Synthesis of some novel 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime ester derivatives and evaluation of their anticonvulsant activity

Article abstract of DOI:10.1016/j.ejmech.2012.08.037

Twenty-three new oxime ester derivatives of nafimidone were synthesized with the prospect of potential anticonvulsant activities. MES and ScM tests were employed for their anticonvulsant activities and rotorod test for neurological deficits. Eighteen compounds were found to be protective against MES seizures. Alkyl (1-8) and arylalkyl (9, 10) oxime ester derivatives were found to be more active than aryl oxime ester derivatives (11-23). Five compounds (2, 3, 7, 9, 10), which were protective at 0.5 h at the doses of 30 mg/kg and higher in MES test, showed the highest activity. Compound 17 was the most active one in ScM test at all dose levels at 4 h.

Full text of DOI:10.1016/j.ejmech.2012.08.037

European Journal of Medicinal Chemistry 57 (2012) 275e282
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of some novel 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime ester
derivatives and evaluation of their anticonvulsant activity
,
a
b
b
b
Arzu Karakurt a , Mehmet A. Alagöz , Burcu Sayoglu , Ünsal Çalıs¸ , Sevim Dalkara
*
ꢀ
a Inonu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 44280 Malatya, Turkey
b Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty-three new oxime ester derivatives of nafimidone were synthesized with the prospect of potential
anticonvulsant activities. MES and ScM tests were employed for their anticonvulsant activities and
rotorod test for neurological deficits. Eighteen compounds were found to be protective against MES
seizures. Alkyl (1e8) and arylalkyl (9, 10) oxime ester derivatives were found to be more active than aryl
oxime ester derivatives (11e23). Five compounds (2, 3, 7, 9, 10), which were protective at 0.5 h at the
doses of 30 mg/kg and higher in MES test, showed the highest activity. Compound 17 was the most active
one in ScM test at all dose levels at 4 h.
Received 24 May 2012
Received in revised form
24 August 2012
Accepted 26 August 2012
Available online 23 September 2012
Keywords:
Oxime ester
Ó 2012 Elsevier Masson SAS. All rights reserved.
(arylalkyl)imidazole
Azole derivatives
Anticonvulsant activity
E/Z isomers
1. Introduction
The first AEDs were in ureide structure. However, AEDs of
different skeletons with various functional groups have been
Epilepsy is a neurological disorder which affects more than 50
million people worldwide and becomes manifest by recurring
attacks [1]. It usually starts at childhood and continues lifetime.
Antiepileptic drug (AED) treatment, which is the main therapeutic
option, is mainly symptomatic since the exact reason of this brain
pathology is not clear yet. Despite many AEDs present in the
market, seizures cannot be taken under control for approximately
30% of the patients [2,3]. Furthermore, AEDs cannot be tolerated
well by most of the patients. These drugs not only cause tiredness,
neurophysiologic disorders, and weight gain but also affect the
metabolism of many drugs. Therefore there is a need to develop
more effective, safer, new anticonvulsant compounds controlling
all types of epileptic seizures and also decreasing the frequency
and/or severity of seizures in people with epilepsy [4,5]. Although
there are many strategies ranging from serendipity to genetic
approach to develop new AEDs, the complexity of action mecha-
nisms of AEDs makes it difficult to use some rational methodologies
of discovery. One of the well-known and productive AED design
strategies is molecular modification of existing drugs and poten-
tially active compounds [1,6,7].
introduced during the last 25 years, which has lead to a remarkable
progress in AED therapy. (Arylalkly)azoles are one of the anticon-
vulsant groups different from the ureide structure; nafimidone and
denzimol are the representative molecules of this group of anti-
convulsant compounds [8,9] (Formulas 1 and 2).
According to the SAR studies of this group, imidazole ring as
an azole group, 2-naphthyl as a lipophilic aryl group, and also
a two carbon chain alkylene bridge with a small oxygen functional
group (such as carbonyl, ethylene dioxy, methoxy, acyloxy,
hydroxyl, amido, and oximino substituents) between these two
rings are important for high anticonvulsant activity [8e16]. In one
of the recent studies it was shown that nafimidone alcohol esters
exhibited significant protection against MES induced seizures [14].
In the literature it was also reported that oxime ether derivatives
of nafimidone were found to be active in MES test whereas nafi-
midone oxime itself does not have any anticonvulsant activity
[16].
According to these results, in this study we aimed to prepare
some new oxime ester derivatives of nafimidone as potential
anticonvulsant compounds and test their anticonvulsant activities.
Various carboxylic acids of different sizes and structures were used
for preparation of the esters in order to establish the relationships
between the activity and structure.
* Corresponding author. Tel.: þ90 422 341 0660.
E-mail address: arzukarakurt@hotmail.com (A. Karakurt).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.08.037

276
A. Karakurt et al. / European Journal of Medicinal Chemistry 57 (2012) 275e282
in the 1H NMR spectra of the compounds was also another evidence
for the formation of the ester group.
O
N
N
It is known that the configurations of the oxime ester and oxime
ester are usually same as the initial oxime configuration [19].
According to the literature, the peak of CH2eC]Ne protons on the
same side with oxime (Z-isomer) shifts to a lower field in 1H NMR
spectrum because of the electronegativity of the oxygen [20]. In the
literature, it was reported that chemical shift values of methylene
(CH2eC]Ne) protons for the E and Z isomers of some nafimidone
oxime ethyl ether derivates obtained separately were 5.50 and
5.80 ppm respectively [16]. Since Z-isomer of nafimidone oxime
was used for the ester synthesis in this study, the ester derivatives
obtained were expected to be in Z-configuration. NMR spectra of
the aliphatic carboxylic acid esters are in accordance with this
expectation. Therefore we can speculate that compounds 1e10 are
Z isomers.
Since the signals for CH2eN protons of the aromatic acid esters
(compounds 11e23) are quite different and the relationship
between the electronic properties and/or locations (o-, m-, p-) of
the substituent and the chemical shift values of CH2eN protons is
unpredictable, it is hard to make any speculation about their
configuration.
Formula 1. Nafimidone.
2. Results and discussion
2.1. Chemistry
The total synthesis of the compounds is given in Scheme 1.
