Figure 16).
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Molecules 2012, 17
29
Figure 16. 1,3,4-oxadiazole with inhibitory activity of
enzymes.
NN
O
O
ClR177
R = NO2; IC50 = 121.62 9.63 nM
R = Cl; IC50 = 115.31 8.39 nM
R = Br; IC50 = 220.61 12.61nM
NN
O
ON
178, Ki = 0.003 M
N
NH
O
COOH
O
NH
OHN
O
O
ON
N
Ph
Ki = 7 nM
179
NH
N
O NH2
O
NN
180
Inhibitor of Polymerase-1 (PARP-1)
Ki = 1.0 nM
EC50 = 3.7 nM
N
N
H2N
O
O
N
HO
O
NN
ONO 6818
Ki = 12.16 nM
ED50 = 1.4 mg/Kg
Various other 1,3,4-oxadiazole derivatives show inhibitory
activity of enzymes such as: 181 [125],
182 [126], 183 [127], 184 [128], 185 [129], 186 [130], 187
[131], 188 [132], 189 [133], 190 [132,134],
191 [135] and 192 [136], (Figure 17).
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Molecules 2012, 17
30
Figure 17. Other 1,3,4-oxadiazole derivatives with inhibitory
activity of enzymes.
S
N
Me
O
OH
N
NN
NO
PalmCoA
181, IC50 = 1.10 MN
N
HN
O
NH
O
N
O
O
ONH
O
ON
N
Ph
182, Ki = 35 M
Inhibitor of hepatitis C
virus NS3-4A proteaseNN
O
N
N
EtNH
N
O
O
183, IC50 = 10 M
Inhibitor of AP-1 and NF-kB N
OHN
N N
O
O
184, IC50 = 74 MInhibitor of Signal Transducer and
Activators of Transcription (STAT3)
R
O
S
NN
O
185Inhibitors of Human Reticulocyte 15-Lipoxygenase-1
NH
O
NH O
NN
C13H27
186Inhibitor of the enzyme Acyl-CoA: Cholesterol
O-Acyltransferase (ACAT) S
NH
O O
N
O
H
O
HN
O
NH
O
O
O
NN
187Inhibitor of proteasome
Ph
ON
O
NH
N
S
188
5-lipoxygenase inhibitor
FLAP binding IC50 = 1.1 nM
N N
OHN
O
MeOCO2H
189, IC50 = 74 MInhibitor of Protein Kinase CK2
ON
CF3
NN
O
NN
N
190, IC50 = 0.03 nM
Stearoyl-CoA desaturase 1 inhibitor
O
NN
N
HO
N
H
HOOC
F
F
191, IC50 = 0.0006MInhibitor for the treatment
of obesity and diabetes
N
O
N
S
O
R S
HN
OO
192hypoglycemic and hypolipidemic activities
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Molecules 2012, 17
31
4. Conclusion
In this review, we emphasize only the main methods of synthesis
of 1,3,4-oxadiazole used by the
scientific community. Although the main synthetic routes, as
emphasized in section 2, is still
continuing: (1) the cyclodehydration of diacylhydrazines, (2)
the reaction oxidaton of acylhydrazones
and (3) reactions of hydrazides with carbon disulfide, these
conventional approaches are still
extensively used in recent years by many research groups using
only new reaction conditions as: new
cyclization reagents, catalysts, polymeric support and microwave
radiation. The broad
pharmacological profile of this class of compounds is evidenced
by the numerous examples cited here.
In each topic on biological activity, we provide only examples
of molecules with activity really
relevant, so that these molecules may serve as prototypes for
readers in the development of more active
derivatives. In short, the various synthetic methods exemplified
can serve for readers as support for the
planning of new molecules containing 1,3,4-oxadiazole unit.
Acknowledgments
This work was supported by the following Brazilian agencies:
CNPq and CAPES.
Conflict of Interest
The authors declare no conflict of interest.
References and Notes
1. Nagaraj.; Chaluvaraju, K.C.; Niranjan M.S.; Kiran, S.
1,3,4-oxadiazole: a potent drug candidate
with various pharmacological activities. Int. J. Pharm. Pharm.
