Design and synthesis of new 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1, 3,4-oxadiazoles as anticonvulsant agents

Article abstract of DOI:10.1248/cpb.56.509

A new series of 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4- oxadiazoles was designed and synthesized as anticonvulsant agents. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group at position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at ortho position of benzyloxy moiety had the best anticonvulsant activity. Our results showed that this effect is mediated through benzodiazepine receptors mechanism.

Full text of DOI:10.1248/cpb.56.509

April 2008
Chem. Pharm. Bull. 56(4) 509—512 (2008)
509
Design and Synthesis of New 2-Substituted-5-[2-(2-halobenzyloxy)phenyl]-
1,3,4-oxadiazoles as Anticonvulsant Agents
Afshin ZARGHI, ,a Zahra HAJIMAHDI,a Shohreh MOHEBBI,a Hootesa RASHIDI,a Sasan MOZAFFARI,b
*
c
Sahar SARRAF,b Mehrdad FAIZI,b Seyed Abbas TABATABAEE,a and Abbas SHAFIEE
a Department of Medicinal Chemistry, Shaheed Beheshti University of Medical Sciences; b Department of Pharmacology,
Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shaheed Beheshti University of Medical Sciences;
Tehran, Iran: and c Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences; Tehran, Iran.
Received November 18, 2007; accepted January 17, 2008; published online January 22, 2008
A new series of 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles was designed and synthesized
as anticonvulsant agents. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the in-
troduction of an amino group at position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at ortho position of
benzyloxy moiety had the best anticonvulsant activity. Our results showed that this effect is mediated through
benzodiazepine receptors mechanism.
Key words benzodiazepine receptor; 1,3,4-oxadiazole; anticonvulsant; structure–activity relationship (SAR)
The benzodiazepines (BZDs) are widely used in the treat- sant activity.13—15) As part of our ongoing research program
ment of central nervous system (CNS) disorders such as anx- to design new anticonvulsant agents, we describe herein the
iety, insomnia and epilepsy.1) The pharmacological effects of synthesis and biological evaluation of a novel group of 2-
the BZDs result from their affinity for a specific binding do- substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles
main on the gamma amino butyric acid (GABAA) receptors, (Fig. 1) with a flexible second out-of-plane aromatic ring,
known as the BZD receptor. The interaction of BZD agonists benzyloxy group which has all the suggested requirements
with GABAA receptor complex increases the GABA-induced for binding to the BZD receptors.
chloride channel opening frequency, which results in mem-
brane hyperpolarization, thus reducing neuronal excitabil- Results and Discussion
ity.2,3) The BZD binding sites in the brain were identified and
Chemistry The target 1,3,4-oxadiazole derivatives were
described by radioligand receptor binding assays and origi- synthesized according to Chart 1. Accordingly, reaction of 2-
nally it was found that only 1,4-BZD derivatives bind to halo-2-benzyloxy benzoic acid methyl ester 1 with hydrazine
these receptors. It has since been shown that many groups of hydrate in N,Nꢀ-dimethyleformamide (DMF) at room tem-
compounds bind to the BZD receptor with high affinity, e.g., perature afforded corresponding 2-halo-2-benzyloxy benzoic
triazolopyridazines, cyclopyrrolones, quinolines and b-car- acid hydrazide 2 high yields (87—90%).16) The hydrazide
bolines.4—7) Several pharmacophore models have been pro- were converted to 2-amino-5-(2-halo-2-benzyloxyphenyl)-
posed for BZDs, and amongst all models suggested for bind- 1,3,4-oxadiazoles 3 using cyanogen bromide in methanol
ing to the BZD receptor at least two features are common: an (71—90%).17) 5-(2-Halo-2-benzyloxyphenyl)-2-mercapto-
aromatic ring and a coplanar proton accepting group in suit- 1,3,4-oxadiazole 4 was prepared by the reaction of hydrazide
able distance (5 Å). Also, the presence of a second out-of- 2 with carbon disulfide under basic condition (60—70%).18)
plane, aromatic ring could potentiate binding to the recep- Sonication of compound 5 in the presence of suitable alkyl
tor.8—12) On this basis, a wide variety of compounds with a halide in alkaline media afforded 2-alkylthio-5-(2-halo-2-
chemical structure different from that of BZDs have been benzyloxyphenyl)-1,3,4-oxadiazole 5a—f (58—90%).19)
synthesized and tested. We recently started a wide research Treatment of hydrazide 2 with phenylisothiocyanate followed
program aimed to design new BZD receptor ligands charac- by reaction with KI/I2 in alkaline hydro-ethanol gave 2-
terized by a higher degree of flexibility compared with clas- anilino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 7
1
sic BZD ligands. Accordingly, we reported several 1,3,4-oxa- (57—80%).20) The compounds were characterized by H nu-
diazole derivatives which showed considerable anticonvul- clear magnetic resonance, infrared, mass spectrometry and
CHN analysis. Physicochemical data of these compounds are
shown in Table 1. Conformational analysis of the synthesized
compounds and estazolam were preliminarily performed by
MMX force field method implemented in Hyperchem 7.0
software. The conformers were optimized further by AM1
calculation using MOPAC 6.0 program.21) Global energy
minima conformers of the designed compounds were super-
imposed on corresponding conformer of estazolam molecule
which was considered as a reference BZD agonist.
