Synthesis, anticonvulsant and antimicrobial activities of some new 2-acetylnaphthalene derivatives

Article abstract of DOI:10.1016/j.bmc.2010.03.010

In this study, as a continuation of our research for new (arylalkyl)imidazole anticonvulsant compounds, the design, synthesis and anticonvulsant/antimicrobial activity evaluation of a series of 2-acetylnaphthalene derivatives have been described. Molecular design of the compounds has been based on the modification of nafimidone [1-(2-naphthyl)-2-(imidazol-1-yl)ethanone], which is a representative of the (arylalkyl)imidazole anticonvulsant compounds as well as its active metabolite, nafimidone alcohol (3, 4). In general, these compounds were variously substituted at the alkyl chain between naphthalene and imidazole rings and subjected to some other modifications to evaluate additional structure-activity relationships. The anticonvulsant activity profile of those compounds was determined by maximal electroshock seizure (MES) and subcutaneous metrazol (scM) seizure tests, whereas their neurotoxicity was examined using rotarod test. All the ester derivatives of nafimidone alcohol (5a-h), which were designed as prodrugs, showed anticonvulsant activity against MES-induced seizure model. Four of the most active compounds were chosen for further anticonvulsant evaluations. Quantification of anticonvulsant protection was calculated via the ip route (ED₅₀ and TD₅₀) for the most active candidate (5d). Observed protection in the MES model was 38.46 mg kg^-1 and 123.83 mg kg^-1 in mice and 20.44 mg kg^-1, 56.36 mg kg^-1 in rats, respectively. Most of the compounds with imidazole ring also showed antibacterial and/or antifungal activities to a certain extent in addition to their anticonvulsant activity.

Full text of DOI:10.1016/j.bmc.2010.03.010

Bioorganic & Medicinal Chemistry 18 (2010) 2902–2911
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, anticonvulsant and antimicrobial activities of some new
2-acetylnaphthalene derivatives
b
c
d
a
Arzu Karakurt a, , Meral Özalp , Sßamil Isßık , James P. Stables , Sevim Dalkara
*
a Pharmaceutical Chemistry Department, Faculty of Pharmacy, Hacettepe University, 06100 Sihhiye Ankara, Turkey
b Pharmaceutical Microbiology Department, Faculty of Pharmacy, Hacettepe University, 06100 Sihhiye Ankara, Turkey
c Physics Department, Faculty of Art and Sciences, Ondokuz Mayıs University, 55139 Kurupelit Samsun, Turkey
d National Institute of Neurological Disorders and Stroke, Anticonvulsant Screening Program, Rockville, MD 20852, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, as a continuation of our research for new (arylalkyl)imidazole anticonvulsant compounds,
the design, synthesis and anticonvulsant/antimicrobial activity evaluation of a series of 2-acetylnaphtha-
lene derivatives have been described. Molecular design of the compounds has been based on the modi-
fication of nafimidone [1-(2-naphthyl)-2-(imidazol-1-yl)ethanone], which is a representative of the
(arylalkyl)imidazole anticonvulsant compounds as well as its active metabolite, nafimidone alcohol (3,
4). In general, these compounds were variously substituted at the alkyl chain between naphthalene
and imidazole rings and subjected to some other modifications to evaluate additional structure–activity
relationships. The anticonvulsant activity profile of those compounds was determined by maximal elec-
troshock seizure (MES) and subcutaneous metrazol (scM) seizure tests, whereas their neurotoxicity was
examined using rotarod test. All the ester derivatives of nafimidone alcohol (5a–h), which were designed
as prodrugs, showed anticonvulsant activity against MES-induced seizure model. Four of the most active
compounds were chosen for further anticonvulsant evaluations. Quantification of anticonvulsant protec-
tion was calculated via the ip route (ED50 and TD50) for the most active candidate (5d). Observed protec-
tion in the MES model was 38.46 mg kgꢀ1 and 123.83 mg kgꢀ1 in mice and 20.44 mg kgꢀ1, 56.36 mg kgꢀ1
in rats, respectively. Most of the compounds with imidazole ring also showed antibacterial and/or anti-
fungal activities to a certain extent in addition to their anticonvulsant activity.
Received 16 September 2009
Revised 25 February 2010
Accepted 4 March 2010
Available online 9 March 2010
Keywords:
2-Acetylnaphthalene
(Arylalkyl)imidazole
Antimicrobial activity
Anticonvulsant activity
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
ease process, it must also be noted that treatments, even achieving
seizure control, are less than optimal in terms of both dose-related
Epilepsy is a disease that affects more than 50 million people
worldwide, and the cost of treatment and lost productivity to soci-
ety is also staggering. So new and better treatments are desper-
ately needed. Many of the older generation of antiepileptic drugs
were approved before 1985 (i.e., phenytoin, phenobarbital, carb-
amazepin). Each of the newer generation anticonvulsants (leveti-
racetam, lamotrigine, felbamate, gabapentin, etc.) has certain
advantages that have resulted in increased treatment options for
clinicians and patients. Although some of the newer drugs were
purported to have decreased side effects and/or fewer drug–drug
interactions, nearly 30–40% of patients remain uncontrolled or suf-
fer breakthrough seizures. While recognizing that the last three
decades have brought significant advances in our understanding
of seizure propagation and associated pathophysiology of the dis-
side effects and breakthrough seizures. For many patients, seizure
control is only achieved at a very high price. Therefore, it is critical
to continue efforts to find safer and more efficacious drugs and
ultimately a treatment for this devastating disease.1,2
Many of the newer antiepileptic drugs (post 1990) as well as
those currently in clinical development were designed through
structural modifications of pre-existing compounds; others were
developed with a specific aim to modify neurotransmitter function
such as enhancement of inhibitory-mediated neurotransmission or
attenuation of excitatory-mediated neurotransmission.3 Most suc-
cessful anticonvulsants possess more than one mechanism of ac-
tion. Having multiple mechanisms or being ‘pharmacologically
rich’ is a characteristic of many AEDs and can be viewed as both
a treatment advantage and a disadvantage for patients and their
clinicians. The disadvantages include increased potential for side
effects and metabolic drug–drug interactions. Some of the advan-
tages can be seen in the form of broad spectrum of actions. Thus,
several AEDs can be useful in different syndromes and even other
neurological disorders such as neuropathic pain, migraine and
bipolar disorder. In general the most common mechanisms
* Corresponding author at present address: Pharmaceutical Chemistry Depart-
ment, Faculty of Pharmacy, Inonu University, 44280 Malatya, Turkey. Tel.: +90 422
341 06 60/1818; fax: +90 422 341 12 17.
E-mail addresses: akarakurt@inonu.edu.tr (A. Karakurt), arzukarakurt@hotmail.
com (A. Karakurt).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.03.010

A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
2903
involved in seizure control can be attributed to a drug’s action on
ion channels (sodium, potassium), neuronal excitation, and inhibi-
tion actions.
ity. Among these compounds, GABA (5f) and valproic acid (5e) es-
ters were also the hybrid molecules of nafimidone alcohol (4) and
these two acids. Recently it has been shown that coupling of val-
proic acid with some aromatic amino alkanes and cyclic alkyl ana-
logs improves the pharmacological profile.15,16 Therefore, valproic,
valeric, isovaleric acid and GABA esters (7a–d) of 1-(naphthalene-
2-yl)ethanol (6) without an imidazole ring were prepared by con-
sidering the naphthalene ring as a carrier to target the brain. The
Schiff base of 2-acetylnaphthalene with GABA was also designed
as another CNS-targeted molecule resembling progabid. Since the
neurotoxicity is the main problem of nafimidone derivatives, we
synthesized 1-hydroxynaphthalene derivatives of nafimidone 11
and its reduction product 12 to decrease neurotoxicity via decreas-
ing the lipophilicity by adding a polar hydroxyl group to the mol-
ecule (Table 1).
