Synthesis and anticonvulsant activity of new 2-substituted-5-(2- benzyloxyphenyl)-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.bmcl.2005.02.014

A series of new 2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles have been synthesized and evaluated as anticonvulsant agents. Compound 4b shows considerable anticonvulsant activity both in PTZ and MES models. It seems this effect is mediated through benzodiazepine receptors mechanism.

Full text of DOI:10.1016/j.bmcl.2005.02.014

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1863–1865
Synthesis and anticonvulsant activity of new
2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles
Afshin Zarghi,a,* Sayyed A. Tabatabai,a Mehrdad Faizi,b Avideh Ahadian,a
Parisa Navabi,a Vahideh Zanganehb and Abbas Shafieec
aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran 141556153, Iran
bDepartment of Pharmacology, Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran 141556153, Iran
cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 141556451, Iran
Received 24 January 2005; revised 1 February 2005; accepted 4 February 2005
Abstract—A series of new 2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles have been synthesized and evaluated as anticon-
vulsant agents. Compound 4b shows considerable anticonvulsant activity both in PTZ and MES models. It seems this effect is medi-
ated through benzodiazepine receptors mechanism.
Ó 2005 Elsevier Ltd. All rights reserved.
Benzodiazepines (BZDs) have been widely used to pro-
vide anxiolysis and sedation in numerous clinical settings
since their discovery over four decades ago.1 BDZs
allosterically enhance the action of c-aminobutyric acid
(GABA) at GABAA receptors by increasing the fre-
quency of the opening of the chlorine channel, potentiat-
ing the inhibitory GABA action in the brain.2,3 Several
pharmacophore models have been proposed for BZDs,
and amongst all models that suggest binding to the ben-
zodiazepine receptor at least two features are common:
an aromatic ring and a coplanar proton accepting group
at a suitable distance. Also, the presence of a second out-
of-plane, aromatic ring could potentiate binding to the
receptor.4–8 On this basis, we reported 2-substituted-5-
(2-phenoxyphenyl)-1,3,4-oxadiazoles and 1,2,4-triazoles,
which had considerable anticonvulsant activity.9,10
of the synthesized compounds, the effect of flumazenil, a
benzodiazepine receptor antagonist, were determined on
the anticonvulsant activity of the compounds.
The designed compounds were synthesized according to
Scheme 1. Reaction of methylsalicylate 1 with appropri-
ate benzyl chloride in alkaline hydromethanolic solution
afforded corresponding 2-benzyloxy benzoic acid methyl
ester 2.11 2-Benzyloxy benzoic acid hydrazides 3 were
readily prepared by treatment with hydrazine hydrate
in methanol.12 The hydrazides were converted to 2-
amino-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles 4 using
cyanogens bromide in methanol (75–84%).13
5-(2-Benzyloxyphenyl)-2-mercapto-1,3,4-oxadiazole 5 was
prepared by reaction of hydrazide 3a with carbon disul-
fide under basic condition.14
In the present study some new 2-substituted-5-(2-benzyl-
oxyphenyl)-1,3,4-oxadiazoles with a flexible second out-
of-plane aromatic ring, benzyoxy group, have been
synthesized (Fig. 1, compounds 4–6) and their anticon-
vulsant effects have been determined through pentylen-
tetrazole (PTZ)-induced lethal convulsion and maximal
electroshock (MES) tests. To clarify the mode of action
N
N
4a: R =H; R =NH
2
1
2
4b: R =F; R =NH
2
R2
1
2
O
4c: R =Cl; R =NH
2
1
2
O
CH2
5
: R =H; R =SH
1 2
6a: R =H; R =SCH
3
1
2
6b: R =H; R =SC H
2
5
1
2
Keywords: Substituted 1,3,4-oxadiazoles; Anticonvulsant; Benzodiaze-
pine receptor.
6c: R =H; R =SBz
1
2
R1
*
Corresponding author. Tel.: +98 2187735215; fax: +98 218795008;
e-mail: azarghi@yahoo.com
Figure 1. The structure of designed compounds.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.014