Anticonvulsant Activity The BZD activity of the syn-
thesized compounds was determined through the evaluation
Fig. 1. The Structure of Designed Compounds and Estazolam
of the ability of the compounds to protect mice against con-
∗ To whom correspondence should be addressed. e-mail: azarghi@yahoo.com
© 2008 Pharmaceutical Society of Japan

510
Vol. 56, No. 4
vulsion induced by a lethal dose of pentylenetetrazole (PTZ)
and electroshock as two routine models.23,24) Diazepam was
considered as a reference BZD agonist with anticonvulsant
effect in both models. The synthesized compounds, di-
azepam or vehicle were administered 30 min before injection
of PTZ 100 mg/kg or application 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 maximal electroshock
(MES) Model. As shown in Table 2, compound 3a with
amino group on position 2 of oxadiazole ring and fluoro sub-
stituent at ortho position of benzyloxy group has the best an-
ticonvulsant activity in both PTZ and MES models. The ac-
Table 2. Pharmacological Evaluation of the Synthesized Compounds
ED50 (mg/kg)a)
Compd.
R1
R2
PTZ
MES
3a
3b
4a
NH2
NH2
SH
F
Cl
F
9.0 (7.3—10.8)b)
37.5 (22.5—61.5)b)
ꢁ100
16.2 (11.4—22.8)b)
49.5 (31.5—76.5)b)
ꢁ100
4b
5a
5b
5c
5d
5e
SH
Cl
F
ꢁ100
ꢁ100
SCH3
SCH3
SC2H5
SC2H5
SBz
59.6 (40.8—88.2)b)
75.1 (52.7—110.5)b)
79.5 (50.1—126.4)b)
75.3 (52.6—110.7)b)
81.4 (50.6—118.5)b)
ꢁ100
Cl 85.6 (59.1—136.4)b)
F
Cl
F
71.5 (45.1—106.4)b)
ꢁ100
ꢁ100
5f
7a
7b
SBz
NHPh
NHPh
Cl
F
Cl
ꢁ100
ꢁ100
ꢁ100
ꢁ100
Reagents: (a) NH2NH2·H2O, EtOH, rt, 10 h; (b) BrCN, NaHCO3, MeOH, rt, 3 h; (c)
CS2, KOH, EtOH, reflux, 12 h; (d) RI, NaOH 10%, EtOH, sonication, 20—45 min; (e)
PhNCS, EtOH, reflux, 3 h; (f) I2/KI, NaOH, H2O/EtOH, rt→reflux, 1 h.
ꢁ100
ꢁ100
Diazepam
0.7 (0.6—0.9)b)
0.8 (0.5—1.1)b)
Chart 1
a) nꢂ10, 95% confidence limits in parentheses, LD50 of all compoounds
ꢁ300 mg/kg. b) ED50 significantly increased in the presence of flumazenil 10 mg/kg
(pꢃ0.05).