GABA is the most common inhibitory neurotransmitter in the
central nervous system. Drugs like progabid, gabapentin and viga-
batrin were specifically designed as GABA prodrugs or lipophilic
GABA analogs.4 Valproic acid, which has a different chemical struc-
ture from classical antiepileptic drugs, was developed as a GABA
agonist, but later it was shown that it can also increase GABA levels
in different ways.5 Numerous studies are reported in the literature
about valeric, isovaleric, and especially valproic acid esters as poten-
tial anticonvulsant agents.6,7 Loreclazole, one of the (arylalkyl)azole
anticonvulsant compounds with broad activity spectrum, has a
modulating action on GABAA.8 Nafimidone and denzimol are the
other examples of (arylalkyl)azoles, which possess a profile of activ-
ity similar to that of phenytoin or carbamazepine but distinct from
barbiturates or valproic acid.9,10 Nafimidone alcohol, the major
metabolite of nafimidone, also has high anticonvulsant activity
(Fig. 1).11 SAR studies of (arylalkyl)azole anticonvulsant compounds
have shown that anticonvulsant properties of this group are associ-
ated with the presence of a small oxygen functional group (such as
carbonyl, ethylene dioxy, methoxy, acyloxy, hydroxyl and oxime
ether substituents) in the alkylene bridge in addition to imidazole
ring and lipophilic aryl portion facilitating penetration through
blood–brain barrier.9,10,12,13
In addition to their anticonvulsant activity, many from the
chemical class represented by the (arylalkyl)azole compounds
show antifungal and/or antibacterial activities largely because of
their structural similarities to 1-substituted-1H-azole antifungals,
which have an important place among the other antifungal groups.
Azole antifungals generally possess an imidazole or triazole ring
(seen with miconazole, ketoconazole, fluconazole and itraconaz-
ole) as an azole group.13,14
In this study, in the light of available literature and as a contin-
uation of our previous studies on nafimidone derived (arylal-
kyl)azole compounds, we aimed to synthesize some new
acetylnaphthalene derivatives as potential anticonvulsant com-
pounds and then to evaluate their anticonvulsant and antimicro-
bial activities in an effort to find more active and less toxic
treatment candidates. In the process, we sought to explore poten-
tial new relationships between the structure and the activities of
this major group. To this end, we prepared some carboxylic acid es-
ters of nafimidone alcohol (5a–h) as prodrugs. These esters were
designed with various alkyl or aryl groups in order to establish
the effects of the size and branching of the alkyl chain on the activ-
2. Results and discussion
2.1. Chemistry
The total synthesis of the compounds is given in Scheme 1.
Nafimidone 3 was obtained by the alkylation of imidazole with
a
-bromo-2-acetylnaphthalene 2.9,15 Reduction of 3 with sodium
borohydride produced nafimidone alcohol 4. Ester derivatives
5a–h were prepared by esterification of the alcohol 4 with acid
anhydride (method A), acyl chloride (method B), carboxylic acid
and dicyclohexilcarbodiimide/4-dimethylaminopyridine (DCC/
DMAP) (method C) or pyridine/DMAP (method D). Reduction of 2-
acetylnaphthalene 1 with sodium borohydride produced alcohol 6
which reacted with carboxylic acid and DCC/DMAP to have esters
7a–d. t-Boc-GABAwas prepared using GABA and di-tert-butyl carba-
mate to synthesize compounds 5f and 7d (Scheme 1).
Synthesis of compounds 11 and 12, which are the 1-hydroxy-
naphthalene analogous of nafimidone 3 and nafimidone alcohol 4,
respectively, was started by using 1-hydroxy-2-acetylnaphthalene
8. To obtain 2-bromo-1-(1-acetyloxynaphthalene-2-yl)ethanone 9,
1-hydroxy-2-acetylnaphthalene 8 was acetylated by acetic anhy-
dride before bromination to protect the hydroxyl group. N-Alkyl-
ation of imidazole with 10 produced 11 and its reduction with
sodium borohydride yielded 12. Deprotection of acetyl group of 10
was realized during N-alkylation reaction due to excess basic imid-
azole. Imine derivative 13 was obtained through Schiff reaction be-
tween the ketone group of 1-hydroxy-2-acetylnaphthalene and
amino group of GABA sodium salt prepared from the reaction of
GABA and sodium ethoxide (Scheme 1).
OH
O
N
F
NH2
O
O
OH
H2N
H2N
OH
O
OH
H2N
O
OH
Cl
GABA
Progabid
Gabapentin
Vigabatrin
Valproic acid
OH
O
Cl
OH
N
N
N
N
N
N
N
N
N
Cl
Cl
Loreclazole
Nafimidone
Denzimol
Nafimidone alcohol
Figure 1. Chemical structure of the compounds.

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A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
Table 1
The structures, crystallization solvents, synthesis methods, yields, melting points and c log P values of the compounds
Compd
R
Crystallization solvent
Method
Yield (%)
Mp (°C)
c log P
O
CO R
CH
CH2
N
. HCl
N
5a
5b
5c
5d
5e
5f
–CH2CH2CH3
–CH(CH3)2
–CH2(CH2)2CH3
–CH2CH(CH3)2
–CH(C3H7)2
Ethyl acetate/petroleum ether
Ethyl acetate
Methanol/ethyl acetate
Methanol/ethyl acetate
Methanol/ethyl acetate
Ethyl acetate
A
B
C
C
C
C
49
57
71
80
75
68
155–156
165–167
133–134
135–137
181–183
130–131
3.80
3.58
4.33
4.20
5.70
4.26
–(CH2)3–NH–COOC(CH3)3
5g
5h
Methanol/ethyl acetate
C
65
58
215–217
179–181
4.59
5.30
Ethyl acetate/petroleum ether
D
Cl
O
CO R
CH3
CH
7aa
7ba
7ca
7d
–CH2(CH2)2CH3
–CH2CH(CH3)2
–CH(C3H7)2
—
—
—
C
C
C
C
82
88
85
79
205 (bp)
208 (bp)
223 (bp)
80–82
5.03
4.90
6.40
4.96
–(CH2)3–NH–COOC(CH3)3
Methanol/water
OH
O
C
11
12
Methanol/ethyl acetate
E
F
38
98
79
250–252
220 (dec.)
171–172
2.55
1.19
2.76
CH2
N
. HCl
. HCl
N
OH OH
CH
Chloroform/petroleum ether
Chloroform/petroleum ether
CH2
N
N
N
C
(CH2)3COOH
OH
13
G
CH3
a
Liquid compounds.
The physical properties of the synthesized compounds are pre-
2.2. Anticonvulsant activity
sented in Table 1. The structure of the compounds was confirmed
by IR, 1H NMR, mass spectral data and elemental analysis has been
provided in Section 4.
Anticonvulsant activity and neurotoxicity screening test results
(MES, scM and rotarod) are summarized in Table 5. None of the
compounds are found to be active against scM test. According to
these screening results (Table 5), it can be concluded that anticon-
vulsant activities of these compounds are MES specific. This result
is in accordance with the findings obtained from other (arylal-
kyl)azole derivatives.9,10,13,14
All the ester derivatives with imidazole ring 5a–h, which were
designed as prodrugs of nafimidone alcohol 4, showed anti-MES
activity at either 30 or 100 mg kgꢀ1 at 0.5 h except 5h which is ac-
tive only at 300 mg kgꢀ1. These compounds are more active at the
0.5th h than at the 4th h, indicating that they have a rapid onset of
action; they also display toxicity at 0.5 h at 300 mg kgꢀ1. Therefore,
although they were designed as prodrugs, they probably do not act
as prodrugs or they are metabolized very fast. The size and branch-
ing of the ‘R’ group in the active ester derivatives 5a–h did not ap-
pear to have an important role in the activity but p-chlorophenyl
ester derivative 5h was the least active one with activity only at
300 mg/kg. This decreased activity is most probably caused by ste-
ric hindrance of chloro substituent rather than lipophilicity
because the compound 5h (c log P: 5.30) is more lipophilic than
phenyl ester derivative 5g (c log P: 4.59).
2.1.1. X-ray analysis of compound 11
Since the activity of compounds 11 and 12, which are the 1-
hydroxynaphthalene derivatives of nafimidone 3 and its active
metabolite nafimidone alcohol 4 were surprisingly found very low
or even inactive compared to nafimidone and nafimidone alcohol,
we decided to evaluate the three-dimensional structure of
compound 11 by X-ray crystallography to determine whether the
H-bond between 1-hydroxyl and carbonyl group exists and blocks
the carbonyl oxygen, which is probably important for receptor
interaction.
The X-ray crystallographic data of compound 11 demonstrated
that there is an intramolecular hydrogen bond between carbonyl
and the hydroxyl group on the naphthalene ring (C@Oꢁ ꢁ ꢁH–O). A
weak intermolecular hydrogen bond between hydroxyl and imid-
azole H4 (C–Hꢁ ꢁ ꢁO–H) was also observed via X-ray crystallographic
study.
The crystal data and a summary of intensity data collections
and structural refinements, bond lengths, bond angles and torsion
angles are given in the tables below (Tables 2–4).