Nafimidone was obtained by the alkylation of imidazole with 1-(2-
naphthyl)-2-bromoethanone [8]. Nafimidone oxime was prepared
by the reaction of nafimidone and hydroxylamine hydrochloride
[16]. O-acylation of nafimidone oxime was realized via four
different esterification methods to gain the final oxime ester
derivatives: 1) The reaction of nafimidone oxime with appropriate
carboxylic acid in the presence of N,N0-dicyclohexylcarbodiimide
and 4-dimethylaminopyridine (DCC/DMAP) (Method A), 2) The
reaction of nafimidone oxime with acid anhydride (Method B), 3)
The reaction of nafimidone oxime with acyl halides in the presence
of DMAP (Method C) and 4) The reaction of nafimidone oxime with
aromatic acyl halides in the presence of TEA (Method D).
At the end of the reactions the crude products of the most
compounds gave very close double spots on TLC plates and the
upper one of these two spots was usually much smaller than the
lower one. We speculated that these double spots indicated
a mixture of E/Z isomers due to the double bond between the
carbon and nitrogen atoms of the oxime group. However the
reaction of the crude products with gaseous hydrochloric acid in
ether yielded their salt forms as single, pure isomer. This may be
explained by probable EeZ isomerisation caused by solvent and/or
pH effect as reported in the literature [16e18]. Another EeZ iso-
merisation case was observed for compounds 7 and 8 during the
NMR run. TLC results confirmed that gaseous hydrochloric acid
treatment yielded isomerically pure products of these compounds
just before their NMR run. Nevertheless their NMR spectra
proposed a mixture of E and Z isomers. Accordingly, we performed
a TLC run of the samples taken from their NMR tubes and observed
double spots on the plates for both compounds just like the double
spots of their crude products. Therefore we concluded that this E/Z
isomerisation occurred during the NMR run due to solvent effect.
Structures and some physicochemical properties of the
synthesized compounds are given in Table 1. The structures of the
compounds were confirmed by IR, 1H NMR, mass spectral and
elementary analysis data provided in the experimental section.
Strong C]O and CeO stretching bands around 1793e1731 and
1280e1091 cmꢀ1 respectively and the absence of the strong broad
eOH band in the 3600e2700 cmꢀ1 region in the IR spectra of the
compounds indicate the presence of oxime ester group. A singlet
around 6.00 ppm which represents the methylene protons of the
alkylene bridge in addition to the protons of R/Ar group of the acid
The 1H NMR spectra of two compounds (compound 7 and 8)
were found to be different from the others due to the duplication of
the signals for CH2eN, CHeC]O, and imidazole H2 protons with
different integral values but in the same ratio for three groups of
protons. For compound 7 two singlets (total 2H) were observed at
5.80 ppm (31%) and 5.90 ppm (69%) for CH2eN protons, two
multiplets (total 1H) with the same appearance were observed at
2.21e2.25 ppm (% 31) and 2.58e2.64 ppm (% 69) for CHeC]O
proton and two singlets (total 1H) were observed at 9.28 ppm
(31%) and 9.35 ppm (69%) for imidazole H2 proton. For compound 8
two singlets (total 2H) were observed at 5.92 ppm (34%) and
6.08 ppm (66%) for CH2eN protons, two multiples (total 1H) with
the same appearance were observed at 2.29e2.36 ppm (% 34) and
2.59e2.66 ppm (% 66) for CHeC]O proton and two singlets (total
1H) were observed at 10.01 ppm (34%) and 10.31 ppm (66%) for
imidazole H2 proton. According to these 1H NMR data we concluded
that compounds 7 and 8 consisted of two isomers (E and Z together)
of different ratios (which was also explained above). Considering
the chemical shifts of CH2eN protons we suggested that the signals
in the lower fields (5.90 ppm and 6.08 ppm) with higher proportion
belonged to the Z isomers and the others (5.80 ppm and 5.92 ppm)
to the E isomers. Since both compounds were obtained as pure
compounds as salt forms after gaseous hydrochloric acid treatment
(one spot in TLC and fine crystal with certain m.p.) it may rather be
speculated that one isomer (probably Z) converted to another one
(E isomer) in deuterated solvent during 1H NMR run. The reason for
having two isomers for compounds 7 and 8 may be the branching
structure of these compounds; in other words only these two
compounds have a-methine group in their acid chain.
The molecular ion peak of the compounds in their mass spectra
also confirmed the structure of the compounds. The other spectral
data were in accordance with the data in the literature and the
elemental analysis results were also consistent with the structure.
2.2. Anticonvulsant activity
Anticonvulsant activity and neurotoxicity screening test results
(MES, ScM and rotorod) of the synthesized compounds are
summarized in Table 2. All of the compounds except compound 6
showed antiMES and/or ScM activity. None of the compounds
except 2 showed neurotoxicity in any dose level. Compound 2
caused motor impairment in the rotorod screen at 300 mg/kg dose
level at 0.5 h, mice resumed their normal motor activity at 4 h,
N
OH
N
Formula 2. Denzimol.

A. Karakurt et al. / European Journal of Medicinal Chemistry 57 (2012) 275e282
277
a
b
c
Br
N
N
N
N
O
O
O
N
OH
d
e
N
N
N
N
. HCl
N
N
O
O
O
R
R
O
a. Br2 in CH3COOH, b. Imidazole in DMF, c. 1) NH2OH.HCl/NaOH in ethanol 2) HCl in H2O, d. method 1:
RCOOH/DCC/DMAP in CH2Cl2, method 2: RCOX, method 3: (RCO)2O, method 4: ArCOX/TEA, e. gaseous
HCl in ether.
Scheme 1. Synthesis of the compounds.
which is consistent with its activity results. Animal deaths were
observed at 300 mg/kg at both time points (0.5 h and 4 h) for
compound 10, which is one of the most active compounds in MES
test due to the protection it exhibited at 30 and 100 mg/kg dose
levels at 0.5 and 4 h respectively.
Almost half of the compounds (3, 4, 9, 10, 12, 15, 16, 19, 21e23)
exhibited MES selective activity whereas only four of the
compounds were found to be ScM selective, namely compounds 5,
13, and 20 at 300 mg/kg and compound 17 at 30 mg/kg. Although it
was reported in the literature [8,9] that the activity of the
compounds derived from nafimidone were highly MES specific in
mice, some of the oxime ester derivatives in this project exhibited
activity against ScM test as well as MES induced seizures. Moreover,
a few of them, mainly aromatic acid esters, showed only anti-ScM
activity. These data are in accordance with our previous studies
including oxime ether and amide derivatives of nafimidone
[15,16,21].