Table 1. Physical Data of the Synthesized Compounds
Compound
R1
R2
mp (°C)a)
Yield (%)b)
Molecular formula
Molecular weight
3a
3b
4a
4b
5a
5b
5c
5d
5e
5f
NH2
NH2
SH
SH
SCH3
SCH3
SC2H5
SC2H5
SBz
SBz
NHPh
NHPh
F
Cl
F
Cl
F
Cl
F
Cl
F
Cl
F
143
200
90
71
70
60
95
85
80
82
58
75
80
57
C15H12N3O2F
285.27
301.73
302.38
318.53
316.41
332.86
330.43
346.89
392.50
408.56
361.37
377.82
C15H12N3O2Cl
C15H11N2O2SF
C15H11N2O2SCl
C16H13N2O2SF
C16H13N2O2SCl
C17H15N2O2SF
C17H15N2O2SCl
C22H17N2O2SF
C22H17N2O2SCl
C21H16N3O2F
175—177
188—190
69—70
85—87
64—66
88—90
125—127
99—101
175
7a
7b
Cl
184
C21H16N3O2Cl
a) Recrystallized from EtOH. b) Yield after recrystallization.

April 2008
511
from Aldrich (U.S.A.) or Merck (Germany) and were used without further
purification.
General Procedure for Preparation of 2-Halo-2-benzyloxy Benzoic
Acid Hydrazide 2 To a solution of 2-halo-2-benzyloxy benzoic acid
methyl ester 1 (10 mmol) in DMF (10 ml), hydrazine hydrate (50 mmol) was
added and stirred at room temperature for 10 h. After this time, 100 ml water
was added and the solid thus separated out was filtered, dried and recrystal-
lized from ethanol.
2-Fluoro-2-benzyloxy Benzoic Acid Hydrazide 2a: Yield 87%; mp
105 °C; IR (KBr): n (cmꢅ1) 3310, 3200 (NH2), 1680 (CꢂO); Mass, m/z (%):
275.9 (Mꢆ, 20), 245 (30), 167 (50), 141.1 (20), 136.1 (30), 109.0 (100), 83.1
(60).
2-Chloro-2-benzyloxy Benzoic Acid Hydrazide 2b: Yield 90%; mp
106 °C; IR (KBr): n (cmꢅ1) 3300, 3200 (NH2), 1680 (CꢂO); Mass, m/z (%):
292.5 (Mꢆ, 30), 261.5 (40), 157.6 (55), 125.1 (100), 89.1 (70).
General Procedure for Preparation of 2-Amino-5-(2-halo-2-benzyl-
oxyphenyl)-1,3,4-oxadiazoles 3 To a methanolic solution of 2 (5.1 mmol),
cyanogens bromide (7.5 mmol) was added. The reaction mixture was stirred
at room temperature for 3 h. The resulting solution was neutralized with
sodium bicarbonate solution. The solid thus separated out was filtered,
washed with water, dried and recrystallized from ethanol.
Fig. 2. Superimposition of the Energy Minima Conformers of Estazolam
and Compound 3a
tivity was antagonized with flumazenil, a BZD antagonist,
which establishes the involvement of BZD receptors in this
effect. In previous related work,13) we also showed that an
amino group on position 2 of oxadiazole or triazole ring and
a fluorine substituent at ortho position of phenoxy group of
2-substituted-5-[2-(2-fluorophenoxy)phenyl]-1,3,4-oxadia-
zoles and 1,2,4-triazoles had the best anticonvulsant activity.