Sci. 2011, 3, 9-16.
2. ostr m, . Hogner, A.; Llin s, A.; Wellner, E.; Plowright,
A.T. Oxadiazoles in medicinal chemistry, J. Med. Chem 2012, 55,
1817-1830.
3. Savarino, A. "A historical sketch of the discovery and
development of HIV-1 integrase inhibitors".
Expert Opinion on Investigational Drugs 2006, 15(12),
1507-1522.
4. James, N. D.; Growcott, J. W. Zibotentan. Drugs Future 2009,
34, 624-633.
5. Scifinder Scholar accessed in 07/06/2012. Search criteria:
Research topic: 1,3,4-oxadiazole.
Publication years: 2000-2012. Document type: Journal, patent and
review. Language: English.
6. Patel, N.B.; Patel, J.C. Synthesis and antimicrobial activity
of 3-(1,3,4-oxadiazol-2-il)quinazolin-
4(3H)-ones. Sci pharm 2010, 78, 171-193.
7. Kerimov, I.; Ayhan-Klcgil, G.; zdamar, E.D.; Can-Eke, B.;
oban, T.; zbey, S.; Kazak, C. Design and one-pot and
microwave-assisted synthesis of 2-Amino/5-aryl-1,3,4-oxadiazoles
bearing
a benzimidazole moiety as antioxidants. Arch. Pharm. Chem. Life
Sci. 2012, 000, 1-8.
8. Katritzky, A.R.; Vvedensky, V.; Cai, X.; Rogovoy, B.; Steel,
P.J. Synthesis of 5-(2-arylazenyl)-
1,2,4-triazoles and 2-amino-5-aryl-1,3,4-oxadiazoles, Arkivoc
2002, (vi), 82-90.
9. Rajak, H.; Agarawal, A.; Parmar, P.; Thakur, B.S.; Veerasamy,
R.; Sharma, P.C.; Kharya, M.D. 2,5-
Disubstituted-1,3,4-oxadiazoles/thiadiazole as surface
recognition moiety: Design and synthesis of
novel hydroxamic acid based histone deacetylase inhibitors,
Bioorganic & Medicinal Chemistry
Letters 2011, 21, 57355738. 10. Gupta, V.; Kashaw, S.K.; Jatav,
V.; Mishra. P. Synthesis and antimicrobial activity of some new
3[5-(4-substituted)
phenyl-1,3,4-oxadiazole-2yl]-2-styrylquinazoline-4(3H)-ones. Med
Chem Res 2008, 17, 205-211.
-
Molecules 2012, 17
32
11. Sharma, L. K.; Kumar, S.; Singh, S.; Singh, R.K.P.
Electrochemical synthesis of 5-substituted-2-
amino-1,3,4-oxadiazoles at the llatinum electrode, Russian
Journal of Electrochemistry. 2010, 46,
No. 1, 34-40.
12. Lotfi, B.; Mustafa, B.; Leila, L.; Salima, M.
Electrocyclization of Semicarbazone; A novel route of
green synthesis of 2,5-disubstituted-1,3,4-oxadiazoles, Int. J.
Electrochem. Sci 2011, 6, 1991-
2000.
13. El-Sayed, W.A.; Ali, O.M.; Hendy, H.A.; Abdel-Rahman, A.
A-H. Synthesis and antimicrobial
activity of new 2,5-disubstituted 1,3,4-oxadiazoles and
1,2,4-triazoles and their sugar derivatives.
Chin. J. Chem. 2012, 30, 77-83.
14. Rivera, N.R.; Balsells, J. Hansen, K.B. Synthesis of
2-amino-5-substituted-1,3,4-oxadiazoles using
1,3-dibromo-5,5-dimethylhydantoin as oxidant. Tetrahedron
Letters 2006, 47, 4889-4891.