Most of the compounds revealed their activity rather at 0.5 h
than at 4 h suggesting that they have a rapid onset of action.
However compound 17, which is ScM selective, was active at 4 h at
all doses despite no protection at 0.5 h and the activities of
compounds 2, 4, 7, 10e12, 16, and 18 against MES-induced seizures
lasted 4 h at least at one of the dose levels. Compounds 2, 3, 7, 9, 10,
11, and 18 were the most active compounds (30 mg/kg) in MES test
at 0.5 h and/or 4 h while compound 17 was the most protective one
against ScM-induced seizures at all dose levels at 4 h.
The other arylalkyl ester derivative (compound 10) is also another
most active compound in MES test. Therefore it may be speculated
that arylalkyl groups in the carboxylic acid structure (compounds 9
and 10) resulted in increased potency and MES selectivity. Various
benzoic acid esters (compounds 11e23) were designed to examine
if the substitution on the phenyl ring is important in terms of SARs
in this group of compounds. But these modifications showed that
no correlation between the physicochemical properties of the
substituent and/or their position on the ring and the activity,
neurotoxicity and the duration of the activity existed.
Lipophilicity (log P 2) is important for CNS drugs to pass BBB,
thus clog P values of the compounds were calculated by ChemDraw
Ultra 8.0 (Table 1). As can be seen in Table 1, increased clog P values
of compound 23 (clog P: 6.36) and compound 6 (clog P: 5.20)
resulted in decreased and lost MES activity respectively, when
compared to more active compounds with less clog P values (clog P:
3.61 for compound 1 and clog P: 4.14 for compound 2). This is
explained by the fact that increased lipophilicity does not neces-
sarily enhance anticonvulsant properties; conversely it may
sometimes even lead to reduced or lost activity. Therefore lip-
ophilicity is not considered the only parameter but some additional
properties and action mechanisms of the compounds account for
the anticonvulsant activity as well.
3. Conclusion
Aliphatic oxime esters proved more effective than aromatic ones
in MES tests. This result is in accordance with the literature data for
the esters of the nafimidone alcohol [14]. The length of the alkyl
chain did not turn out important for the activity unless it is a five-
carbon chain since the only inactive compound was 6 which has
a six-carbon alkyl chain. Cyclization of the alkyl chain (compound
8) resulted in increased activity compared to straight chain deriv-
ative (compound 6). Branching of the “R” group in the active
aliphatic oxime ester derivatives did not appear to have an
important role in the potency but in the prolonged activity duration
when the activity of compound 3 (valeric acid ester) compared to
the activity of compound 4 (isovaleric acid ester). Incorporation of
a double bond and a tertiary alpha-methine group in the alkyl chain
(compound 5) resulted in an inactive compound however,
compound 9 (cinnamic acid ester), which also has a double bond in
arylalkyl group, is one of the most active MES selective compounds.
As a continuation of our research interest in developing novel
nafimidone-like anticonvulsant compounds and establishing new
relationships between their structure and activity, we designed and
synthesized a series of nafimidone oxime ester derivatives and
evaluated their anticonvulsant activities according to the screening
tests of ASP. We found that most of the ester derivatives of nafi-
midone oxime showed MES and/or ScM activity to some extent
with almost no neurotoxicity; this result is in consistence with the
results of oxime ether derivatives except their higher neurotoxicity
compared to that of oxime esters [16]. So we concluded that it was
worth to continue to study on this group; firstly selecting the most
promising compounds according to the criteria of ASP for further
tests, for example, activity tests for p.o. administration in rats,
determination of TPE and quantification of the pharmacological
parameters (ED50 and TD50) and also to design new derivatives with
better activity profiles.

278
A. Karakurt et al. / European Journal of Medicinal Chemistry 57 (2012) 275e282
Table 1 (continued)
Table 1
The structures, clog P values, yields, melting points of the synthesized compounds.
Comp.
R
X
Method clog P Yield (%) M.p. (ꢁC)
N
19
e
D
4.40 58.89
135e6
N
. X
N
O
OCH3
O
R
20
21
e
e
D
D
4.40 76.54
4.22 74.17
156e7
OCH3
Comp.
R
X
Method clog P Yield (%) M.p. (ꢁC)
1
2
3
4
5
6
7
eCH2CH3
eCH2CH2CH3
HCl
HCl
HCl
HCl
HCl
HCl
HCl
A
B
A
A
A
B
A
3.61 66.80
4.14 59.28
4.67 96.44
4.54 53.45
4.33 82.79
5.20 56.71
6.04 55.54
150
149e50
144e5
102e5
141e3
132e3
95e8
eCH2(CH2)2CH3
eCH2CH(CH3)2
eC(CH3)]CHCH3
eCH2(CH2)3CH3
eCH(CH2CH2CH3)2
NO2
Br
105e8
22
23
e
D
A
5.34 66.77
6.36 79.84
124e6
8
9
HCl
HCl
A
C
5.12 87.73
5.44 62.14
120e1
155e8
HCl
175
CH CH
O
4. Experimental part
10
11
e
e
A
D
4.50 53.18
4.48 76.25
165e7
H2CH2C
C
4.1. Chemistry
149e51
All chemicals used in this study were purchased from E.
Merck, Fluka AG, A. Aesar, and Aldrich. Purity of the compounds
was checked by TLC with Merck Kieselgel 60 F254 aluminum
plates. Column chromatography for purification of the
compounds was performed on Kieselgel 60 (0.040e0.063 mm)
(230e400 mesh ASTM) (Merck). Melting points were deter-
mined with a Thomas Hoover capillary melting point apparatus
and are uncorrected. IR spectra were recorded in KBr disks with
a Jasco 420 Fourier FT-IR Spectrometer or ATR method with
a Perkin Elmer Spectrometer.