Figure 2 shows the superimposition of energy minima con-
formers of the compound 3a, the most potent synthesized
analogues, and estazolam. Obviously, the main BZD pharma-
cophores, aromatic rings and proton accepting groups (p1
interaction), nitrogen (N-3) of the 1,3,4-oxadiazole and tria-
zolobenzodiazepine rings, are well matched. Replacement of
fluoro substituent with a larger electron-withdrawing group
such as Cl (3b) decreases the activity which may be ex-
plained by a steric hindrance effect. These results are in good
agreement with the classical SAR data of BZDs22) and our
previous studies on 1,3,4-oxadiazoles.13—15) In the series of
2-alkylthio oxadiazoles, compounds 5a and 5b possessing a
small alkylthio group at C-2 of 1,3,4-oxadiazole ring had
moderate anticonvulsant activity in both models. Increasing
the size of alkyl group (5c—f) significantly decreases the an-
ticonvulsant activity in both PTZ and MES models. Accord-
ingly, compounds 5e and 5f with a bulky benzyloxy group
did not show any anticonvulsant effects. Similarly, com-
pounds 7a and 7b did not have any considerable anticonvul-
sant activity in both models. Therefore, the size and nature of
groups at C-2 position of 1,3,4-oxadiazole ring are very im-
portant on anticonvulsant activity in both PTZ and MES
models. In addition, the size of electron withdrawing sub-
stituent at ortho position of benzyloxy moiety is also impor-
tant for their anticonvulsant effects. In conclusion, the results
of this investigation indicate that 1,3,4-oxadiazoles having
amino group at C-2 position with a benzyloxy moiety pos-
sessing a suitable ortho electron withdrawing substituent can
show high BZD activity confirming the suggested SARs for
BZD agonists.
2-Amino-5-(2-fluoro-2-benzyloxyphenyl)-1,3,4-oxadiazoles 3a: Yield
90%; mp 143 °C; IR (KBr): n (cmꢅ1) 3380, 3290 (NH2), 16010—1490 (aro-
1
matic); H-NMR (methanol-d4): d (ppm) 5.34 (s, 2H, CH2), 7.10—7.38 (m,
5H, ArH), 7.62 (m, 1H, phenyl H4), 7.69 (t, 1H, 2-fluorophenyl H3), 7.81
(dd, 1H, phenyl H6, J5,6ꢂ7.8 Hz, J4,6ꢂ1.6 Hz); Mass, m/z (%): 285.1 (Mꢆ,
10), 243.1 (20), 121.1 (80), 150.1 (50), 109 (100), 83.1 (60). Anal. Calcd for
C15H12N3O2F: C, 63.15; H, 4.24; N, 14.73. Found: C, 63.35; H, 4.42; N,
14.85.
2-Amino-5-(2-chloro-2-benzyloxyphenyl)-1,3,4-oxadiazoles 3b: Yield
71%; mp 200 °C; IR (KBr): n (cmꢅ1) 3300, 3150 (NH2), 1600—1480 (aro-
1
matic); H-NMR (methanol-d4): d (ppm) 5.33 (s, 2H, CH2), 7.10—7.41 (m,
5H, ArH), 7.50 (m, 1H, phenyl H4), 7.70 (d, 1H, 2-chlorobenzyl H3,
Jꢂ7.7 Hz), 7.78 (dd, 1H, phenyl H6, J5,6ꢂ7.7 Hz, J4,6ꢂ1.6 Hz); Mass, m/z
(%): 301.1 (Mꢆ, 10), 228.1 (10), 207.1 (10), 125.0 (100), 109.1 (50), 89.1
(40). Anal. Calcd for C15H12N3O2Cl: C, 59.71; H, 4.01; N, 13.93. Found: C,
59.50; H, 3.92; N, 14.15.
General Procedure for Preparation of 5-(2-Halo-2-benzyloxyphenyl)-
2-mercapto-1,3,4-oxadiazole 4 A mixture of 2 (3.6 mmol), KOH (10
mmol) and carbon disulphide (10 mmol) in ethanol (10 ml) was refluxed on a
steam bath for 12 h. The solution was then concentrated, cooled and acidi-
fied with dilute HCl. The solid product that separated out was filtered,
washed with cold ethanol, dried and recrystallized from ethanol.
5-(2-Fluoro-2-benzyloxyphenyl)-2-mercapto-1,3,4-oxadiazole 4a: Yield
70%; mp 175-177 °C; IR (KBr): n (cmꢅ1) 2550 (SH), 1600—1490 (aro-
matic); Mass, m/z (%): 302.4 (Mꢆ, 20), 227.1 (10), 150.1 (40), 136 (70), 109
(100), 83.1 (45). Anal. Calcd for C15H11N2O2SF: C, 59.59; H, 3.67; N, 9.27.
Found: C, 59.75; H, 3.85; N, 8.99.