15. Dolman, S.J.; Gosselin, F.; O`shea, P.D.; Davies, I.W.
Superior reactivity of thiosemicarbazide in
the synthesis of 2-amino-1,3,4-oxadizaoles, J. Org. Chem 2006,
71, 9548-9551.
16. Koparr, M.; etin, A.; Cansz, A.
5-Furan-2yl[1,3,4]oxadiazole-2-thiol, 5-furan-2yl-4H [1,2,4]
triazole-3-thiol and their thiol-thione tautomerism. Molecules
2005, 10(2), 475-480.
17. Amir, M.; Shikha, K. Synthesis and anti-inflammatory,
analgesic, ulcerogenic and lipid
peroxidation activities of some new
2-[(2,6-dichloroanilino)phenyl]acetic acid derivatives.
European Journal Medicinal Chemistry 2004, 39, 535-545.
18. Vosooghi, M.; Akbarzadeh, T.; Fallah, A.; Fazeli, M. R.;
Jamalifar, H.; Shafiee, A. Synthesis of
substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and
1,2,4-triazole derivatives as potential
antimicrobial agents. Journal of Sciencies, Islamic Republic of
Iran 2005, 16(92), 145-151.
19. Almasirad, A.; Vousooghi, N.; Tabatabai, S.A.;
Kebriaeezadeh, A.; Shafiee, A. Synthesis,
anticonvulsant and muscle relaxant activities of substituted
1,3,4-oxadiazole, 1,3,4-thiadiazole and
1,2,4-triazole. Acta Chim. Slov 2007, 54, 317-324.
20. Manjunatha, K.; Poojary, B.; Lobo, P.L.; Fernandes, J.;
Kumari, N.S. Synthesis and biological
evaluation of some 1,3,4-oxadiazole derivatives. European
Journal of Medicinal Chemistry 2010,
45(11), 5225-5233.
21. Saitoh, M.; Kunitomo, J.; Kimura, E.; Hayase, Y.; Kobayashi,
H.; Uchiyama, N.; Kawamoto, T.;
Tanaka, T.; Mol, C.D.; Dougan, D.R.; Textor, G.S. Design,
synthesis and structure-activity
relationships of 1,3,4-oxadiazole derivatives as novel
inhibitors of glycogen synthase kinase-3, Bioorganic &
Medicinal Chemistry. 2009, 17, 2017-2029.
22. Almasirad, A.; Shafiee, A.; Abdollahi, M.; Noeparast, A.;
Shahrokhinejad, N.; Vousooghi, N.;
Tabatabai, S.A.; Khorasami, R. Synthesis and analgesic activity
of new 1,3,4-oxadiazoles and
1,2,4-triazoles, Med Chem Res 2011, 20, 435-442.
23. Xu, W.; He, J.; He, M.; Han, F.; Chen, X.; Pan, Z.; Wang,
J.; Tong, M. Synthesis and antifungal
activity of novel sulfone derivatives containing
1,3,4-oxadiazole moieties. Molecules 2011, 16,
9129-9141.
24. Kaplancikli, Z.A. Synthesis of some oxadiazole derivatives
as new anticandidal agents. Molecules
2011, 16, 7662-7671.
25. Liu, Z.-M.; Chen, Q.; Chen, C.-N.; Tu, H.-Y.; Yang, G.-F.
Syntheses of diheterocyclic compounds
based on
2-thioacetohydrazide-5,7-dimethyl-1,2,4-triazolo[1,5-a]-
pyrimidine. Molecules 2008,
13, 1353-1360.
26. Zheng, X.; LI, Z.; Wang, Y.; Chen, W.; Huang, Q.; Liu, C.;
Song, G. Synthesis and Insecticidal
Activities of Novel 2,5-disubstituted 1,3,4-Oxadiazoles. Journal
of Fluorine Chemistry, 2003,
123, 163-169.
27. Amir, M.; Kumar, S. Synthesis and evaluation of
anti-inflammatory, analgesic ulcerogenic and
lipid peroxidation properties of ibuprofen derivatives. Acta
Pharm 2007, 57, 31-45.