A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
2905
O
R
O
C
R'
R
OH
CH
CH
R'COOH
CH3
CH3
DCC/DMAP
R= -H (Compound 7a-d)
R= -H (6)
NaBH4
R
O
C
R
OH
CH
R
O
C
HN
R
O
C
R
O
C
NaBH4
Br2
(CH3CO)2O
N
CH2
N
CH2
N
CH2 Br
CH3
CH3
N
N
R= -H (1)
R= -OCOCH3 (9)
R= -H (2)
R= -H (Nafimidone 3)
R=-OH (Compound 11)
R= -H (Nafimidone alcohol 4)
R=-OH (Compound 12)
R= -OH (8)
R= -OCOCH3 (10)
(Method E)
(Method F)
GABA
C2H5ONa
(Method G)
O
C
R
O
C3H7
R
NCH2CH2CH2COOH
CH
(C3H7CO)2O
C
CH2
N
(Method A)
CH3
N
R= -H (Compound 5a)
R= -OH (Compound 13)
O
R
O
C
CH(CH3)2
CH
(CH3)2CHCOCl
(Method B)
CH2
N
R
OH
CH
N
R= -H (Compound 5b)
CH2
N
O
N
R
O
C
R'
R= -H (Nafimidone alcohol 4)
DCC/DMAP
R'COOH,
CH
CH2
N
(Method C)
N
R= -H (Compound 5c-g)
O
R
O
C
Cl
CH
prydine/DMAP
p-ClPhCOOH,
CH2
N
(Method D)
N
R= -H (Compound 5h)
Scheme 1. Synthesis of the compounds.
the activity. For example, the absence of the imidazole ring
brings about the lack of the activity in compounds 7a–d and
13 with very high log P values (c log P: 2.76–6.40). The valproic
acid ester 5e, which was designed also as a hybrid molecule,
did not provide an advantage in the activity compared to the
other esters probably because the dose used was not high en-
ough to provide effective dose of valproic acid (MES ED50 in mice
ip: 263 mg kgꢀ1).17
Table 2
Hydrogen bonding geometry (Å, °)
Donor–Hꢁ ꢁ ꢁacceptor [Symmetry code] D–H Hꢁ ꢁ ꢁA Dꢁ ꢁ ꢁA
D–Hꢁ ꢁ ꢁA
2.573(3) 147
3.398(4) 152
3.242(4) 134
3.503(4) 133
3.599(3) 150
O(2)–H(7O)ꢁ ꢁ ꢁO
C(1)–H(1)ꢁ ꢁ ꢁCl
C(2)–H(2)ꢁ ꢁ ꢁO
C(3)–H(3)ꢁ ꢁ ꢁCl
C(4)–H(4B)ꢁ ꢁ ꢁCl
[Intra]
0.82 1.85
0.93 2.55
0.93 2.53
0.93 2.80
0.97 2.72
[7545.02]
[6545.01]
[4655.02]
[1655.02]
On the other hand, ester derivatives without imidazole ring
7a–d and Schiff base derivative 13, which were designed as brain
targeted molecules of valproic, valeric, isovaleric acids and GABA,
did not show any significant efficacy or toxicity in the MES and
ScM models at the times and doses used in these assays (neither
anticonvulsant activity nor neurotoxicity) probably because of
the high effective dose level of these acids and also metabolic
decomposition (hydrolysis or reduction) problems of ester and
azomethine (C@N) groups.
Although the nafimidone dose providing anti-MES activity in
mice is 15 mg kgꢀ1 ip, compound 11, which has only an extra hy-
droxyl group on the naphthalene ring compared to nafimidone,
has activity at 300 mg kgꢀ1 and unfortunately shows neurotoxicity
at the same dose level as well.9 Lipophilicity is not the cause of the
drop in the activity since c log P is 2.55 for compound 13 and 2.22
for nafimidone. Therefore, it may be speculated that this is proba-
bly because of the hydrogen bond between hydroxyl on the naph-
thalene ring and carbonyl group, which is also important for the
receptor interaction (Fig. 2). Moreover, differences in some other
Symmetry code:
[7545.] = 1/2 ꢀ x, ꢀ1/2 + y, z.
[6545.] = 1/2 + x, ꢀ1/2 + y, 1/2 ꢀ z.
[4655.] = 1 ꢀ x, y, 1/2 ꢀ z.
[1655.] = 1 + x, y, z.
Since the lipophilicity (log P >2) is crucial for CNS drugs to pass
BBB, c log P values of the compounds were calculated by
ChemDraw Ultra 8.0. The predicted c log P values of these ester
derivatives 5a–h were in the range of 3.58–5.70 which are much
higher than 2. But an increase in the lipophilicity from isopropyl
ester derivative 5b (c log P: 3.58) to valproyl ester derivative 5e
(c log P: 5.70) did not result in an increase in the activity. Because
an increase in lipophilicity does not result in an increased activity
after a point and, sometimes even an activity drop or loss may be
seen depending on the optimal log P value.
Although it is well known that high log P values are impor-
tant for BBB passage, lipophilicity is not the only parameter for
the activity and some other properties are also responsible from

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A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
Table 3
Geometric parameters (Å, °, °)
Bond length (Å)
Bond angle (°)
Torsion angle (°)
N2–C1
N2–C3
N2–C4
O1–C5
C6–C11
C6–C7
1.337(4)
1.371(4)
1.451(3)
1.235(4)
1.393(4)
1.417(4)
1.445(4)
1.317(4)
1.374(4)
1.357(3)
1.522(4)
1.411(4)
1.417(4)
1.419(4)
1.368(4)
1.399(5)
1.354(4)
1.346(4)
1.419(4)
1.341(5)
1.395(4)
C1–N2–C3
C1–N2–C4
C3–N2–C4
C11–C6–C7
C11–C6–C5
C7–C6–C5
C1–N1–C2
N2–C4–C5
C12–C10–C9
C12–C10–C11
C9–C10–C11
C14–C15–C9
O2–C11–C6
O2–C11–C10
C6–C11–C10
N1–C1– N2
C13–C12–C10
C8–C7–C6
C15–C9–C10
C15–C9–C8
C10–C9–C8
O1–C5–C6
O1–C5–C4
C6–C5–C4
106.9(3)
127.1(3)
125.9(3)
117.7(3)
120.1(3)
122.2(3)
106.5(3)
112.2(3)
119.6(3)
122.8(3)
117.6(3)
120.2(4)
121.3(3)
116.2(3)
122.5(3)
110.8(3)
119.5(3)
121.6(3)
118.9(3)
121.7(4)
119.4(3)
123.6(3)
118.4(3)
118.0(3)
107.2(3)
121.2(3)
108.6(3)
121.3(3)
120.4(4)
C1–N2–C4–C5
C3–N2–C4–C5
C7–C6–C11–O2
C5–C6–C11–O2
C7–C6–C11–C10
C5–C6–C11–C10
C12–C10–C11–O2
C9–C10–C11–O2
C12–C10–C11–C6
C9–C10–C11–C6
C2–N1–C1–N2
C3–N2–C1–N1
C4–N2–C1–N1
C9–C10–C12–C13
C11–C10–C12–C13
C11–C6–C7–C8
C5–C6–C7–C8
C14–C15–C9–C10
C14–C15–C9–C8
C12–C10–C9–C15
C11–C10–C9–C15
C12–C10–C9–C8
C11–C10–C9–C8
C11–C6–C5–O1
C7–C6–C5–O1
91.2(4)
ꢀ84.5(4)
ꢀ179.3(3)
0.9(4)
ꢀ0.2(4)
ꢀ180.0(3)
0.8(4)
179.5(3)
ꢀ178.4(3)
0.3(4)
C6–C5
N1–C1
N1–C2
O2–C11
C4–C5
C10–C12
C10–C9
C10–C11
C15–C14
C15–C9
C12–C13
C7–C8
0.6(4)
ꢀ0.8(4)
ꢀ177.1(3)
ꢀ0.2(4)
178.6(3)
ꢀ0.1(5)
179.7(3)
0.9(5)
ꢀ178.4(3)
ꢀ0.7(4)
ꢀ179.5(3)
178.6(3)
ꢀ0.2(4)
ꢀ2.9(5)
177.3(3)
176.6(3)
ꢀ3.2(5)
ꢀ1.3(5)
179.2(3)
0.6(4)
C9–C8
C3–C2
C13–C14
C2–C3–N2
C7–C8–C9
C3–C2–N1
C12–C13–C14
C15–C14–C13
C11–C6–C5–C4
C7–C6–C5–C4
N2–C4–C5–O1
N2–C4–C5–C6
C1–N2–C3–C2
C4–N2–C3–C2
C6–C7–C8–C9
177.0(3)
0.2(5)
C15–C9–C8–C7
C10–C9–C8–C7
N2–C3–C2–N1
C1–N1–C2–C3
C10–C12–C13–C14
C9–C15–C14–C13
C12–C13–C14–C15
179.2(3)
0.0(5)
ꢀ0.2(4)
ꢀ0.3(4)
1.0(5)
ꢀ0.1(5)
ꢀ0.8(5)
properties of compound 13 compared to nafimidone may also play
a role in the activity loss.
anticonvulsant data in mice for compound 5d were found to be
MES ED50 38.46 mg kgꢀ1, ScM ED50 >138 mg kgꢀ1 and MES TD50
123.83 mg kgꢀ1; therefore, therapeutic index (TI) of this compound
is 3.22 (ip). In the rat model (ip), MES ED50, TD50 and TI values were
20.44 mg kgꢀ1, 56.36 mg kgꢀ1 and 2.76, respectively (Table 9).