5-(2-Chloro-2-benzyloxyphenyl)-2-mercapto-1,3,4-oxadiazole 4b: Yield
60%; mp 188—190 °C; IR (KBr): n (cmꢅ1) 2580 (SH), 1590—1480 (aro-
matic); 1H-NMR (DMSO-d6): d (ppm) 5.35 (s, 2H, CH2), 7.08—7.51 (m,
6H, ArH), 7.76 (d, 1H, 2-chlorobenzyl H3, Jꢂ7.6 Hz), 7.82 (d, phenyl H6,
Jꢂ7.9 Hz); Mass, m/z (%): 318.0 (Mꢆ, 50), 245.1 (20), 151.1 (20), 125
(100), 89.1 (40). Anal. Calcd for C15H11N2O2SCl: C, 56.52; H, 3.48; N, 8.79.
Found: C, 56.26; H, 3.65; N, 8.54.
General Procedure for Preparation of 2-Alkylthio-5-(2-halo-2-benzyl-
oxyphenyl)-1,3,4-oxadiazole 5 An ethanolic solution of appropriate alkyl
iodide (3.0 mmol) was added to a solution of compound 4 (2.4 mmol) in
10% aqueous sodium hydroxide (5 ml), and the mixture was sonicated on a
sonication bath for 30—60 min. The reaction mixture was poured in cold
water (50 ml) and the solid thus separated out was filtered, washed with
water, dried and recrystallized from ethanol.
2-Methylthio-5-(2-fluoro-2-benzyloxyphenyl)-1,3,4-oxadiazole 5a: Yield
Experimental
1
95%; mp 69—70 °C; IR (KBr): n (cmꢅ1) 1590—1460 (aromatic); H-NMR
Melting points (mp) were determined using a Thomas Hoover capillary
apparatus (Philadelphia, U.S.A.). Infrared spectra acquired on a Perkin-
Elmer 1420 ratio recording spectrometer. A Bruker FT-500 MHz instrument
(Brucker Biosciences, U.S.A.) was used to acquire 1H-NMR spectra; chloro-
form-d, dimethyle sulfoxide (DMSO)-d6 and methanol-d4 were used as sol-
vents. Mass spectra were acquired with a Finnigan TSQ-70 mass spectrome-
ter. Electron-impact ionization was performed at an ionizing energy of
70 eV; the source temperature was 250 °C. Elemental analyses were carried
out with a Perkin Elmer Model 240-C apparatus (Perkin Elmer, Norwalk,
CT, U.S.A.). The results of the elemental analyses (C, H, N) were within
ꢄ0.4% of the calculated amounts. All chemicals and reagents were obtained
(CDCl3): d (ppm) 2.76 (s, 3H, CH3), 5.34 (s, 2H, CH2), 7.12—7.54 (m, 6H,
ArH), 7.79 (t, 1H, 2-fluorobenzyl H3), 8.01 (d, phenyl H6, Jꢂ7.7 Hz); Mass,
m/z (%): 316.2 (Mꢆ, 20), 269.2 (50), 243.2 (65), 150.1 (70), 121.1 (80),
109.1 (100), 92.1 (60). Anal. Calcd for C16H13N2O2SF: C, 60.74; H, 4.14; N,
8.85. Found: C, 60.96; H, 4.32; N, 8.64.
2-Methylthio-5-(2-chloro-2-benzyloxyphenyl)-1,3,4-oxadiazole 5b: Yield
1
85%; mp 85—87 °C; IR (KBr): n (cmꢅ1) 1580—1480 (aromatic); H-NMR
(CDCl3): d (ppm) 2.75 (s, 3H, CH3), 5.31 (s, 2H, CH2), 7.08—7.54 (m, 6H,
ArH), 7.80 (d, 1H, 2-chlorobenzyl H3, Jꢂ7.6 Hz), 7.96 (d, phenyl H6,
Jꢂ7.6 Hz); Mass, m/z (%): 333.1 (Mꢆ, 90), 297.1 (25), 259.1 (20), 166.1

512
Vol. 56, No. 4
(20), 125 (100), 89.1 (20). Anal. Calcd for C16H13N2O2SCl: C, 57.74; H, 30 min, the dead mice were counted in PTZ test and occurrences of HLTE
3.94; N, 8.42. Found: C, 57.56; H, 3.80; N, 8.21.