28. Mickeviius, V. Vaickelionien, R. Sapijanskait, . Synthesis
of substituted 1,3,4-oxadiazole derivatives. Chemistry of
Heterocyclic Compounds 2009, 45 (2), 215-218.
29. Martin, P.J.; BRUCE, D.B. Hydrogen-bonded oxadiazole
mesogens. Liquid Crystals 2007, 34 (6),
767-774.
-
Molecules 2012, 17
33
30. Hernndez-Ainsa, S.; Barber, J.; Marcos, M.; Serrano, J.L.
Liquid crystalline ionic dendrimers
containing luminescent oxadiazole moieties. Macromolecules 2012,
45, 1006-1015.
31. Nagendra, G.; Lamani, R.S.; Narendra, N.; Sureshbabu, V.V. A
convenient synthesis of 1,3,4-
thiadiazole and 1,3,4-oxadiazole based peptidomimetics employing
diacylhydrazines derived from
amino acids. Tetrahedron Letters 2010, 51, 6338-6341.
32. Li, Z.; Zhu, A.; Mao, X.; Sun, X.; Gong, X. Silica-supported
dichlorophosphate: a recoverable
cyclodehydrant for the eco-friendly synthesis of
2,5-disubstituted 1,3,4-oxadiazoles under solvent-
free and microwave irradiation conditions. J. Braz. Chem. Soc.
2008, 19, 1622-1626.
33. Sharma, G.V.M.; Rakesh, B.A.; Krishna, P.R. Zirconium (IV)
chloride mediated cyclodehydration
of 1,2-diacylhydrazines: A convenient synthesis of 2,5-diaryl
1,3,4-oxadiazoles. Synthetic
Communications 2004, 34, 23872391. 34. Yang, Y-H.; Shi, M.
Halogen effects in Robinson-Gabriel type reaction of
cyclopropanecarboxylic
acid N-substituted-hydrazides with PPh3/CX4. Tetrahedron Letters
2005, 46, 6285-6288.
35. Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F.
Synthesis of 1,3,4-oxadiazoles from 1,2-
diacylhydrazines using [Et2NSF2]BF4 as a practical
cyclodehydration agent. Org. Biomol. Chem.
2012, 10, 988.
36. Li, C.; Dickson, H.D. A mild, one-pot preparation of
1,3,4-oxadiazoles. Tetrahedron Letters 2009,
50, 6435-6439.
37. Rajapakse, H.A.; Zhu, H.; Young, M.B.; Mott, B.T. A mild and
efficient one pot synthesis of 1,3,4-
oxadiazoles from carboxylic acids and acyl hydrazides.
Tetrahedron Letters 2006, 47, 4827-4830.
38. Kangani, C.O.; Kelley, D.E.; Day, B.W. One pot direct
synthesis of oxazolines, benzoxazoles and
oxadiazoles from carboxylic acids using the deoxo-fluor reagent.
Tetrahedron Letters 2006, 47,
6497-6499.
39. Mashraqui, S.H.; Ghadigaonkar, S.G.; Kenny, R.S. An
expeditious and convenient one pot
synthesis of 2,5-disubstituted-1,3,4-oxadiazoles. Synthetic
Communications. 2003, 33 (14), 2541-
2545.
40. Kumar, G.V.S.; Rajendraprasad, Y.; Mallikarjuna, B.P.;
Chandrashekar, S.M.; Kistayya, C.
Synthesis of some novel 2-substituted -5-[isopropylthiazole]
clubbed 1,2,4-triazole and 1,3,4-
oxadiazoles as potential antimicrobial and antitubercular
agents, European Journal of Medicinal
Chemistry 2010, 45, 2063-2074.
41. Dabiri, M.; Salehi, P.; Baghbanzadeh, M.; Bahramnejad, M. A
facile procedure for the one-pot
synthesis of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles,
Tetrahedron Letters 2006, 47,
6983-6986.
