synthesis and pharmacological activity of 1
TRANSCRIPT
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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
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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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
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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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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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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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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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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.
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