12
e
D
4.98 59.28
132e3
H3C
13
14
15
e
e
e
D
D
D
4.98 79.58
4.98 74.44
5.19 69.51
128e30
153e4
157e9
1H NMR spectra were recorded on a Varian Mercury 400 MHz
FT-NMR spectrometer or a Brucker Avance Ultrashield FT-NMR
spectrometer in DMSO or CDCl3 at 300 MHz. All the chemical
CH3
shifts are expressed in
d (ppm) values. Splitting patterns are
CH3
designated as follows: s: singlet; d: doublet; dd: doublet of
doublets; t: triplet; q: quartet; and m: multiplet. Mass spectra were
obtained by 73DIP-1 Direct Insertion Probe and Agilent 5973-
network Mass Selective Detector (EI) or by Agilent 1100 HPLC and
ACE 5C18 detector (ES-API). Elemental analysis was performed on
Leco 982 CHNS elemental analysis apparatus at TUBITAK (Scientific
and Technical Research Council of Turkey) and Leco 932 CHNS
elemental analysis apparatus at Ankara University Faculty of
Pharmacy Center Laboratory or at Inonu University, Malatya.
2-bromo-1-(naphthalene-2-yl)ethanone [22], 1-(2-naphthyl)-
2-(imidazol-1-yl)ethanone [8], 1-(2-naphthyl)-2-(imidazol-1-yl)
ethanone oxime [16] were prepared according to the procedures
described in the relevant literature.
Cl
16
17
e
e
D
D
5.19 51.81
5.19 76.44
153e5
152e4
Cl
Cl
4.1.1. Preparation of the compounds.1-(2-naphthyl)-2-(imidazol-1-yl)
ethanone oxime esters
Method A: Appropriate carboxylic acids (3.5 mmol), DCC
(3.5 mmol) and DMAP (0.17 mmol) were stirred in dry methylene
chloride and 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime
(1.5 mmol) was added. Reaction mixture was stirred for 18e36 h at
18
e
D
4.40 64.86
145e7
H3CO

A. Karakurt et al. / European Journal of Medicinal Chemistry 57 (2012) 275e282
279
Table 2
Anticonvulsant and neurotoxicity screening data in mice dosed ip with the compounds.
Test
MES
0.5 h
30
ScM
0.5 h
30
Tox
0.5 h
30
Time
4 h
30
4 h
30
4 h
30
Dose (mg/kg)
100
300
100
300
100
300
100
300
100
300
100
300
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0/1
1/1
1/1
0/1
0/1
0/1
1/1
0/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
1/1
1/1
1/1
1/1
0/1
0/1
1/1
1/1
1/1
1/1
1/1
0/1
0/1
1/1
1/1
1/1
0/1
1/1
0/1
0/1
0/1
1/1
0/1
1/1
1/1
0/1
1/1
1/1
1/1
1/1
0/1
0/1
1/1
1/1
1/1
*
1/1
1/1
0/1
1/1
1/1
1/1
0/1
1/1
1/1
0/1
0/1
1/1
0/1
1/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
1/1
0/1
0/1
*
1/1
1/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
1/1
0/1
1/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
*
0/1
0/1
1/1
1/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
0/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
1/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
*
1/1
0/1
1/1
1/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
4/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
*
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
4/4
4/4
0/4
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
2/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
*
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
0/2
2/2
0/2
0/2
Phenytoin
Carbamazepine
Sodium Valproate
MES: Maximal electroshock seizure test (number of animal protected/number of animal tested). ScM: Subcutaneous metrazole seizure test (number of animal protected/
number of animal tested). Tox: rotarod test (number of animal exhibiting toxicity/number of animal tested). 0/1: no activity at dose level. 1/1: noticeable activity at dose level
(given in bold). * Animal death.
room temperature. The precipitate was filtered off; the solution was
dried over anhydrous sodium sulphate and then was evaporated to
dryness. The residue was dissolved in ether and treated with
etheral hydrochloric acid to obtain the hydrochloric acid salt of the
compounds. The precipitated salt was filtered and washed with
appropriate solvents.
(s, 1H, imidazole H4), 7.75 (s, 1H, imidazol H5), 7.62e8.47 (m, 7H,
naphthalene protons), 9.34 (s, 1H, imidazole H2); 13C NMR (DMSO-
d6):
d 9.19 (1C; CH3), 25.97 (1C; CH2eC]O), 44.35 (1C; CH2eN),
120.44e136.79 (13C, naphthalene and imidazole), 159.32 (C]N),
171.32 (C]O); Mass (API-ES): m/e 307 (Mþ, % 100); Anal. Calcd. for
C18H18ClN3O2. 2H2O (379.13): C, 56.92; H, 5.84; N, 11.06. Found: C,
Method B: Appropriate acid anhydride (3.5 mmol) and 1-(2-
naphthyl)-2-(imidazol-1-yl)ethanone oxime (1.5 mmol) were stir-
red for 6 h. Ether was added to the reaction mixture, which then
treated with etheral hydrochloric acid. The compounds were
crystallized from appropriate solvents.
Method C: Appropriate acid chloride (3.5 mmol),1-(2-naphthyl)-
2-(imidazol-1-yl)ethanone oxime (0.24 g, 1 mmol), and DMAP
(0.17 mmol) were stirred at room temperature for 12 h. Ether was
added to the reaction mixture; the precipitate was filtered off,
treated with etheral hydrochloric acid and crystallized from the
appropriate solvents.
Method D: 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime
(0.01 mol) was resolved in dry acetone (20 ml) and then triethyl-
amine (TEA) (0.015 mol) was added drop wise to the solution at 0 ꢁC
and then reaction mixture was stirred for 5 min at 0 ꢁC, for 6 h at
room temperature. Appropriate acid chloride (0.01 mol) was added
to the mixture and then reaction mixture was stirred for 10e30 min
at 0 ꢁC. Acetone was evaporated to dryness. The residue was
washed with cold ether (5 ml) and hot water and then purified by
column chromatography on silica gel eluting with chloroform or/
and crystallized from the appropriate solvents.
56.18; H, 5.01; N, 10.65.