42. Guin, S.; Ghosh, T.; Rout, S.K.; Banerjee, A.; Patel, B.K.
Cu(II) Catalyzed imine C-H
functionalization leading to synthesis of 2,5-substituted
1,3,4-oxadiazoles. Org. Lett 2011, 13 (22),
59765979. 43. Li, X.; He, D. Synthesis and optical properties of
novel anthracene-based stilbene derivatives
containing an 1,3,4-oxadiazole unit. Dyes and Pigments 2012, 93,
1422-1427
44. Gaonkar, S. L.; Nagashima, I.; Shimizu, H.
Microwave-assisted solution phase synthesis of novel
2-{4-[2-(N-methyl-2-pyridylamino)ethoxy]phenyl}-5-substituted
1,3,4-oxadiazole library.
Organic Chemistry International 2011, DOI:
10.1155/2011/751894.
45. Pore, D.M.; Mahadik, S.M.; Desai, U.V. Trichloroisocyanuric
acid-mediated one-pot synthesis of
unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles at ambient
temperature. Synthetic
Communications 2008, 38, 3121-3128.
46. Pardeshi, S.P.; Patil, S.P.; Bobade, V.D.
N-chlorosuccinimide/1,8-diazabicyclo[5.4.0]undec-7-ene
(dbu)-mediated synthesis of 2,5-disubstituted 1,3,4-oxadiazoles.
Synthetic Communications 2010,
40, 1601-1606.
47. Dobrot, C.; Paraschivescu, C.C.; Dumitru, I.; Matache, M.;
Baciu, I.; Rut, L.L. Convenient
preparation of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles
promoted by Dess-Martin
reagent. Tetrahedron Letters 2009, 50, 1886-1888.
-
Molecules 2012, 17
34
48. Polshettiwar, V.; Varma, R.S. Greener and rapid access to
bio-active heterocycles: one-pot solvent-
free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles.
Tetrahedron Letters 2008, 49, 879-883.
49. Kudelko, A. Zieliski, W. Microwave-assisted synthesis of
2-styryl-1,3,4-oxadiazoles from cinnamic acid hydrazide and
triethyl orthoesters. Tetrahedron Letters 2012, 53, 76-77.
50. Cui, L.; Liu, Q.; Yu, J.; Ni, C.; Yu, H. A novel one-pot
synthesis of a-keto-1,3,4-oxadiazole
derivatives based on isocyanide-Nef reaction. Tetrahedron
Letters 2011, 52, 55305533. 51. Ramazani, A.; Rezaei, A. Novel
one-pot, four-component condensation reaction: An efficient
approach for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole
derivatives by a Ugi-4CR/aza-
wittig sequence. Organic Letters 2010, 12(12), 2852-2855.
52. Baranov, A.B.; Tsypin, V.G.; Malin, A.S.; Laskin, B.M.
Synthesis of 2-chloromethyl-5-(5-methyl-
2-furyl)-, and
2-chloromethyl-5-(1,5-dimethyl-2-pyrrolyl)-1,3,4-oxadiazoles from
tetrazole
derivatives, Russian Journal of Applied Chemistry 2005, 78(5),
773-775.
53. Jiang, X.; Register, R.A. Statistical copolymers with
side-chain hole and electron transport groups
for single-layer electroluminescent device applications. Chem.
Mater. 2000, 12, 2542-2549.
54. Guan, M.; Bian, Z.Q.; Zhou, Y.F.; Li, F.Y.; Li, Z.J.; Huang,
C.H. High-performance blue
electroluminescent devices based on
2-(4-biphenylyl)-5-(4-carbazole-9-yl)phenyl-1,3,4-
oxadiazole. Chem. Commun. 2003, 2708-2709.
55. Zheng, Y.; Batsanov, A.S.; Jankus, V.; Dias, F.D.; Bryce,
M.R.; Monkman, A.P. Bipolar molecules
with high triplet energies: Synthesis, photophysical, and
structural properties. J. Org. Chem. 2011,
76, 8300-8310.
56. Efimova, Y.A.; Artamonova, T.V. Koldobskii, G.I. Tetrazoles:
LIII.* Microwave-activated
acylation of 5-substituted tetrazoles. Russian Journal of
Organic Chemistry 2008, 44, 1345-1347.
