Synthesis and anticonvulsant activity of new 2-substituted-5-[2-(2- fluorophenoxy)phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles

Article abstract of DOI:10.1016/j.bmcl.2004.09.072

1,3,4-Oxadiazole and 1,2,4-triazole derivatives were prepared as anticonvulsant agents. Pharmacological evaluation was performed on the synthesized compounds. A series of new 2-substituted-5-[2-(2-fluorophenoxy) phenyl]-1,3,4-oxadiazoles has been synthesized and screened for their anticonvulsant activities. Compound 3 shows considerable anticonvulsant activity both in PTZ and MES models. It seems that this effect is mediated by benzodiazepine receptors and other unknown mechanism, respectively.

Full text of DOI:10.1016/j.bmcl.2004.09.072

Bioorganic & Medicinal Chemistry Letters 14 (2004) 6057–6059
Synthesis and anticonvulsant activity of new 2-substituted-5-
[2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles
Ali Almasirad,a Sayyed A. Tabatabai,b Mehrdad Faizi,c Abbas Kebriaeezadeh,d
Nazila Mehrabi,c Afshin Dalvandia and Abbas Shafieea,*
aDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran, Iran
bDepartment of Medicinal Chemistry, Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran
cDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran
dDepartment of Pharmacology and Toxicology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran, Iran
Received 17July 2004; revised 23 September 2004; accepted 23 September 2004
Available online 12 October 2004
Abstract—A series of new 2-substituted-5-[2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazoles has been synthesized and screened for their
anticonvulsant activities. Compound 3 shows considerable anticonvulsant activity both in PTZ and MES models. It seems that this
effect is mediated by benzodiazepine receptors and other unknown mechanism, respectively.
Ó 2004 Elsevier Ltd. All rights reserved.
Many compounds bearing five-membered heterocyclic
rings such as triazoles, oxadiazoles, thiadiazoles and
pyrazoles have been synthesized and evaluated for their
anticonvulsant and antidepressant activities.1–3 In our
previous works, we reported that 3-amino-5-[4-chloro-
2-(2-chlorophenoxy)phenyl]-4H-1,2,4-triazole 1 (Fig. 1)
and 2-amino-5-phenyl-1,3,4-thiadiazole 2 (Fig. 1) had
considerable anticonvulsant activity.4,5 These results
are in good agreement with the ones reported for some
thio)-4H-thiadiazole and 2,4-dihydro-3H-1,2,4-triazole-
3-thione derivatives.6,7
Moreover we showed that compound 1 exerts its anti-
convulsant activity through benzodiazepine receptors
but compound 2 did not.
In the present study some new 1,3,4-oxadiazoles and
1,2,4-triazoles have been synthesized (Fig. 2 compounds
3–8) and their anticonvulsant effects have been deter-
mined using pentylenetetrazole (PTZ)-induced lethal
convulsion and maximal electroshock (MES) tests. To
confirm the mode of action of the synthesized com-
pounds. The effect of flumazenil, a benzodiazepine
antagonist, on the anticonvulsant activity of the com-
pounds were determined.
2-aryl-5-hydrazino-1,3,4-thiadiazole,
5-aryl-3-(alkyl-
N
N
N
N
NH2
S
NH2
N
H
Cl
O
N
N
2
Cl
1
R
X
X
R
3
O
O
O
NH
SH
2
O
4
Figure 1.
5
SCH
OH
3
F
6
7
8
O
NH SH
3-8
NH OC H
2
5
Keywords: Substituted 1,3,4-oxadiazoles; Anticonvulsant; PTZ; MES.
*
Corresponding author. Tel.: +98 21 6406757; fax: +98 21 6461178;
e-mail: ashafiee@ams.ac.ir
Figure 2.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.09.072