This compound was also tested in the hippocampal kindled rat
model at a dose of 300 mg kgꢀ1 (ip); but it did not have any appar-
ent activity in this model in the single animal tested.
No activity (neither anticonvulsant nor neurotoxicity) was ob-
served in compound 12, which is the reduction product of com-
pound 11 (1-hydroxynaphthalene analog of nafimidone), mainly
due to its very low log P value (c log P: 1.19), which is not enough
to pass BBB and, less likely due to the hydrogen bond between both
hydroxyl groups on the naphthalene ring and alkyl chain (nafimi-
done alcohol anti-MES ED50: 34 mg kgꢀ1, TD50: 89 mg kgꢀ1 and
c log P: 1.91).9 Finally, the results obtained from the screening tests
have revealed that anticonvulsant activity mainly depends on the
existence of azole ring and the ester group on the alkyl chain.
Among these potent ester derivatives with imidazole ring, four
compounds 5b, 5d, 5e and 5g were selected for evaluation of their
oral anti-MES activity and neurotoxicity in rats at several time
points (Table 6). The compounds were dosed at 30 mg kgꢀ1. At this
dose level, none of the candidates exhibited neurotoxicity. The
activity spectrum of compound 5d was non-linear probably be-
cause of poor oral absorption.
2.3. Antifungal and antibacterial activities
Antifungal and antibacterial activities of the compounds with
imidazole ring were evaluated since the structure of these com-
pounds resembles azole antifungals. The antimicrobial activity test
results of these compounds are given in Table 10.
Most of the compounds (5a–h, 11) were found to be active
against Gr (+) bacteria especially Staphylococcus aureus at 8–
64
lg/ml concentration. Compounds 5c–e and 5g were also found
to be active against Enterococcus faecalis at 16–64
l
g/ml concentra-
Anti-MES activity and neurotoxicity of compounds 5d and 5e
were also evaluated intraperitoneally in rats at 30 mg kgꢀ1 (Table
7). Both of these compounds were found to be active at this dose
level and no toxicity was observed at any of the time points used.
Compound 5d was selected for quantification of its pharmaco-
logical parameters (Tables 8 and 9). Time to peak effect (TPE) test
results in mice and rats dosed ip with compound 5d are presented
in Table 8. According to the ED50 biological response data in mice
and rats dosed ip with compound 5d at TPE (0.5 h), quantitative
tion. All of the compounds were found to be inactive against Gr (ꢀ)
bacteria.
Compounds 5a–d were active against Candida albicans at 8–
64
showed antifungal activity against Candida parapsilosis. Only com-
pound 11 was active against Candida krusei at 64 g/ml concentra-
lg/ml concentration. Some of the compounds (5a, 5d and 11)
l
tion. Surprisingly, chloro substituted benzyl derivative 5h was
found to be inactive against fungi, while alkyl derivatives 5a–d
were active.

A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
2907
Table 4
advantage in the activity compared to nafimidone alcohol since
ED50 of nafimidone alcohol (34 mg kgꢀ1) is lower than that of ester
derivatives. In this group, not only lipophilicity but also the pres-
ence of imidazole ring is essential for the anti-MES activity. A hy-
Crystal data and details of the structure determination of compound 11
Formula
C15H13ClN2O2
288.72
Orthorhombic
Pbcn
Molecular weight
Crystal system
Space group
droxyl group at
a-position of the naphthalene ring caused loss in
the activity probably because of the hydrogen bond with carbonyl
(in nafimidone) or hydroxyl group (in nafimidone alcohol) on the
alkyl chain as well as the reduction in the lipophilicity. Anticonvul-
sant activities of these compounds appear to be MES selective.
Some of the ester derivatives were selected for further investiga-
tions in addition to the screening tests; according to these results,
compound 5d (isovaleric acid ester of nafimidone alcohol) was
selected for quantification of its pharmacological parameters and
the findings were as follows: MES ED50 38.46 mg kgꢀ1, TD50
123.83 mg kgꢀ1 and TI 3.22 in mice (ip).
a (Å), b (Å), c(Å)
10.742(1), 11.542(1), 22.075(2) 22.075(2)
a
(°), b (°),
c
(°)
90, 90, 90
2737.0(5)
8
1.369
1192
Volume (Å3)
Z
D (calculated) (g cmꢀ3
F 0 0 0
)
Linear absorption
0.281
coefficient (mmꢀ1
)
Absorption correction type
Crystal size (mm)
Diffractions radiation type
k (Å)
Integration (X-RED32)
0.580 ꢂ 0.343 ꢂ 0.110
MoK
a
0.71073
Concerning the antifungal and antibacterial activities of the
compounds with imidazole ring, it can be concluded that these
compounds were more active against Gr (+) bacteria than Gr (ꢀ)
bacteria and some of the ester derivatives also showed antifungal
activities to some extent especially against C. albicans.
Monochromator
Diffractions measurement
device type
Diffractions measurement device u scans
Total reflection number
Graphite
Stoe IPDS-II (Image Plate)
11521
2258
Independent reflection number
Collected reflection for I > 2
r(I)
979
Rint
0.0492
4. Experimental part
4.1. Chemistry
h, k, l ranges
hmin , hmax range (°)
Solution
Least squares refine
weighting details
Number of variable
R
ꢀ12?12, ꢀ10?13, ꢀ22?25
2.59, 24.54
Direct methods, SHELXS-97, SHELXL-97, WINGX
w = 1/r
2(F)2
All the chemicals used in this study were purchased from E.
Merck, Fluka AG and Aldrich. Purity of all the compounds was
checked by using TLC with Merck Kieselgel 60 F254 aluminum
plates. Column chromatography was performed on Kieselgel 60
(0.040–0.063 mm) (230–400 mesh ASTM) (Merck). Melting points
were determined with a Thomas Hoover capillary melting point
apparatus and were uncorrected. Boiling points were determined
by distillation. IR spectra were recorded on KBr disks with a Bruker
Vector 22 IR (Opus Spectroscopic Software Version 2.0) Spectrome-
ter. 1H NMR spectra were recorded on a Bruker 80 MHz and Bruker
Avance 400 MHz FT NMR spectrometer. All the chemical shifts were
expressed in d (ppm) values. Splitting patterns are designated as fol-
lows: s: singlet; d: doublet; dd: doublet of doublets; t: triplet; q:
quartet; and m: multiplet. Mass spectra were obtained by using
73DIP-1 Direct Insertion Probe and Agilent 5973-network Mass
Selective Detector. Elemental analysis was performed on Leco 982
CHNS elemental analysis apparatus at TUBITAK (Scientific and Tech-
181
0.0397
0.0506
0.701
0.254, ꢀ0.168
wR
S(F2)
D
qmax
,
D
qmin (e/Å3)
3. Conclusion
As a continuation of our interest in developing nafimidone-like
anticonvulsant compounds we designed and synthesized a series
of (arylalkyl)azole derivatives with different functional groups at
the alkyl chain between aryl and azole rings and evaluated their
anticonvulsant, antifungal and antibacterial activities. The results
obtained revealed that most of the ester derivatives with imidazole
ring were found to be active in MES screen. Nafimidone alcohol es-
ters 5a–g, which were designed as its prodrug, did not provide an
Table 5
Anticonvulsant and neurotoxicity screening data in mice dosed ip with the compounds
Tests
Hours
Dose (mg kgꢀ1
)
Compound
5a
5b
5c
5d
5e
5f
5g
5h
7a
7b
7c
7d
11
12
13
MESa
1/2
30
100
300
0/1
3/3
1/1c
1/1
3/3
0/0
1/1
3/3
1/1
0/1
3/3
1/1
0/1
3/3
1/1
0/1
3/3
1/1
0/1
3/3
1/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
MES
4
30
100
300
0/1
0/3
1/1
0/1
1/3
1/1
0/1
1/3
0/0
0/1
1/3
1/1
0/1
1/3
1/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
Toxicityb
Toxicity
1/2
4
30
100
300
0/4
0/4
0/4
0/4
0/4
0/4
1/4e
0/4
0/8
1/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
1/8
0/4
0/4
0/4
0/8
1/4
0/4
1/8
4/4
6/8
1/8
0/8
0/8
0/8
3/8e
3/4d,e
2/8e
0/8
4/4d
4/4d,e,f
4/4d,g
4/4d,g
4/4d,e
4/4c,d,e
2/4d,e
30
100
300
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/2
0/2
0/2
0/4
0/2
0/2
0/4
1/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/4
0/4
0/4
2/2d,f
2/2d,f
2/2d,e
a
b
c
d
e
f
Maximal electroshock test (number of animal protected/number of animal tested).