1864
A. Zarghi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1863–1865
COOMe
CONHNH2
COOMe
OH
i
ii
O
CH2
O
CH2
3
2
1
R1
N
R1
N
NH2
O
iii
O
CH2
4a : R1 = H
b : R1 = F
c : R1 = Cl
4
4
R1
N
N
N
N
SR2
SH
O
O
v
iv
3a
O
CH2
O
CH2
6a: R =CH
2
3
5
6b: R =C H
2 5
2
6c: R =Bz
2
Scheme 1. Reagents and conditions: (i) BzCl, KOH 10%; MeOH, rt, 6 h; (ii) NH2NH2ÆH2O; MeOH, rt, 5 h; (iii) BrCN, NaHCO3; MeOH, rt, 3 h; (iv)
CS2, KOH, EtOH, reflux, 6 h; (v) RI, NaOH 10%, EtOH, sonication, 20 min.
Table 1. Pharmacological evaluation of the synthesized compounds
Sonication of compound 5 in the presence of suitable al-
kyl halide in alkaline media afforded 2-alkylthio-5-(2-
N
N
benzyloxyphenyl)-1,3,4-oxadiazoles 6a–c (78–95%).15
The compounds were characterized by H nuclear mag-
1
R2
O
netic resonance, infrared, mass spectrometry and CHN
analysis.
O
CH2
Benzodiazepine activity of the synthesized compounds
was determined through the evaluation of the ability
of the compounds to protect mice against convulsion in-
duced by a lethal dose of PTZ16 and electroshock17 as
two routine models. Diazepam was considered as a ref-
erence benzodiazepine agonist with anticonvulsant effect
in both models. The synthesized compounds, diazepam
or vehicle were administered 30 min before injection of
PTZ 100 mg/kg or indication of electroshock (60 Hz,
37.2 mA and 0.25 s). After 30 min, the dead mice were
counted in PTZ test and occurrences of HLTE (hind
limb tonic extension) were observed in MES Model.
R1
Compd
R1 R2
ED50 mg/kga
MES
PTZ
4a
4b
H
F
NH2
NH2
85.2 (62.1–125.9)b 63.2 (41.9–82.9)b
2.5 (1.5–4.1)b
>100
>100
3.3 (2.1–5.1)b
>100
>100
4c
Cl NH2
5
6a
H
H
H
H
SH
SCH3
91.2 (55.1–196.4)b >100
6h
6c
SC2H5 >100
>100
>100
>100
1.8 (1.1–2.6)b
As shown in Table 1, compound 4b with amino group
on position 2 of oxadiazole ring and fluoro substituent
at the para position of benzyloxy group has the best
anticonvulsant activity in both PTZ and MES models.
The activity was antagonized with flumazenil, a benzo-
diazepine antagonist, which establishes the involvement
of benzodiazepine receptors in this effect. However,
replacement of the fluoro substituent with a larger elec-
tron withdrawing group such as Cl (4c) abolished the
activity. This effect appears to be steric since the unsub-
stituted analogue 4a had a moderate anticonvulsant
activity. These results are in good agreement with the
SBz
Diazepam
1.4 (1.1–2.0)b
a n = 10, 95% confidence limits in parentheses, LD50 of all compounds
>300 mg/kg.
b ED50 significantly increased in the presence of flumazenil 10 mg/kg
(P < 0.05).
classical SAR of BZDs18 and our previous studies on
1,3,4-oxadiazole and 1,2,4-triazole derivatives.9,10 In
the series of 2-alkylthio oxadiazoles, only compound
6a had
a weak anticonvulsant activity but the

A. Zarghi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1863–1865
1865
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compounds 5, 6b and 6c did not have any significant
anticonvulsant activities in both models.
In conclusion, the results of this investigation indicates
that some synthesized 2-amino-5-aryl-1,3,4-oxadiazoles
with a simple nonrigid structure in which the second
out-of-plane aromatic ring, benzyloxy group, with a
suitable substituent could show benzodiazepine activity
comparable with diazepam confirms the suggested SARs
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Acknowledgements
This work was partially supported by a grant from the
research council of Shaheed Beheshti University of
Medical Sciences.
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