6058
A. Almasirad et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6057–6059
Target compounds 3–8 were obtained according to
Scheme 1. The starting hydrazide 9 and 2-amino-5-[2-
(2-fluorophenoxy)phenyl]-1,3,4-oxadiazole 3 were pre-
pared as described previously.8 Reaction of compound
9 with carbon disulfide under basic condition afforded
5-[2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazole-2(3H)-
thione 4.9 Sonication of compound 4 in the presence of
methyl iodide in alkaline ethanol gave 2-methyltio-5-[2-
(2-fluorophenoxy)phenyl]-1,3,4-oxadiazole 5.4 Hydraz-
ide 9 was converted to 5-[2-(2-fluorophenoxy)phenyl]-
1,3,4-oxadiazole-2(3H)-one 6 by addition of 1,10-car-
bonyldiimidazole in the presence of triethylamine.10 5-
[2-(2-fluorophenoxy)phenyl]-2,4-dihydro-3H-1,2,4-triaz-
ole-3-thione 7 was synthesized by reaction of compound
9 with KSCN followed by cyclization of the thiose-
micarbazide intermediate with an aqueous solution of
NaOH.11 Compound 3 was rearranged to 3-ethoxy-5-
[2-(2-fluorophenoxy)phenyl]-1,2,4-triazole 8 upon treat-
ment with ethanolic KOH.4
As shown in Table 1, compound 3 with amino substitu-
ent on position 2 of oxadiazole ring has the best anticon-
vulsant activity in both PTZ and MES models. The
effect was antagonized with flumazenil, a benzodiaze-
pine antagonist, in PTZ test which verifies the involve-
ment of benzodiazepine receptors in this effect. These
results are in good agreement with our pervious studies
on 1,2,4-triazole derivatives with the same activity.
Table 1. Pharmacological evaluation of the synthesized compounds
N
N
R
X
O
F
The anticonvulsant activity of the synthesized com-
pounds was determined by evaluation of the ability of
the compounds to protect mice against convulsion in-
duced by a lethal dose of PTZ12 and electroshock13 as
two routine models.
Compd
X
R
ED50 mg/kga
MES
PTZ
3
O
O
O
O
N
N
NH2 39.21 (32.69–45.49)b 9.57(6.30–13.88)
4
SH
SCH3 >100
>100
43.11 (27.37–70.06)
>100
>100
5
Diazepam was considered as a reference benzodiazepine
agonist with anticonvulsant effect in both models. The
synthesized compounds, diazepam or vehicle were
administered 30min before injection of PTZ 100mg/kg
or induction of electroshock (60Hz, 37.2mA and 0.25s).
6
OH
SH
>100
>100
7
92.00 (78.96–107.18)
8
Diazepam
OEt
84.84 (73.96–97.02)b NDc
b
b
1.87(1.30–2.60)
1.57(1.16–2.14)
a n = 10, 95% confidence limits in parentheses, LD50 of all compounds
>300mg/kg.
b ED50 significantly increased in the presence of flumazenil 10mg/kg
(P < 0.05).
The dead mice were counted in PTZ test and occurrence
of HLTE (hind limb tonic extension) were observed in
MES Model, 30min later.
c Not determined.
H
N
N
N
N
O
O
S
NH2
O
NHNH2
O
a
b
O
O
F
F
F
4
9
3
e,f
d
g
c
H
F
H
N
N
N
N
N
N
N
N
OC2H5
SCH3
S
O
N
H
O
N
H
O
O
O
O
O
F
F
F
5
6
7
8
Scheme 1. Reagents and conditions: (a) BrCN, NaHCO3, dioxane, rt, 3h; (b) CS2, KOH, EtOH, reflux, 7h; (c) MeI, NaOH 10%, EtOH, sonication,
20min; (d) 1,10-carbonyldiimidazole, THF, rt, 18h; (e) KSCN, HCl, H2O, reflux, 3h; (f) aq NaOH, reflux, 4h; (g) EtOH, KOH, reflux, 15h.

A. Almasirad et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6057–6059
6059
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The compounds with substituents other than amino
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In conclusion a group of agents with wide anticonvulsant
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Acknowledgements
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This work was supported by grants from the research
council of Tehran University of Medical Sciences, Sha-
heed Beheshti University of Medical Sciences and INSF
(Iran National Science Foundation).
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¨