Toxicity (number of animal exhibiting toxicity/number of animal tested).
Clonic seizures.
Unable to grasp rotarod.
Muscle spasms.
Dead.
g
Hiperactivity.

2908
A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
thalene-2-yl)ethanone 5,19 1-(naphthalene-2-yl)ethanol 69 were
prepared according to the procedures described in relevant
literature.
4.1.1. Preparation of the compounds. 2-(Imidazol-1-yl)-1-
(naphthalene-2-yl)ethanol esters and 1-(naphthalene-2-
yl)ethanol esters (compounds 5a–h, 7a–d)
4.1.1.1. Method A. Appropriate acid anhydride (1 mmol) and 2-
(imidazol-1-yl)-1-(naphthalene-2-yl)ethanol (0.24 g, 1 mmol)
were refluxed for 4 h in dry ether (25 ml). After ether was evapo-
rated, the residue was purified by column chromatography on sil-
ica gel eluting with chloroform/methanol (90:10), dissolved in
ether, and treated with etheral hydrochloric acid crystallized from
the appropriate solvents.
Figure 2. An ORTEPII drawing of compound 11, showing 50% probability displace-
ment ellipsoids and atom-numbering scheme.
4.1.1.2. Method B. Appropriate acid chloride (1 mmol), 2-(imida-
zol-1-yl)-1-(naphthalene-2-yl) ethanol (0.24 g, 1 mmol) and pyri-
dine (4 ml) were stirred at room temperature for 4 h. The
mixture was poured onto ice, extracted with ethyl acetate, and
the solvent was evaporated to dryness. The residue was purified
by column chromatography on silica gel eluting with chloroform/
methanol (90:10), dissolved with ether, and treated with etheral
hydrochloric acid crystallized from the appropriate solvents.
Table 6
Anticonvulsant (anti-MES) and toxicity qualitative screening data in rats dosed orally
with selected compoundsa
Compound
Test
Time in hours
1
0.25
0.5
2
4
5b
5d
5e
5g
MES
TOX
0/4
0/4
1/4
0/4
1/4
0/4
1/4
0/4
1/4
0/4
MES
TOX
0/4
0/4
3/4
0/4
0/4
0/4
0/4
0/4
2/4
0/4
4.1.1.3. Method C20. Appropriate carboxylic acids (2.5 mmol) and
2-(imidazol-1-yl)-1-(naphthalene-2-yl)ethanol (0.60 g, 2.5 mmol)
or 1-(naphthalene-2-yl)ethanol (0.43 g, 2.5 mmol) were stirred in
dry methylene chloride under nitrogen atmosphere at 0 °C. N,N0-
Dicyclohexylcarbodiimide (DCC) (0.52 g, 2.5 mmol) and 4-dimeth-
ylaminopyridine (DMAP) (0.02 g, 0.17 mmol) in dry methylene
chloride were added drop wise to the mixture at 0 °C, and then,
reaction mixture was stirred for 5 min at 0 °C, for 6 h at room tem-
perature. The precipitate was filtered off; the solvent was dried
over anhydrous sodium sulfate and then was evaporated to dry-
ness. The residue was purified by column chromatography on silica
gel eluting with chloroform/methanol (90:10) or chloroform. The
eluent was evaporated under reduced pressure, and then the resi-
due was dissolved in ether and treated with etheral hydrochloric
acid. Precipitated hydrochloric acid salt of the compound was crys-
tallized from the appropriate solvents. Purification of liquid com-
pounds (7a–c) was realized by distillation in vacuo.
MES
TOX
0/4
0/4
0/4
0/4
1/4
0/4
2/4
0/4
0/4
0/4
MES
TOX
1/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
a
At each time point, rats were given a single dose of 30 mg of compound per kg
of body weight.
Table 7
Anticonvulsant (anti-MES) and toxicity qualitative screening data in rats dosed ip
with selected compoundsa
Compound
Test
Time in hours
1
0.25
0.5
2
4
5d
5e
MES
TOX
3/4
0/4
3/4
0/4
3/4
0/4
1/4
0/4
1/4
0/4
MES
TOX
—
—
2/2
0/2
3/4
0/4
3/4
0/4
—
—
4.1.1.4. Method D19. Appropriate acid chloride (1.25 mmol), 2-
(imidazol-1-yl)-1-(naphthalene-2-yl)ethanol (0.29 g, 1 mmol),
pyridine (0.10 g, 1.25 mmol) and DMAP (0.003 g, 0.025 mmol)
were stirred in dichloromethane at room temperature for 4 h.
The mixture was poured onto ice, extracted with chloroform, dried
at sodium sulfate and the solvent was evaporated to dryness. The
residue was purified by column chromatography on silica gel elut-
ing with chloroform/methanol (90:10) after evaporation, dissolved
with ether and treated with etheral hydrochloric acid crystallized
from the appropriate solvents.
a
At each time point, rats were given a single dose of 30 mg of compound per kg
of body weight.
Table 8
Time to peak effect test results in mice and rats dosed ip
Compd
Test Dose (mg/kg) 0.25 h 0.5 h 1 h 2 h 4 h 6 h
5d
Mice MES 23
1/8
—
2/8
2/4
4/4
3/8a
0/8
2/4 0/4
4/4 2/4 0/4
0/8 0/8
—
—
—
ip
MES 35
MES 70
TOX 150
3/4
8/8a,b
—
4.1.2. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl butyrate
Rats MES 30
3/4
0/2
0/2
2/8
—
4/4
0/2
0/2
3/8
8/8
3/4
—
—
hydrochloride (5a)
ip
TOX 10
TOX 30
TOX 50
TOX 75
0/2 0/2 0/2
0/2 0/2 0/2
3/8 0/8 0/8 0/8
6/8
Yield: 49%; mp: 155–6 °C; IR (m
cmꢀ1, KBr): 3150–2550 (N+–H),
3051 (C–H aromatic), 2963 (C–H aliphatic), 1743 (C@O); 1H NMR
(CDCl3, 400 MHz): d 0.90 (t, 3H, CH3), 1.59–1.65 (m, 2H, CH2–
—
—
a
CH3), 2.38 (t, 2H, CH2–C@O), 4.74–4.76 (dd, 1H, CH2–N HA, JAB
14.46 Hz, JAX 7.62 Hz), 4.84–4.89 (dd, 1H, CH2–N HB, JAB
:
:
Unable to grasp rotarod.
Muscle spasms.