4.1.1.2. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-butanoyl oxime
hydrochloride (2). Compound was purified by precipitation with
acetone. IR (
NMR (DMSO-d6, 300 MHz):
n
cmꢀ1, KBr): 1758 (C]O), 1570 (C]N), 1148 (CeO); 1H
d
0.96 (t, 3H, J ¼ 7.3 Hz, eCH3), 1.62e
1.69 (m, 2H, eCH2eCH3), 2.57 (t, 2H, J ¼ 7.3 Hz, eCH2eC]O),
5.88 (s, 2H, eCH2eN), 7.58 (s, 1H, imidazole H4), 7.72 (s, 1H, imi-
dazol H5), 7.61e8.42 (m, 7H, naphthalene protons), 9.25 (s, 1H,
imidazole H2); 13C NMR (DMSO-d6):
d 13.71 (1C; CH3), 18.16 (1C;
CH2eCH3), 34.22 (1C; CH2eC]O), 44.45 (1C; CH2eN), 120.66e
136.79 (13C, naphthalene and imidazole), 159.37 (C]N), 170.29
(C]O); Mass (API-ES): m/e 321 (Mþ, % 100); Anal. Calcd. for
C19H20ClN3O2 (357.12): C, 63.77; H, 5.63; N, 11.74. Found: C, 63.23;
H, 5.54; N, 11.53.
4.1.1.3. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanoneO-pentanoyloxime
hydrochloride (3). IR (
n
cmꢀ1, KBr): 1770 (C]O), 1600 (C]N), 1091
(CeO); 1H NMR (DMSO-d6, 300 MHz):
d
0.91 (t, 3H, J ¼ 7.3 Hz, e
CH3), 1.30e1.40 (m, 2H, eCH2eCH3), 1.56e1.66 (m, 2H, eCH2eCH2),
2.59 (t, 2H, J ¼ 7.3 Hz, eCH2eC]O), 5.89 (s, 2H, eCH2eN), 7.58 (s,
1H, imidazole H4), 7.73 (s, 1H, imidazol H5), 7.61e8.44 (m, 7H,
naphthalene protons), 9.28 (s, 1H, imidazole H2); 13C NMR (DMSO-
4.1.1.1. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-propanoyl oxime
hydrochloride (1). Compound was purified by precipitation with
d6): d 14.10 (1C; CH3), 22.08 (1C; CH2eCH3), 26.72 (1C; CH2eCH2),
acetone. IR (
NMR (DMSO-d6, 300 MHz):
2.66 (q, 2H, J ¼ 7.4 Hz, eCH2eC]O), 5.92 (s, 2H, eCH2eN), 7.58
n
cmꢀ1, KBr): 1793 (C]O), 1602 (C]N), 1108 (CeO); 1H
32.11 (1C; CH2eC]O), 44.43 (1C; CH2eN), 120.97e136.88 (13C,
naphthalene and imidazole), 159.35 (C]N), 170.37 (C]O); Mass
(API-ES): m/e 335 (Mþ, % 100); Anal. Calcd. for C20H22ClN3O2. H2O
d
1.14 (t, 3H, J ¼ 7.4 Hz, eCH3), 2.59e

280
A. Karakurt et al. / European Journal of Medicinal Chemistry 57 (2012) 275e282
(389.15): C, 61.61; H, 6.20; N, 10.78. Found: C, 61.30; H, 6.02; N,
10.70.
2H2O (406.16): C, 64.94; H, 6.19; N, 10.33. Found: C, 64.43; H,
5.99; N, 9.98.
4.1.1.4. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanoneO-3-methylbutanoyl
oxime hydrochloride (4). Compound was recrystallized from acetone/
4.1.1.9. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-cinnamoyl oxime
hydrochloride (9). IR (
n
cmꢀ1, ATR): 1725 (C]O), 1634 (C]N), 1111
petroleum ether. IR (
n
cmꢀ1, KBr): 1766 (C]O),1568 (C]N), 1151 (Ce
(CeO); 1H NMR (CDCl3-d, 300 MHz):
d 6.02 (s, 2H, eCH2eN), 6.76 (d,
O); 1H NMR (DMSO-d6, 300 MHz):
d
0.98 (d, 6H, J ¼ 6.6 Hz, eCH3),
1H, J ¼ 16.0 Hz, ]CHeC]O), 7.28e7.45 (m, 15H, ]CHePh, naph-
2.06e2.10 (m, 1H, eCH), 2.47 (d, 2H, J ¼ 7.0 Hz, eCH2eC]O), 5.88 (s,
2H, eCH2eN), 7.57 (s, 1H, imidazole H4), 7.71 (s, 1H, imidazol H5),
7.58e8.43 (m, 7H, naphthalene protons) and 9.25 (s, 1H, imidazole
thalene, phenyl protons and imidazole H4,5), 9.55 (s, 1H, imidazole
H2); 13C NMR (DMSO-d6):
d 44.44 (1C; CH2eN), 115.98 (1C; CH]
CHeC]O), 120.60e136.88 (19C, naphthalene, benzene and imid-
azole), 147.11 (1C; CH]CHeC]O), 159.81 (C]N), 163.53 (C]O);
Mass (API-ES): m/e 381 (Mþ, % 100); Anal. Calcd. for C24H20ClN3O2.
1/3H2O (423.89): C, 68.00; H, 4.91; N, 9.91. Found: C, 68.05; H, 4.81;
N, 9.64.
H2); Mass (API-ES): m/e 335 (Mþ,
%
100); Anal. Calcd. for
20H22ClN3O2. 1/2H2O (380.15): C, 63.07; H, 6.09; N, 11.03. Found: C,
63.01; H, 6.08; N, 11.35.
C
4.1.1.5. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-2-methylbut-2-
enoyl oxime hydrochloride (5). Compound was purified by precip-
4.1.1.10. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(4-oxo-4-
itation with acetone. IR (
n
cmꢀ1, ATR): 1745 (C]O), 1646 (C]N),
phenyl)butanoyl oxime (10). IR (
n
cmꢀ1, ATR): 1779, 1682 (C]O),
1299 (CeO); 1H NMR (CDCl3-d, 300 MHz):
d
1.79 (d, 3H, J ¼ 6.1 Hz,
1596 (C]N), 1111 (CeO); 1H NMR (CDCl3-d, 300 MHz):
d 3.04 (t,
eC(CH3)]CHCH3), 1.86 (s, 3H, eC(CH3)]CHCH3), 5.99 (s, 2H, e
CH2eN), 6.91e6.94 (q, 1H, J ¼ 5.7 Hz, eC(CH3)]CHCH3), 7.13 (s,
1H, imidazole H4), 7.18 (s, 1H, imidazole H5), 7.39e8.43 (m, 7H,
naphthalene protons), 9.86 (s, 1H, imidazole H2); Mass (API-ES):
m/e 334 (M þ H, % 100); Anal. Calcd. for C20H20ClN3O2. 4/3H2O
(393.12): C, 60.99; H, 5.80; N, 10.67. Found: C, 60.56; H, 5.57; N,
11.65.