2-Ethylthio-5-(2-fluoro-2-benzyloxyphenyl)-1,3,4-oxadiazole 5c: Yield
(hind limb tonic extension) were observed in MES model. In general, the
dose-response curves were estimated by testing three or four doses using at
80%; mp 64—66 °C; IR (KBr): n (cmꢅ1) 1570—1480 (aromatic); H-NMR least 10 mice for each dose. To clarify the mode of action of the synthesized
(CDCl3): d (ppm) 1.51 (t, 3H, CH3), 3.29 (q, 2H, CH2), 5.33 (s, 2H, OCH2), compounds, the effect of flumazenil (10 mg/kg), a BZD receptor antagonist,
7.12—7.53 (m, 6H, ArH), 7.80 (t, 1H, 2-fluorobenzyl H3), 8.01 (d, phenyl on the anticonvulsant activity of the compounds were determined. The Insti-
H6, Jꢂ7.7 Hz); Mass, m/z (%): 330.2 (Mꢆ, 15), 269.2 (40), 243.2 (65), 150.1 tutional Animal Ethics Committee approved the protocol adopted for the ex-
1
(70), 121.1 (90), 109.1 (100), 92.1 (50). Anal. Calcd for C17H15N2O2SF: C,
perimentation of animals.
61.80; H, 4.58; N, 8.48. Found: C, 61.65; H, 4.22; N, 8.25.
Statistical Analysis Statistical analysis of the anticonvulsant activity of
2-Ethylthio-5-(2-chloro-2-benzyloxyphenyl)-1,3,4-oxadiazole 5d: Yield the synthesized compounds on animals was evaluated using a one-way
1
82%; mp 88—90 °C; IR (KBr): n (cmꢅ1) 1580—1470 (aromatic); H-NMR analysis of variance (ANOVA). In all cases, post-hoc comparisons of the
(CDCl3): d (ppm) 1.50 (t, 3H, CH3), 3.28 (q, 2H, CH2), 5.30 (s, 2H, OCH2),
7.08—7.54 (m, 6H, ArH), 7.85 (d, 1H, 2-chlorobenzyl H3, Jꢂ7.9 Hz), 7.98
means of individual groups were performed using Fisher’s exact probability
test. A significance level of pꢃ0.05 considered significance in all cases. All
(d, phenyl H6, Jꢂ8.0 Hz); Mass, m/z (%): 346.9 (Mꢆ, 80), 311.1 (20), 285.1 values were expressed as meanꢄS.D. (standard deviations). For statistical
(30), 150.1 (40), 125 (100), 89.1 (40). Anal. Calcd for C17H15N2O2SCl: C,
58.87; H, 4.36; N, 8.08. Found: C, 58.65; H, 4.12; N, 7.86.
analysis we used SPSS Software 13.0 version. (SPSS Software 13.0 version,
Inc. Chicago, Ilinois, U.S.A.).
2-Benzylthio-5-(2-fluoro-2-benzyloxyphenyl)-1,3,4-oxadiazole 5e: Yield
58%; mp 125—127 °C; IR (KBr): n (cmꢅ1) 1600—1480 (aromatic); 1H-
NMR (CDCl3): d (ppm) 4.50 (s, 2H, SCH2), 5.34 (s, 2H, OCH2), 7.14—7.53
(m, 11H, ArH), 7.77 (t, 1H, 2-fluorobenzyl H3), 8.01 (d, phenyl H6,
Satisfactory analysis for C, H, N was obtained for all the compounds
within ꢄ0.4% of the theoretical values.
Acknowledgement This work was partially supported by a grant from
Jꢂ7.7 Hz); Mass, m/z (%): 392.2 (Mꢆ, 5), 269.2 (10), 243.2 (10), 150.1 the research council of Shaheed Beheshti University of Medical Sciences.
(10), 121.1 (40), 109.1 (100), 91.2 (65). Anal. Calcd for C22H17N2O2SF: C,
67.33; H, 4.37; N, 7.14. Found: C, 67.55; H, 4.64; N, 7.01.