b
:
14.37 Hz, JBX: 3.70 Hz), 6.34–6.36 (dd, 1H, CH–O HX, JAX: 7.45 Hz,
JBX: 3.64 Hz), 7.04 (s, 1H, imidazole H4), 7.30 (s, 1H, imidazole
H5), 7.45–7.55 (m, 3H, naphthalene H3, H6, H7), 7.80–7.90 (m, 4H,
naphthalene H1, H4, H5, H8), 9.49 (s, 1H, imidazole H2), 15.96
(1H, s, N+–H); EIMS (70 eV): m/e 308 [M+] (55%), 240, 227, 221,
194, 181, 170, 152, 127, 115, 82 (base peak, 100%), 71, 43 and
nical Research Council of Turkey). 2-Bromo-1-(naphthalene-2-
yl)ethanone 1,18 2-(imidazol-1-yl)-1-(naphthalene-2-yl)ethanone
2,9 2-(imidazol-1-yl)-1-(naphthalene-2-yl)ethanol 3,9 1-(1-acetyl-
oxynaphthalene-2-yl)ethanone 4,19 2-bromo-1-(1-acetyloxy-naph-

A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
2909
Table 9
Anticonvulsant quantification test results-mice and rats ipa
Compd
Test
Time (h)
ED50
95% Confidence interval low
High
Slope
Std. err
Low
5d
Mice
Rats
MES
Toxicity
0.5
0.25
38.46
123.83
25.25
109.85
55.32
133.83
3.97
16.21
1.17
4.88
MES
Toxicity
0.5
0.5
20.44
56.36
16.32
41.57
24.78
64.36
7.23
10.88
2.47
4.27
a
The reference compound was valproic acid and the values were: MES ED50: 263 mg kgꢀ1(237–282), TD50: 398 mg kgꢀ1 (356–445) in mice ip and MES ED50
:
485 mg kgꢀ1(324–677), TD50: 784 mg kgꢀ1 (503–1176) in rat ip.17
Table 10
Antibacterial and antifungal activities of the compounds 5a–h, 11 and 12 (MIC in
lg/ml)
Compound
Bacteria (MIC-
E. faecalis
l
g/ml)
Fungi (MIC-lg/ml)
S. aureus
E. coli
ATCC 25922
P. auruginosa
ATCC 27853
C. albicans
ATCC 90028
C. krusei
ATCC 6258
C. parapsilosis
ATCC 22019
ATCCa 25923
ATCC 29212
5a
5b
5c
5d
5e
5f
5g
5h
8
16
8
8
8
16
8
32
64
512
—
128
128
32
64
16
128
32
128
64
256
—
2
>1024
>1024
>1024
>1024
>1024
>1024
>1024
1024
1024
>1024
—
>1024
>1024
>1024
>1024
>1024
>1024
>1024
1024
>1024
>1024
—
8
64
16
256
256
128
128
1024
>1024
512
512
64
64
256
128
64
1024
>1024
1024
512
32
32
1024
>1024
1024
512
>1024
512
1
11
12
512
64
—
512
8
—
Fluconazole
Ampicilline
1
8
—
—
a
ATCC is the registered trademark of ‘American Type Culture Collection’.
41. Anal. Calcd for C19H21ClN2O2ꢁ1/2H2O (353.85): C, 64.49; H,
(CDCl3, 400 MHz): d 0.80 (d, 6H, CH3), 1.92–2.01 (m, 1H, CH–
6.27; N, 7.92. Found: C, 64.12; H, 6.36; N, 8.00.
CH2), 2.18 (d, 2H, CH2–(C@O)), 4.64–4.69 (dd, 1H, CH2–N HA, JAB
14.30 Hz, JAX 7.61 Hz), 4.75–4.79 (dd, 1H, CH2–N HB, JAB
:
:
:
4.1.3. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl 2-
14.34 Hz, JBX: 3.45 Hz), 6.25–6.32 (dd, 1H, CH–O HX, JAX: 7.01 Hz,
JBX: 3.19 Hz), 6.95 (s, 1H, imidazole H4), 7.20 (s, 1H, imidazole
H5), 7.37–7.46 (m, 3H, naphthalene H3, H6, H7), 7.70–7.80 (m, 4H,
naphthalene H1, H4, H5, H8), 9.43 (s, 1H, imidazole H2), 16.02 (s,
1H, N+–H); EIMS (70 eV): m/e 322 [M+] (46%), 241, 221, 194, 180,
166, 153, 127, 82 (base peak, 100%), 57 and 41. Anal. Calcd for
C20H23ClN2O2 (358.86): C, 66.94; H, 6.46; N, 7.81. Found: C,
66.28; H, 6.47; N, 7.67.
methylpropionate hydrochloride (5b)
Yield: 57%; mp: 165–7 °C; IR (m
cmꢀ1, KBr): 3094 (C–H aro-
matic), 2979, 2910 (C–H aliphatic), 2820–2250 (N+–H), 1713
(C@O); 1H NMR (CHCl3, 80 MHz), d 1.20 (d, 6H, CH3), 2.30–2.90
(m, 1H, CH–CH3), 4.90 (d, 2H, CH2–N), 6.40 (t, 1H, CH–O), 7.00 (s,
1H, imidazole H4), 7.30 (s, 1H, imidazole H5), 7.35–7.70 (m, 3H,
naphthalene H3, H6, H7), 7.70–8.00 (m, 4H, naphthalene H1, H4,
H5, H8), 9.45 (s, 1H, imidazole H2); EIMS (70 eV): m/e 308 [M+]
(55%), 241, 240, 221, 194, 181, 170, 152, 127, 115, 82 (base peak,
100%), 71, 43 and 41. Anal. Calcd for C19H21ClN2O2 (344.84): C,
66.18; H, 6.14; N, 8.12. Found: C, 65.94; H, 5.86; N, 8.19.
4.1.6. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl 2-
propylpentanoate hydrochloride (5e)
Yield: 75%; mp: 181–3 °C; IR (m
cmꢀ1, KBr): 3070 (C–H aro-
matic), 2953, 2927 (C–H aliphatic), 2850–2400 (N+–H), 1718
(C@O); 1H NMR (CDCl3, 400 MHz): d 0.74 (t, 3H, CH3), 0.78 (t, 3H,
CH3), 1.00–1.09 (m, 4H, CH2–CH3), 1.30–1.40 (m, 2H, CH2–CH2),
1.40–1.50 (m, 2H, CH2–CH2), 2.35–2.39 (m, 1H, (C@O)–CH), 4.73
(d, 2H, CH2–N), 6.25 (t, 1H, CH–O), 7.04 (s, 1H, imidazole H4),
7.22 (s, 1H, imidazole H5), 7.40–7.46 (m, 3H, naphthalene H3, H6,
H7), 7.72–7.80 (m, 4H, naphthalene H1, H4, H5, H8), 9.45 (s, 1H,
imidazole H2), 16.06 (s, 1H, N+–H); EIMS (70 eV): m/e 364 [M+]
(52%), 322, 297, 283, 237, 220, 170, 156, 127, 99, 82 (base peak,
100%), 57, 43 and 41. Anal. Calcd for C23H29ClN2O2ꢁ1/2H2O
(409.95): C, 67.39; H, 7.38; N, 6.83. Found: C, 67.91; H, 8.08; N,
7.06.
4.1.4. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl
pentanoate hydrochloride (5c)
Yield: 71%; mp: 133–4 °C; IR (m
cmꢀ1, KBr): 3200–2680 (N+–H),
3057 (C–H aromatic), 2958 (C–H aliphatic), 1742 (C@O); 1H NMR
(CDCl3, 80 MHz): d 0.85 (t, 3H, CH3), 1.00–1.80 (m, 4H, (CH2)2–
CH3), 2.40 (t, 2H, CH2–C@O), 4.25 (d, 2H, CH2–N), 6.15 (t, 1H, CH–
O), 6.75 (s, 1H, imidazole H4), 7.00 (s, 1H, imidazole H5), 7.10–
7.90 (m, 8H, naphthalene and imidazole H2); EIMS (70 eV): m/e
322 [M+] (41%), 293, 280, 254, 241, 221, 194, 180, 166, 153, 127,
82 (base peak, 100%) and 57. Anal. Calcd for C20H23ClN2O2ꢁ1/
2H2O (367.87): C, 65.30; H, 6.58; N, 7.62. Found: C, 64.85; H,
6.07; N, 7.68.
4.1.7. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl 4-(tert-
4.1.5. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl 3-
butoxycarbonyl) aminobutanoate hydrochloride (5f)
methylbutanoate hydrochloride (5d)
Yield: 68%; mp: 130–1 °C; IR (m
cmꢀ1, KBr): 3405 (N–H), 3094
Yield: 80%; mp: 135–7 °C; IR (
m
cmꢀ1, KBr): 3050–2320 (N+–H),
(C–H aromatic), 2974, 2924 (C–H aliphatic), 2750–2300 (N+–H),
3017 (C–H aromatic), 2957 (C–H aliphatic), 1721 (C@O); 1H NMR
1721 and 1678 (C@O); 1H NMR (CDCl3, 400 MHz): d 1.40 (s, 9H,

2910
A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
CH3), 1.73–1.79 (m, 2H, CH2–CH2), 2.37–2.51 (m, 2H, CH2–NH),
4.1.13. 1-(Naphthalene-2-yl)ethyl 4-(tert-butoxycarbonyl)
3.09 (t, 2H, CH2–C@O), 4.70–4.75 (dd, 1H, CH2–N HA, JAB
:
:
aminobutanoate (7d)
14.35 Hz, JAX 7.30 Hz), 4.89–4.94 (dd, 1H, CH2–N HB, JAB
:
Yield: 79%; mp: 80–2 °C; IR (m
cmꢀ1, KBr): 3363 (N–H), 3048 (C–
14.45 Hz, JBX: 3.55 Hz), 6.36–6.38 (dd, 1H, CH–O HX, JAX: 7.30 Hz,
JBX: 3.60 Hz), 7.07 (s, 1H, imidazole H4), 7.25 (s, 1H, imidazole
H5), 7.44–7.50 (m, 3H, naphthalene H3, H6, H7), 7.76–7.82 (m, 4H,
naphthalene H1, H4, H5, H8), 9.65 (s, 1H, imidazole H2), 15.85 (s,
1H, N+–H); EIMS (70 eV): m/e 423 [M+] (2%), 350, 323, 280, 157,
129, 127, 82 (base peak, 100%), 71, 57 and 41. Anal. Calcd for
C24H30ClN3O4ꢁ1/2H2O (468.98): C, 61.47, H, 6.66; N, 8.96. Found:
C, 61.82; H, 7.14; N, 9.00.