J ¼ 6.4 Hz, 2H, eCOCH2CH2COC6H5), 3.49 (t, 2H, J ¼ 6.4 Hz, e
COCH2CH2COC6H5), 5.49 (s, 2H, eCH2eN), 7.00 (s, 1H, imidazole
H4), 7.05 (s, 1H, imidazole H5), 7.49e8.04 (12H, m, naphthalene and
phenyl protons), 8.15 (1H, s, imidazole H2); 13C NMR (DMSO-d6):
d
27.23 (1C; CH2e(C]O)eO), 33.55 (1C; CH2e(C]O)ePh), 41.61
(1C; CH2eN), 120.16e136.88 (13C, naphthalene, benzene and
imidazole), 161.33 (C]N), 170.43 (OeC]O), 198.76 (PheC]O);
Mass (API-ES): m/e 412 (Mþ, % 100); Anal. Calcd. for C25H21N3O3.
H2O (429.17): C, 69.92; H, 5.40; N, 9.78. Found: C, 70.49; H, 5.21; N,
9.83.
4.1.1.6. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-hexanoyl oxime
hydrochloride (6). Compound was purified by precipitation with
acetone. IR (
NMR (DMSO-d6, 300 MHz):
n
cmꢀ1, KBr): 1765 (C]O), 1603 (C]N), 1134 (CeO); 1H
d
0.88 (t, 3H, J ¼ 7.0 Hz, eCH3), 1.30e
4.1.1.11. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-benzoyloxime
(11). Compound was recrystallized from acetone and ethyl acetate.
1.34 (m, 4H, eCH2eCH2eCH3), 1.60e1.65 (m, 2H, eCH2eCH2eC]
O), 2.58 (t, 2H, J ¼ 7.3 Hz, eCH2eC]O), 5.90 (s, 2H, eCH2eN),
7.58 (s, 1H, imidazole H4), 7.73 (s, 1H, imidazol H5), 7.59e8.44 (m,
7H, naphthalene protons), 9.30 (s, 1H, imidazole H2); Mass (API-
ES): m/e 349 (Mþ, % 100); Anal. Calcd. for C21H24ClN3O2. H2O
(403.17): C, 62.45; H, 6.49; N, 10.40. Found: C, 61.96; H, 6.36; N,
10.16.
IR (
(CDCl3-d):
n
cmꢀ1, KBr): 1749 (C]O), 1652 (C]N), 1240 (CeO); 1H NMR
d
5.55 (s; 2H; eCH2eN), 6.98e8.17 (m; 15H; naphtha-
lene, benzene and imidazole); Mass (EI, 70 eV): m/e 355 [Mþ] (34%),
332, 301, 233, 206, 179, 153, 122, 105 (base peak, 100%), 77, 51; Anal.
Calcd. for C22H17N3O2. 1/5H2O (358.73): C, 73.60; H, 4.89; N, 11.71.
Found: C, 73.88; H, 5.39; N, 11.72.
4.1.1.7. (E/Z)-1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-2-pro-
4.1.1.12. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(2-methy-
pylpentanoyl oxime hydrochloride (7). Compound was purified by
lbenzoyl)oxime (12). Compound was recrystallized from ethanol/
precipitation with acetone. IR (
n
cmꢀ1, ATR): 1758 (C]O), 1577
water and acetone/water. IR (
n
cmꢀ1, KBr): 1759 (C]O), 1652 (C]
(C]N), 1089 (CeO); 1H NMR (DMSO-d6, 300 MHz):
d
0.66 (% 31)
N), 1228 (CeO); 1H NMR (DMSO-d6):
d 2.59 (s; 3H; eCH3), 5.75 (s;
and 0.88 (% 69) (t, 6H, J ¼ 7.3 Hz, eCH3), 1.02e1.09 (% 31) and
1.43e1.62 (% 69) (m, 4H, eCH2eCH3), 1.19e1.38 (m, 4H, eCH2e
CH), 2.21e2.25 (% 31) vs 2.58e2.64 (% 69) (m, 1H, eCHeC]O),
5.80 (% 31) and 5.90 (% 69) (s, 2H, eCH2eN), 7.58 (s, 1H, imid-
azole H4), 7.71 (s, 1H, imidazol H5), 7.59e8.45 (m, 7H, naphtha-
lene protons), 9.28 (% 31 E isomer) and 9.35 (s, 1H, imidazole H2);
2H; eCH2eN), 6.79e8.42 (m; 14H; naphthalene, benzene and
imidazole); Mass (EI, 70 eV): m/e 369 [Mþ] (23%), 332, 301, 273, 233,
206, 153, 136, 127, 119 (base peak, 100%), 91, 77, 68; Anal. Calcd. for
C23H19N3O2 (369.41): C, 74.78; H, 5.18; N, 11.37. Found: C, 74.43; H,
4.96; N, 11.38.
Mass (API-ES): m/e 377 (Mþ,
23H28ClN3O2. 1/2H2O (422.19): C, 65.31; H, 6.91; N, 9.94. Found:
C, 65.18; H, 6.71; N, 9.90.
%
100); Anal. Calcd. for
4.1.1.13. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(3-methy-
C
lbenzoyl)oxime (13). Compound was recrystallized from ethanol/
water. IR (
NMR (DMSO-d6):
n
cmꢀ1, KBr): 1745 (C]O), 1652 (C]N), 1265 (CeO); 1H
d
2.44 (s; 3H; eCH3), 5.59 (s; 2H; eCH2eN), 6.99e
4.1.1.8. (E/Z)-1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-cyclohex-
anecarbonyl oxime hydrochloride (8). IR (
cmꢀ1, ATR): 1781 (C]O),
1682 (C]N), 1113 (CeO); 1H NMR (CDCl3-d, 300 MHz):
1.18e
2.12 (m, 10H, cyclohexane CH2 protons), 2.29e2.36 (34%) and
2.59e2.66 (66%) (m, 1H, cyclohexane CH protons), 5.92 (% 34)
and 6.08 (% 66) (s, 2H, eCH2eN), 7.09e8.58 (m, 7H, imidazole H2
and naphthalene protons), 10.01 (34%) and 10.31 (66%) (1H, s,
imidazole H2), and 15.88 (s, 1H, NþeH); 13C NMR (DMSO-d6):
8.20 (m; 14H; naphthalene, benzene and imidazole); Mass
(EI, 70 eV): m/e 369 [Mþ] (8%), 332, 301, 273, 233, 206, 179, 153,
136, 119 (base peak, 100%), 91, 68, 41; Anal. Calcd. for C23H19N3O2.