57. Reichart, B.; Kappe, C.O. High-temperature continuous flow
synthesis of 1,3,4-oxadiazoles via N-
acylation of 5-substituted tetrazoles. Tetrahedron Letters 2012,
53, 952-955.
58. de Oliveira, C.S.; Lira, B.F.; dos Santos Falco-Silva, V.;
Siqueira-Junior, J.P.; Barbosa-Filho,
J.M.; de Athayde-Filho, P.F. Synthesis, molecular properties
prediction, and anti-staphylococcal
activity of N-acylhydrazones and new 1,3,4-oxadiazole
derivatives. Molecules 2012, 17, 5095-
5107.
59. Sahin, G.; Palaska, E.; Ekizoglu, M.; Ozalp, M. Synthesis
and antimicrobial activity of some 1,3,4-
oxadiazole derivatives. Il Farmaco 2002, 57, 539-542.
60. Fuloria, N.K.; Singh, V.; Shaharyar, M.; Ali, M. Synthesis
and antimicrobial evaluation of some
new oxadiazoles derived from phenylpropionohydrazides, Molecules
2009, 14, 1898-1903.
61. Kumar, S. Anodic synthesis, spectral characterization and
antimicrobial activity of novel 2-amino-
5-substituted-1,3,4-oxadiazoles, J. Chil. Chem. Soc 2010, 55(1),
126-129.
62. Sangshetti, J.N.; Chabukswar, A.R.; Shinde, D.B. Microwave
assisted one pot synthesis of some
Novel 2,5-disubstituted 1,3,4-oxadiazoles as antifungal agents.
Bioorganic & Medicinal Chemistry
Letters 2011, 21, 444-448.
63. Chandrakantha, B.; Shetty, P.; Nambiyar, V.; Isloor, N.;
Isloor, A.M. Synthesis, characterization
and biological activity of some new 1,3,4-oxadiazole bearing
2-flouro-4-methoxi phenyl moiety,
European Journal of Medicinal Chemistry 2010, 45, 1206-1210.
64. Bakht, M.A.; M. Yar, M.S.; Abdel-Hamid, S.G.; Qasoumi, S.I.;
Samad, A. Molecular properties
prediction, synthesis and antimicrobial activity of some newer
oxadiazole derivatives. European
Journal of Medicinal Chemistry 2010, 45, 5862-5869.
65. Kumar, R.; Kumar, A.; Jain, S.; Kaushik, D. Synthesis,
antibacterial evaluation and QSAR studies
of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolone
derivatives. European Journal of
Medicinal Chemistry 2011, 46, 3543-3550.
66. Palekar, V.S.; Damle, A.J.; Shukla, S.R. Synthesis and
antibacterial activity of some novel bis-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and
bis-4-thiazolidinone derivatives from terephthalic
dihydrazide. European Journal of Medicinal Chemistry 2009, 44,
5112-5116.
67. Ramaprasad, G.C.; Kalluraya, B.; Kumar, B.S.; Hunnur, R.K.
Synthesis and biological property of
some novel 1,3,4-oxadiazoles. European Journal of Medicinal
Chemistry 2010, 45, 4587-4593.
-
Molecules 2012, 17
35
68. Patel, R.V.; Kumari, P.; Rajani, D.P.; Chikhalia, K.H.
Synthesis of coumarin-based 1,3,4-
oxadiazol-2ylthio-N-phenyl/benzothiazolyl acetamides as
antimicrobial and antituberculosis
agents. Med Chem Res. DOI 10.1007/s00044-012-0026-x.
69. Patel, R.V.; Patel, A.B.; Kumari, P.; Chikhalia, K.H.
Synthesis of novel 3-(5-sulfanyl-1,3,4-
oxadiazol-2-yl)-2H-chromen-2-one condensed s-triazinyl
piperazines and piperidines as
antimicrobial agents. Med Chem Res. DOI
10.1007/s00044-011-9842-7.