References
2-Benzylthio-5-(2-chloro-2-benzyloxyphenyl)-1,3,4-oxadiazole 5f: Yield
75%; mp 99—101 °C; IR (KBr): n (cmꢅ1) 1580—1490 (aromatic); 1H-NMR
(CDCl3): d (ppm) 4.49 (s, 2H, SCH2), 5.31 (s, 2H, OCH2), 7.08—7.54 (m,
11H, ArH), 7.72 (d, 1H, 2-chlorobenzyl H3, Jꢂ7.6 Hz), 7.97 (d, phenyl H6,
Jꢂ7.8 Hz); Mass, m/z (%): 409.1 (Mꢆ, 10), 373.1 (20), 285.1 (20), 166.1
(10), 125 (80), 91.1 (100). Anal. Calcd for C22H17N2O2SCl: C, 64.62; H,
4.19; N, 6.85. Found: C, 64.35; H, 4.30; N, 6.67.
General Procedure for Preparation of 2-Anilino-5-(2-halo-2-benzyl-
oxyphenyl)-1,3,4-oxadiazole 7 A mixture of 2 (8.5 mmol), phenyl isothio-
cyanate (8.5 mmol) and dry tetrahydrofran (THF) (50 ml) was stirred at
room temperature for 10 h. It was then concentrated and cooled. The ob-
tained solid was filtered and dispersed in ethanol (50 ml) and to this suspen-
sion, aqueous sodium hydroxide (5 N, 8 ml) was added with stirring to obtain
a clear solution. To this solution, iodine in potassium iodide solution (5%)
was added gradually with stirring till the colour of iodine persisted at room
1) Smith G. B., Olsen R. W., Trends. Pharmacol. Sci., 16, 162 (1995).
2) Kerr I. B., Ong J., Med. Res. Rev., 12, 593—636 (1992).
3) Macdonal R. I., Olsen R. W., Annu. Rev. Neurosci., 17, 569 (1994).
4) Yokoyama N., Ritter B., Neubert A. D., J. Med. Chem., 25, 337—339
(1982).
5) Allen M. S., Hagen T. J., Trrudell M. L., Codding P. W., Skolnick P.,
Cook J. M., J. Med. Chem., 31, 1854—1861 (1988).
6) Shindo H., Takada S., Murata S., Eigyo M., Matsushita A., J. Med.
Chem., 32, 1213—1217 (1989).
7) Trudell M. L., Lifer S. L., Tan Y. C., Martin M. J., Deng L., Skolnick
P., Cook J. M., J. Med. Chem., 33, 2412—2420 (1990).
8) Ghose A. K., Crippen G. M., Mol. Pharmacol., 37, 725—734 (1990).
9) Codding P. W., Muir A. K., Mol. Pharmacol., 28, 178—184 (1985).
10) Fryer R. I., Cook C., Gilman N. W., Wasler A., Life Sci., 39, 1947—
1957 (1986).
temperature. The reaction mixture was refluxed for 2 h on steam bath. It was 11) He X., Zhang J. M., Cook J. M., Med. Chem. Res., 10, 269—308
then cooled and poured over crushed ice. The solid product that separated
out was filtered, dried and recrystallized from ethanol.
2-Anilino-5-(2-fluoro-2-benzyloxyphenyl)-1,3,4-oxadiazole 7a: Yield
80%; mp 175 °C; IR (KBr): n (cmꢅ1) 3250 (NH), 1580—1490 (aromatic);
1H-NMR (CDCl3): d (ppm) 5.36 (s, 2H, OCH2), 7.09—7.54 (m, 9H, ArH),
7.57 (d, 2H, 2-aminophenyl H2, H6, Jꢂ8.3 Hz), 7.60 (br s, 1H, NH), 7.74 (t,
(2001).
12) Diaz-Arauzo H., Koehler K. F., Hagan T. J., Cook J. M., Life Sci., 49,
207—216 (1991).
13) Almasirad A., Tabatabai S. A., Faizi M., Kebriaeezadeh A., Mehrabi
N., Dalvandi A., Shafiee A., Bioorg. Med. Chem. Lett., 14, 6057—
6059 (2004).