1/3H2O (375.15): C, 73.58; H, 5.28; N, 11.19. Found: C, 73.48; H, 5.39;
N, 10.89.
n
d
4.1.1.14. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(4-methy-
lbenzoyl)oxime (14). Compound was washed with ethylacetate
d
25.38 (2C; cyclohexyl C3 and C5), 25.66 (2C; cyclohexyl C4),
and recrystallized from acetone. IR (
n
cmꢀ1, KBr): 1741 (C]O), 1652
28.91 (2C; cyclohexyl C2 and C6), 44.66 (1C; CH2eN), 115.98 (1C;
CH]CHeC]O), 120.59e136.74 (13C, naphthalene and imidazole),
147.11 (1C; CH]CHeC]O), 159.78 (C]N), 171.93 (C]O); Mass
(API-ES): m/e 361 (Mþ, % 100); Anal. Calcd. for C22H24ClN3O2. 1/
(C]N), 1250 (CeO); 1H NMR (DMSO-d6):
d 2.08 (s; 3H; eCH3), 6.08
(s; 2H; eCH2eN), 7.42e9.24 (m; 14H; naphthalene, benzene and
imidazole); Mass (EI, 70 eV): m/e 369 [Mþ] (18%), 233, 206, 191, 179,
166, 153, 136, 127, 119 (base peak, 100%), 111, 91, 68, 53, 41; Anal.

A. Karakurt et al. / European Journal of Medicinal Chemistry 57 (2012) 275e282
281
Calcd. for C23H19N3O2 (369.41): C, 74.60; H, 5.18; N, 11.37. Found: C,
74.43; H, 4.67; N, 11.10.
naphthalene, benzene and imidazole); Mass (EI, 70 eV): m/e 400
[Mþ] (3%), 332, 301, 273, 233, 206, 179, 165, 153 (base peak, 100%),
137, 121, 104, 81, 65, 41; Anal. Calcd. for C22H16N4O4. H2O (418.40): C,
63.15; H, 4.34; N, 13.39. Found: C, 63.46; H, 3.67; N, 13.04.
4.1.1.15. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(2-chloro-
benzoyl)oxime (15). Compound was recrystallized from chloro-
form/n-hexane. IR (
(CeO); 1H NMR (DMSO-d6):
14H; naphthalene, benzene and imidazole); 13C NMR (DMSO-d6):
45.42 ( 1C; CH2eN),121.02e137.07 (19C, naphthalene, benzene and
imidazole), 161.47 (C]N), 162.29 (C]O); Mass (EI, 70 eV): m/e 389
[Mþ] (17%), 332, 301, 233, 207, 194, 180, 166, 153, 139 (base peak,
100%), 126, 111 75, 63, 41; Anal. Calcd. for C22H16ClN3O2. 1/3H2O
(395.09): C, 66.75; H, 4.24; N,10.62. Found: C, 66.54; H, 3.78; N,10.48.
n
cmꢀ1, KBr): 1743 (C]O), 1652 (C]N), 1232
4.1.1.22. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(3-bromoben-
zoyl) oxime (22). Compound was purified by column chromatog-
raphy and then recrystallized from acetone. Yield: 66.77%; mp: 124e
d
6.00 (s; 2H; eCH2eN), 7.53e9.23 (m;
d
6 ꢁC; IR (
(DMSO-d6):
n
cmꢀ1, KBr): 1753 (C]O),1571 (C]N),1231 (CeO); 1H NMR
d 5.74 (s; 2H; eCH2eN), 7.03e8.39 (m; 14H; naphtha-
lene, benzene and imidazole); Mass (EI, 70 eV): m/e 435 [Mþ1] (12%),
433 (Mꢀ1 12%), 339, 301, 273, 251, 233, 202, 200, 185, 183, 166, 153
(base peak, 100%), 139, 126, 101, 76, 68, 50, 41; Anal. Calcd. for
C22H16BrN3O2. 1/4H2O (442.05): C, 59.61; H, 3.87; N, 9.48. Found: C,
4.1.1.16. 1-(2-Naphthyl)-2-(imidazol-1-yl)ethanone O-(3-chloro-
59.86; H, 3.54; N, 9.53.
benzoyl)oxime (16). Compound was purified by column chroma-
tography and then recrystallized from acetone. IR (
n
cmꢀ1, KBr): 1748
4.1.1.23. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-4-phenylben-
(C]O), 1652 (C]N), 1238 (CeO); 1H NMR (DMSO-d6):
d
6.12 (s; 2H;
zoyl oxime hydrochloride (23). Compound was recrystallized from
eCH2eN), 7.53e9.22 (m; 14H; naphthalene, benzene and imid-
azole); Mass (EI, 70 eV): m/e 389 [Mþ] (10%), 332, 301, 233, 207, 194,
179, 153, 139 (base peak, 100%), 11175, 50, 41; Anal. Calcd. for C22H16
ClN3O2. 1/5H2O (392.69): C, 67.16; H, 4.20; N, 10.68. Found: C, 66.94;
H, 4.08; N, 10.68.
methanol/petroleum ether, IR (
n
cmꢀ1, ATR): 1742 (C]O), 1606 (C]
N), 1247 (CeO); 1H NMR (DMSO-d6, 300 MHz):
d
6.09 (s, 2H, eCH2e
N), 6.97e8.43 (m, 18H, naphthalene, benzene protons and imidazole
H4,5), 9.08 (s, 1H, imidazole H2); Mass (API-ES): m/e 431 (Mþ, % 100);
Anal. Calcd. for C28H22ClN3O2. 3/2H2O (494.15): C, 67.94; H, 5.09; N,
8.49. Found: C, 67.55; H, 4.97; N, 9.02.
4.1.1.17. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(4-chloroben-
zoyl)oxime (17). Compound was purified by column chromatog-
4.2. Anticonvulsant activity
raphy and then recrystallized from ethanol. IR (
n
cmꢀ1, KBr): 1750
(C]O), 1590 (C]N), 1258 (CeO); 1H NMR (DMSO-d6):
d
6.11 (s; 2H;
The present study was approved by the Ethics Committee of
Hacettepe University, (Date: 27/12/2006, Number: 2006/72-2) and
the Ethics Committee of Inonu University, School of Medicine
(Date: 24/05/2010, Number: 2010/31).