H aromatic), 2985, 2972 (C–H aliphatic), 1708 (C@O); 1H NMR
(CDCl3, 80 MHz): d 1.40 (s, 9H, CH3–C–O), 1.60 (d, 3H, CH3–CH),
1.70–2.00 (m, 2H, CH2–CH2), 2.40 (t, 2H, CH2–C@O), 3.20 (q, 2H,
CH2NH), 4.40–4.70 (s br, 2H, N–H), 6.10 (q, 1H, CH–O), 7.30–8.00
(m, 7H, naphthalene); EIMS (70 eV): m/e 357 [M+] (1%), 301, 172,
155 (base peak, 100%), 127, 102, 86, 57 and 41. Anal. Calcd for
C21H27NO4 (357.44): C, 70.56; H, 7.61; N, 3.92. Found: C, 70.00;
H, 7.02; N, 3.96.
4.1.8. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl benzoate
4.1.14. 1-(1-Hydroxynaphthalene-2-yl)-2-(1H-imidazol-1-
yl)ethanone hydrochloride (11)
hydrochloride (5g)
Yield: 65%; mp: 215–7 °C; IR (
m
cmꢀ1, KBr): 3126, 3094 (C–H
A stirred, ice-cooled solution of imidazole (1.02 g, 15 mmol) in
DMF (2.5 ml) was added drop wise onto 2-bromo-1-(1-acetyloxy-
naphthalene-2-yl)ethanone (1.53 g, 5 mmol) in DMF (2.5 ml). The
mixture was stirred for 2 h at 0 °C and overnight at room temper-
ature. The solution was poured onto ice. The precipitate which
formed as a result was filtered, washed with water, and dissolved
in benzene. The benzene solution was then treated with gas hydro-
chloric acid. The precipitated salt was filtered, and recrystallized
aromatic), 2979 (C–H aliphatic), 2800–2250 (N+–H), 1713 (C@O);
1H NMR (DMSO-d6, 80 MHz): d 4.90 (d, 2H, CH2–N), 6.50 (t, 1H,
CH–O) 7.20–8.20 (m, 10H, benzene, naphthalene and imidazole),
9.20 (s, 1H, imidazole H2); EIMS (70 eV): m/e 342 [M+] (46%),
274, 261, 238, 219, 186, 155, 127, 105 (base peak, 100%), 77, 51
and 36.
4.1.9. 2-(1H-Imidazol-1-yl)-1-(naphthalene-2-yl)ethyl 4-
through methanol/ethyl acetate. Yield: 38%; mp: 250–2 °C; IR (m
chlorobenzoate (5h)
cmꢀ1, KBr): 3700–3240 (O–H), 3021 (C–H aromatic), 2919 (C–H
aliphatic), 2900–2460 (N+–H), 1632 (C@O); 1H NMR (DMSO-d6,
400 MHz): d 6.16 (s, 2H, CH2), 7.55 (d, 1H, imidazole H4), 7.63 (t,
1H, imidazole H5), 7.74–7.77 (m, 3H, naphthalene H4, H6, H7),
7.90 (d, 1H, naphthalene H5), 7.97 (d, 1H, naphthalene H3), 8.38
(d, 1H, naphthalene H8), 9.11 (s, 1H, imidazole H2), 12.87 (s, 1H,
N+–H); EIMS (70 eV): m/e 252 [M+] (94%), 184, 171 (base peak,
100%), 143 and 82. Anal. Calcd for C15H13ClN2O2 (288.73): C,
62.40; H, 4.54; N, 9.70. Found: C, 62.23; H, 5.03; N, 9.69.
Yield: 58%; mp: 179–181 °C; IR (m
cmꢀ1, KBr): 3097 (C–H aro-
matic), 2920 (C–H aliphatic), 1720 (C@O), 1H NMR (CDCl3,
80 MHz): d 5.00 (d, 2H, CH2–N), 6.60 (t, 1H, CH–O), 7.00–8.10 (m,
13H, benzene, naphthalene and imidazole), 9.60 (s, 1H, imidazole
H2); EIMS (70 eV): m/e 378 [M+2] (9%), 376 [M+] (26%), 295, 220,
192, 156, 139 (base peak, 100%), 111, 75 and 54. Anal. Calcd for
C22H17ClN2O2ꢁH2O (base) (394.85): C, 66.92; H, 4.85; N, 7.09.
Found: C, 67.39; H, 5.62; N, 6.88.
4.1.10. 1-(Naphthalene-2-yl)ethyl pentanoate (7a)
4.1.15. 1-(1-Hydroxynaphthalene-2-yl)-2-(1H-imidazol-1-
yl)ethanol hydrochloride (12)
Yield: 82%; bp: 205 °C; IR (m
cmꢀ1, KBr): 3056 (C–H aromatic),
2960, 2932 (C–H aliphatic), 1739 (C@O); 1H NMR (CDCl3,
400 MHz): d 0.80 (t, 3H, CH3–CH2), 1.20–1.26 (m, 2H, CH3–CH2),
1.48–1.56 (m, 2H, CH2–CH2), 1.51 (d, 3H, CH3–CH), 2.25 (t, 2H,
CH2–C@O), 5.96 (q, 1H, CH–O), 7.33–7.38 (m, 3H, naphthalene
H3, H6, H7), 7.69–7.73 (4H, m, naphthalene H1, H4, H5, H8); EIMS
(70 eV): m/e 256 [M+] (14%), 172, 155 (base peak, 100%), 127,
115, 57 and 41. Anal. Calcd for C17H20O2.H2O (274.35): C, 74.42;
H 8.08. Found: C, 74.38, H, 7.48.
1-(1-Hydroxynaphthalene-2-yl)-2-(1H-imidazol-1-yl)ethanone
hydrochloride (0.500 g, 1.5 mmol) was dissolved in methanol
(25 ml). Sodium borohydride (0.170 g, 4.5 mmol) was added to
the solution and stirred at 0 °C for 1 h. The solvent was evaporated;
the residue was dissolved in water (100 ml) and acidified with
hydrochloric acid until the precipitation was complete. The precip-
itate was filtered off, washed with water and recrystallized
through chloroform/petroleum ether. Yield: 98%; mp: 220 °C
(dec.); IR (m
cmꢀ1, KBr): 3700–2700 (O–H and N+–H), 3050 (C–H
4.1.11. 1-(Naphthalene-2-yl)ethyl 3-methylbutanoate (7b)
aromatic), 2926 (C–H aliphatic); 1H NMR (DMSO-d6, 80 MHz): d
2.40 (s, 1H, CH–OH), 4.10 (d, 2H, CH2), 4.90 (t, 1H, CH), 5.20 (s,
1H, Ar–OH), 6.50–8.20 (10H, m, aromatic); EIMS (70 eV): m/e 236
[M+ꢀ18] (7%), 218, 168 (base peak, 100%), 139, 127, 115, 89, 68
and 41. Anal. Calcd for C15H15ClN2O2 (290.74): C, 61.97; H, 5.20;
N, 9.64. Found: C, 61.90; H, 4.66; N, 9.73.
Yield: 88%; bp: 208 °C; IR (m
cmꢀ1, KBr): 3058 (C–H aromatic),
2962, 2933 (C–H aliphatic), 1731 (C@O); 1H NMR (CDCl3,
400 MHz): d 0.83 (d, 3H, CH3–CH–CH2), 0.85 (d, 3H, CH3–CH–
CH2), 1.51 (d, 3H, CH3–CH–O), 2.02–2.08 (m, 1H, CH–CH2), 2.13
(d, 2H, CH2–C@O), 6.07 (q, 1H, CH–O), 7.33–7.38 (m, 3H, naphtha-
lene H3, H6, H7), 7.68–7.73 (m, 4H, naphthalene H1, H4, H5, H8);
EIMS (70 eV): m/e 256 [M+] (7%), 225, 172, 155 (base peak,
100%), 127, 85, 57 and 41. Anal. Calcd for C17H20O2ꢁ1/4H2O
(260.84): C, 78.28; H, 7.92. Found: C, 78.39; H, 8.55.