1H, 2-fluorobenzyl H3), 7.96 (dd, phenyloxadiazole H6,
J
J5,6ꢂ7.7 Hz,
14) Zarghi A., Tabatabai S. A., Faizi M., Ahadian A., Navabi P., Zanganeh
V., Shafiee A., Bioorg. Med. Chem. Lett., 15, 1863—1865 (2005).
4,6ꢂ1.6 Hz); Mass, m/z (%): 361.2 (Mꢆ, 10), 243.2 (10), 124.1 (25), 109.1
(100), 93.1 (30). Anal. Calcd for C21H16N3O2F: C, 69.79; H, 4.46; N, 11.62. 15) Zarghi A., Faizi M., Shafaghi B., Ahadian A., Khojastehpoor H. R.,
Found: C, 69.95; H, 4.64; N, 11.31.
Zanganeh V., Shafiee A., Bioorg. Med. Chem. Lett., 15, 3126—3129
(2005).
16) Firoozi F., Javidnia K., Kamal M., Fooladi A., Foroumadi A., Shafiee
A., J. Het. Chem., 32, 123—128 (1995).
2-Anilino-5-(2-chloro-2-benzyloxyphenyl)-1,3,4-oxadiazole 7b: Yield
57%; mp 184 °C; IR (KBr): n (cmꢅ1) 3300 (NH), 1560—1460 (aromatic);
1H-NMR (CDCl3): d (ppm) 5.21 (s, 2H, OCH2), 6.88 (t, 1H, aminophenyl
H4),6.99—7.35 (m, 8H, ArH), 7.50 (d, 2H, 2-aminophenyl H2, H6, 17) Goswami B. H., Sarmah Kataky J. C., Baruah J. N., J. Het. Chem., 21,
Jꢂ8.3 Hz), 7.77 (m, 2H, 2-chlorobenzyl H3 and phenyloxadiazole H6), 9.59 1225—1228 (1984).
(br s, 1H, NH); Mass, m/z (%): 377.8 (Mꢆ, 10), 317.7 (10), 246.7 (10), 230.8 18) Almasirad A., Sheikha M., Hosseini R., Tabatabai S. A., Shafiee A.,
(20) 150.1 (20), 89.1 (100). Anal. Calcd for C21H16N3O2Cl: C, 66.76; H,
4.27; N, 11.12. Found: C, 66.97; H, 4.45; N, 10.92.
Pharmacological Evaluation Anticonvulsant evaluation of the synthe-
Arch. Pharm. Pharmacol. Med. Chem., 337, 193—200 (2004).
19) Shafiee A., Naimi E., Mansoobi P., Foroumadi A., Shekari M., J. Het.
Chem., 32, 1235—1239 (1995).
sized compounds was performed following the standard procedure provided 20) Amir M., Shikha K., J. Med. Chem., 39, 535—545 (2004).
by the antiepileptic drug development program.23,24) It includes qualitative 21) QCPE, Department of Chemistry, Indiana University, Bloomington, IN
assays using MES and PTZ tests. The first assay is related to electrical in-
duction of seizure and the second test generates convulsion by chemical in- 22) Fryer R. I., “Comprehensive Medicinal Chemistry,” Vol. 3, ed. by Han-
duction. The compounds were administered to adult male albino mice (25— sch C., Pergamon, Oxford, 1990, pp. 539—637.
30 g) intraperitoneally at four or five doses (0.1,1, 10, and 100 or 150 23) Krall R. L., Penry J. K., White B. G., Kupferberg H. J., Swinyard E.
mg/kg), and all the results are summarized in Table 2. Diazepam and all A., Epilepsia, 19, 409—428 (1978).
tested compounds were dissolved in DMSO. The synthesized compounds, 24) Porter R. J., Hessie B. J., Cereghino J. J., Gladding G. D., Kupferberg
47405, U.S.A.
diazepam or vehicle were administered 30 min before injection of PTZ
100 mg/kg or application of electroshock (60 Hz, 37.2 mA and 0.25 s). After
H. J., Scoville B., White B. G., Fed. Proc., 44, 2645—2649 (1985).