70. Sridhara, A.M.; Reddy, K.R.V.; Keshavayya, J.; Goud, P.S.K.;
Somashekar, B.C. Bose, P.;
Peethambar, S.K.; Gaddam, S.K. Synthesis and antimicrobial
activity of 2-substituted [4-(1,3,4-
oxadiazol-2-yl methyl)] phthalazin-1(2H)-one derivatives.
European Journal of Medicinal
Chemistry 2010, 45, 4983-4989.
71. Yar, M.S.; Siddiqui, A.A.; Ali, M.A. Synthesis and anti
tuberculostatic activity of novel 1,3,4-
oxadiazole derivatives, Journal of the Chinese Society 2007, 54,
5-8.
72. Yoshida, Y.; Matsuda, K.; Sasaki, H.; Matsumoto, Y.;
Matsumoto, S.; Tawara, S.; Takasugi, H.
Studies on anti-helicobacter pylori agents. Part 2: New cephem
derivatives. Bioorganic &
Medicinal Chemistry 2000, 8, 2317-2335.
73. Bakal, R.L.; Gattan, S.G.; Identification and development of
2,5-disubstituted oxadiazole as
potential candidate for treatment of XDR and MDR tuberculosis.
European Journal of Medicinal
Chemistry 2012, 47, 278-282.
74. Alia, M.A.; Shaharyar, M. Oxadiazole mannich bases:
Synthesis and antimycobacterial activity.
Bioorganic & Medicinal Chemistry Letters 2007, 17, 33143316.
75. Kashaw, S.K.; Gupta, V.; Varsha Kashaw, V.; Mishra, P.;
Stables, J.P. Jain, N.K. Anticonvulsant
and sedative-hypnotic activity of some novel
3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-
styrylquinazoline-4(3H)-ones. Med Chem Res 2010, 19,
250-261.
76. Zarghi, A.; Tabatabai, S.A.; Faizi, M.; Ahadian, A.; Navabi,
P.; Zanganeh, V.; Shafiee, A.
Synthesis and anticonvulsant activity of new
2-substituted-5-(2-benzyloxyphenyl)-1,3,4-
oxadiazoles. Bioorg. Chem. Lett 2005, 15, 1863-1865.
77. Rajak, H.; Deshmukh, R.; Veerasamy, R.; Sharma, A.K.;
Mishra, P.; Kharya, M.D. Novel
semicarbazones based 2,5-disubstituted-1,3,4-oxadiazoles: One
more step towards establishing
four binding site pharmacophoric model hypothesis for
anticonvulsant activity. Bioorganic &
Medicinal Chemistry Letters 2010, 20, 4168-4172.
78. Kaur, H.; Kumar, S.; Vishwakarma, P.; Sharma, M.; Saxena,
K.K.; Kumar, A. Synthesis and
antipsychotic and anticonvulsant activity of some new
substituted
oxa/thiadiazolylazetidinonyl/thiazolidinonylcarbazoles. European
Journal of Medicinal Chemistry
2010, 45, 2777-2783.
79. Bhat, M.A.; Al-Omar, M.A.; Siddiqui, N. Synthesis,
anticonvulsant and neurotoxicity of some
novel 1,3,4-oxadiazole derivatives of phthalimide. Der Pharma
Chemica, 2010, 2(2), 1-10.
80. Jain, N.; Kashaw, S.K.; Agrawal, R.K.; Gupta, A.; Soni, A.
Synthesis, anticonvulsant and
neurotoxic activity of some new
2,5-disubstituted-1,3,4-oxadiazoles. Med Chem Res 2011, 20,
1696-1703.
81. Jalilian, A.R.; Sheikhha, M.; Mirzaei, M.; Aslani, G.R.;
Shafiee, A. Radiosynthesis of [18
F]-5-[2-
(2-chlorophenoxy)phenyl]-1,3,4-oxadiazole-2-yl-
4-fluorobenzoate: A labeled ligand for
benzodiazepine receptors. Journal of Radioanalytical and Nuclear
Chemistry 2004, 260 (2), 373-
377.