eCH2eN), 7.55e9.27 (m; 14H; naphthalene, benzene and imid-
azole); Mass (EI, 70 eV): m/e 389 [Mþ] (15%), 301, 233, 206, 194, 179,
166, 153, 139 (base peak, 100%), 126, 111, 75, 50, 41; Anal. Calcd. for
C
22H16 ClN3O2.1/10H2O (391.63): C, 67.47; H, 4.17; N,10.73. Found: C,
The compounds were tested for anticonvulsant activity
according to the phase I tests of ASP (Antiepileptic Drug Screening
Programme) which were developed by National Institutes of Health
(NIH), National Institute of Neurological Disorders and Stroke
(NINDS) [23,24].
67.14; H, 4.18; N, 10.74.
4.1.1.18. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(2-methoxyben-
zoyl)oxime (18). Compound was recrystallized from acetone. IR (
cmꢀ1, KBr): 1742 (C]O), 1601 (C]N), 1290 (CeO); 1H NMR (DMSO-
d6): 3.89 (s; 3H; OeCH3), 5.64 (s; 2H; eCH2eN), 7.03e8.26 (m;
14H; naphthalene, benzene and imidazole); Mass (EI, 70 eV): m/e
385 [Mþ] (18%), 332, 301, 233, 206, 180, 153, 135 (base peak, 100%),
105, 77, 51, 41; Anal. Calcd. for C23H19N3O3 (385.42): C, 71.67; H, 4.97;
N, 10.90. Found: C, 71.42; H, 4.74; N, 10.86.
n
Stimulator (Grass S88, Astro-Med., Grass Instrument Division,
W. Warwick, RI, USA), constant current unit (Grass CCU1A, Grass
Medical Instrument, Quincy, MA, USA), and corneal electrodes were
used for the evaluation of anticonvulsant activity. Suspension of the
compounds in 30% aqueous of PEG 400 were administered intra-
peritoneally at three dose levels (30,100 and 300 mg/kg) 30 min
and 4 h after the administration. Twelve Swiss albino mice (20e
24 g) were used for each compound (in other words 4 mice at
each dose level or 6 mice for MES test and 6 mice for ScM test)
(mice were obtained from the Hacettepe University Animal Farm
and Laboratory Animals Research Center of Inonu University).
Phase I evaluation was designed to identify anticonvulsant activity
and neurotoxicity with three tests: MES, ScM, and rotorod. Penty-
lenetetrazole was supplied by Sigma Chemical Co. and was
administered subcutaneously over the back of the neck. The
rotorod toxicity test was performed for neurological deficits.
d
4.1.1.19. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(3-methoxyben-
zoyl)oxime (19). Compound was recrystallized from ethanol/water
and acetone. IR (
n
cmꢀ1, KBr): 1752 (C]O), 1599 (C]N), 1267 (CeO);
1H NMR (DMSO-d6):
d
3.87 (s; 3H; OeCH3), 5.80 (s; 2H; eCH2eN),
6.78e8.45 (m; 14H; naphthalene, benzene and imidazole); Mass
(EI, 70 eV): m/e 385 [Mþ] (4%), 332, 301, 273, 233, 206, 194, 152 (base
peak, 100%), 135, 107, 92, 77, 68, 53, 41; Anal. Calcd. for C23H19N3O3
(385.42): C, 71.67; H, 4.97; N,10.90. Found: C, 71.31; H, 4.98; N,10.65.
4.1.1.20. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(4-methoxyben-
zoyl)oxime (20). Compound was recrystallized from ethanol/water.
4.2.1. Maximal electroshock seizure (MES) test
IR (n
cmꢀ1, KBr): 1731 (C]O), 1604 (C]N), 1253 (CeO); 1H NMR
MES seizures were elicited with a 60 Hz alternating current of
50 mA intensity delivered for 0.2 s via corneal electrodes. A drop of
0.9% saline was instilled in the eyes prior to the application of the
electrodes in order to prevent the death of the animal. Abolition of
the hind limb tonic extension component of the seizure was
defined as protection.
(DMSO-d6):
d
3.90 (s; 3H; OeCH3), 5.53 (s; 2H; eCH2eN), 6.98e8.16
(m; 14H; naphthalene, benzene and imidazole); Mass (EI, 70 eV): m/
e 385 [Mþ] (18%), 301, 273, 233, 206, 179, 153, 154, 135 (base peak,
100%), 107, 77, 53, 41; Anal. Calcd. for C23H19N3O3 (385.42): C, 71.67;
H, 4.97; N, 10.90. Found: C, 71.31; H, 5.06; N, 10.86.
4.1.1.21. 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone O-(4-nitrobenzoyl)
4.2.2. Subcutaneous pentylenetetrazole (metrazol) (ScM) test
Pentylenetetrazole (85 mg/kg) (which produces seizures in
greater than 95% of mice) was administered as a 0.5% solution
subcutaneously. The animals were observed for 30 min, failure to
oxime (21). Compound was recrystallized from ethanol/water and
acetone. IR (
NMR (DMSO-d6):
n
cmꢀ1, KBr): 1749 (C]O), 1652 (C]N), 1280 (CeO); 1H
d
6.15 (s; 2H; eCH2eN), 7.30e9.50 (m; 14H;

282
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4.2.3. Neurotoxicity test
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three trials. In rats, neurological deficit is indicated by ataxia and
loss of placing response and muscle tone.
Acknowledgments
This project was supported by Hacettepe University Scientific
Research Fund, (Project no: 06 D03 301 001), TUBITAK, (Project no:
110S270) and Inonu University Scientific Researches Unit (Project
no: 2011/66).
We thank Suat Sarı for his help editing English of the
manuscript.
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