82. Somani, R.R.; Kadam, G.; Vohra, R.; Vijayaraghavan, S.;
Shirodkar, P.Y. Studies of CNS
activities of some mannich bases of 1,3,4-oxadiazole.
International Journal of Pharmacology
2010, 6(5), 696-704.
83. Almasirad, A.; Tabatabai, S.A.; Faizi, M.; Kebriaeezadeh,
A.; Mehrabi, N.; Dalvandia, A.; Shafiee,
A. Synthesis and anticonvulsant activity of new
2-substituted-5-[2-(2-fluorophenoxy)phenyl]-
1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorganic &
Medicinal Chemistry Letters 2004, 14, 6057-
6059.
-
Molecules 2012, 17
36
84. Husain, A.; Ahmad, A.; Alam, M.M.; Ajmal, M.; Ahuja, P.
Fenbufen based 3-[5-(substituted aryl)-
1,3,4-oxadiazol-2-yl)]-1-(biphenyl-4-yl)propan-1-ones as safer
anti-inflammatory and analgesic
agents, European Journal of Medicinal Chemistry 2009, 44,
3798-3804.
85. Kadi, A.A.; El-frollosy, N.R.; Al-deeb, O,A.; Habib, E.E.;
Ibrahim, T.M.; El-emam, A.A.
Synthesis, antimicrobial, and anti-inflammatory activities of
novel 2-(1-adamantyl)-5-substituted-
1,3,4-oxadiazoles and
2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazoles, European
Journal
of Medicinal Chemistry 2007, 42, 235-242.
86. Burbuliene, M.M.; Jakubkiene, V.; Mekuskiene, G.; Udrenaite,
E.; Smicius, R.; Vainilavicius, P.
Synthesis and anti-inflammatory activity of derivatives of
5-[(2-disubstitutedamino-6-methyl-
pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-2-thiones.
Il Farmaco 2004, 59, 767-774.
87. Kumar, A.; Rajput, C.S. Synthesis and anti-inflammatory
activity of newer quinazolin-4-one
derivatives. European Journal of Medicinal Chemistry 2009, 44,
83-90.
88. Kkgzel, .G.; Kkgzel, . Tatar, E. Rollas, S. ahin, F.; Gllce,
M.; Clercq, E.D.; Kabasakal, L. Synthesis of some novel
heterocyclic compounds derived from diflunisal hydrazide
as potential anti-infective and anti-inflammatory agents.
European Journal of Medicinal
Chemistry 2007, 42, 893-901.
89. Akhter, M.; Husain, A.; Azad, B.; Ajmal, M. Aroylpropionic
acid based 2,5-disubstituted-1,3,4-
oxadiazoles: Synthesis and their anti-inflammatory and analgesic
activities. European Journal of
Medicinal Chemistry 2009, 44, 2372-2378.
90. Jayashankar, B.; Rai, K.M.L.; Baskaran, N.; Sathish, H.S.
Synthesis and pharmacological
evaluation of 1,3,4-oxadiazole bearing bis(heterocycle)
derivatives as anti-inflammatory and
analgesic agents. European Journal of Medicinal Chemistry 2009,
44, 3898-3902.
91. Kumar, H.; Javed, S.A.; Khan, S.A.; Amir, M.
1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole
derivatives of biphenyl-4-yloxy acetic acid: Synthesis and
preliminary evaluation of biological
properties. European Journal of Medicinal Chemistry 2008, 43,
2688-2698.
92. Chandra, T.; Garg, N.; Lata, S.; Saxena, K.K.; Kumar, A.
Synthesis of substituted acridinyl
pyrazoline derivatives and their evaluation for
anti-inflammatory activity. European Journal of
Medicinal Chemistry 2010, 45, 17721776. 93. Bhandari, S.V.;
Parikh, J.K.; Bothara, K.G.; Chitre, T.S.; Lokwani, D.K.; Devale,
T.L.; Modhave,
N.S.; Pawar, V.S.; Panda, S. Design, synthesis, and evaluation
of anti-inflammatory, analgesic,
ulcerogenicity, and nitric oxide