4.1.16. 4-(1-(1-Hydroxynaphthalene -2-yl)ethylideneamino)
butanoic acid (13)
GFDF (0.515 g, 5 mmol) was added to a solution of sodium
(0.115 g, 5 mmol) in ethanol (25 ml). 1-Hydroxy-2-acetylnaphtha-
lene (0.465 g, 2.5 mmol) was added into this solution. The solution
was then refluxed for 2 h. Ethanol was evaporated in vacuo. The
residue was dissolved in water and acidified to pH 3 with citric
acid. The compound was precipitated out of solution and recrystal-
lized through chloroform/petroleum ether. Yield: 79%; mp: 171–
4.1.12. 1-(Naphthalene-2-yl)ethyl 2-propylpentanoate (7c)
Yield: 85%; bp: 223 °C; IR (m
cmꢀ1, KBr): 3056 (C–H aromatic),
2963 (C–H aliphatic), 1738 (C@O); 1H NMR (CDCl3, 400 MHz): d
0.73 (t, 3H, CH3–CH2), 0.78 (t, 3H, CH3–CH2), 1.09–1.22 (m, 4H,
CH2–CH2), 1.23–1.36 (m, 2H, CH2–CH), 1.45–1.56 (m, 2H, CH2–
CH), 1.49 (d, 3H, CH3–CH) 2.28–2.35 (m, 1H, CH–C@O), 5.97 (q,
1H, CH–O), 7.30–7.35 (m, 3H, naphthalene H3, H6, H7), 7.66–7.69
(m, 4H, naphthalene H1, H4, H5, H8); EIMS (70 eV): m/e 298 [M+]
(10%), 172, 155 (base peak, 100%), 127, 99, 87, 57 and 41. Anal.
Calcd for C20H26O2 (298.42): C, 80.50; H, 8.78. Found: C, 80.57; H,
8.73.
2 °C; IR (m
cmꢀ1, KBr): 3700–2700 (O–H), 3062 (C–H aromatic),
2926 (C–H aliphatic), 1702 (C@O), 1597 (C@N), 1226 (C–O); 1H
NMR (CHCl3, 80 MHz): d 1.90–2.20 (m, 2H, CH2–CH2), 2.25–2.70
(t, 2H, CH2–COOH), 2.45 (s, 3H, CH3), 3.70 (t, 2H, CH2–N), 6.60–
8.50 (m, 6H, naphthalene); EIMS (70 eV): m/e 271 [M+] (base peak,
100%), 270, 236, 226, 212,198, 185, 170, 141, 128, 115 and 87. Anal.

A. Karakurt et al. / Bioorg. Med. Chem. 18 (2010) 2902–2911
2911
Calcd for C16H17NO3 (271.31): C, 70.83; H, 6.32; N, 5.16. Found: C,
71.49; H, 5.92; N, 5.21.
(BBL, MD, USA) for bacteria and RPMI-1640 medium buffered with
MOPS [3-(N-morpholino)propane sulfonic acid] (ICN-Flow, Aurora,
OH, USA) for fungi. (Final concentration: 0.165 mol/l at pH 7.0).
Ampicillin and fluconazole were used as the reference compounds
for antibacterial and antifungal activity, respectively. The stock
solutions of the compounds were prepared in dimethylsulfoxide.
The solution in the test medium furnished the required concentra-
4.1.17. X-ray crystallography
Data collection: X-AREA21
; cell refinement: X-AREA; data
reduction: X-RED3221; program used to solve structure: SHEL-
XS9722; programs used to refine structure: SHELXL9722; molecular
graphics: ORTEPIII23: software used to prepare material for publica-
tion ranging from 64 lg/ml to 0.06 lg/ml. The microtiter plates
24
25
tion: WINGX and PARST
.
were incubated at 35 °C and read visually after 24 h. but for Can-
dida species, after 48 h. The MIC values were recorded as the low-
est concentrations of the substances that inhibit the visible growth
of microorganisms.
4.2. Anticonvulsant activity
The anticonvulsant activity and neurotoxicity evaluations of the
compounds were sponsored by the National Institutes of Health
(NIH) and long-standing translational drug development program
of National Institutes of Neurological Disorders and Stroke
(NINDS), known as the Anticonvulsant Screening Program (ASP),
using the procedures described by Stables and Kupferberg.26,27
The anticonvulsant activity of the compounds were tested against
various seizure models including MES and scM-induced seizures
model. Testing was undertaken in two rodent species: CF#1 mice
and Sprague-Dawley rats. Male albino animals were used for all
the experiments. The animals had free access to food and water ex-
cept during actual times of testing. Policies and protocols for the
ethical treatment of the animals were strictly enforced under IA-
CUC, AAALAC, PHS and USDA policies and registrations. A topical
anesthetic (0.5% tetracaine HCl in normal saline) was applied to
the eyes of each test animal prior to MES stimulation. At 60 Hz, a
stimulus of 150 mA and 50 mA for 0.2 s was used for the rats and
mice, respectively. The apparatus for current was similar to that
of Woodbury and Davenport.28
To measure potential neurotoxicity, the rotarod test was used in
mice, while the positional sense, gait, and stance tests were used
for rat evaluations. All the compounds were suspended in methyl-
cellulose 0.5% prior to administration of a candidate drug to the
test animals. The weight of the animals ranged from 105 to 130 g
for rats and from 18 to 25.5 g for mice. The compounds were
administered to the mice by ip route, 0.5 h and 4 h before the eval-
uation. The endpoint in evaluation of anti-MES action in the mice
was inhibition of hindlimb tonic extension.
Acknowledgment
This project was supported by Hacettepe University Scientific
Research Fund (HÜBAB 02 02 301 002).
References and notes
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Berlin, 1999; pp 359–373.
6. Yiu, S. H.; Knaus, E. E. Drug Dev. Res. 1999, 48, 26.
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2000, 51, 143.
8. Wingrove, P. B.; Wafford, K. A.; Bain, C.; Whiting, P. J. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 4569.
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Subissi, A. J. Med. Chem. 1981, 24, 727.
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Dalkara, S. Arch. Pharm. (Weinheim) 2006, 339, 513.
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16. Shimshoni, J. A.; Bialer, M.; Yagen, B. Bioorg. Med. Chem. 2008, 16, 6297.
17. White, H. S.; Woodhead, J. H.; Wilcox, K. S.; Stables, J. P.; Kupferberg, H. J.; Wolf,
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18. Immediata, T.; Day, A. R. J. Org. Chem. 1940, 5, 512.
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Fernandez-Ruiz, J.; Ramos, J. Eur. J. Med. Chem. 2003, 38, 403.
21. Stoe & Cie. X-AREA (Version 1.18) and X-RED32 (Version 1.04). Stoe & Cie,
Darmstadt, Germany, 2002.
UAPMWBZ)
All the quantitative anticonvulsant/toxicity evaluations of the
most active compounds were conducted at the time of peak phar-
macodynamic activity (TPE) of the compound. Groups of at least
eight mice or rats were tested with various doses of the candidate
drug until at least two points were established between the limits
of 100 per cent protection or toxicity and 0 per cent protection or
minimal toxicity. Slope of the regression lines and standard errors
of the slopes were calculated for each quantitative determination.
ED50 and TD50 values were then calculated by a computer program
based on the method described by Finney.29
22. Sheldrick, G. M. SHELXS97 and SHELXL97; University of Goettingen: Germany,
1997.
23. Burnett, M. N., Johnson, C. K. ORTEPIII. Report ORNL-6895, Oak Ridge National
Laboratory, Tennessee, USA, 1996.
24. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
25. Nardelli, M. J. Appl. Crystallogr. 1995, 28, 659.
4.3. Antibacterial and antifungal activity
26. Stables, J. P.; Kupferberg, H. J. In Molecular and Cellular Targets for Antiepileptic
Drugs; Avanzini, G., Tanganelli, P., Avoli, M., Eds.; John Libbey & Company:
London, 1997; pp 191–198.
27. Kupferberg, H. J.; Stables, J. P. In Challenge Epilepsy-new Anticonvulsant Drugs;
Stefan, H., Kramer, G., Mamoli, B., Eds.; Blackwell Science: Boston, 1998; pp 7–
29.
28. Woodbury, L. A.; Davenport, V. D. Arch. Int. Pharmacodyn. Ther. 1952, 92, 97.
29. Finney, D. J. Probit Analysis, 3rd ed.; Cambridge University Press: London, 1971.
30. NCCLS Approved Standard M-27-A, 17(9) Villanova, PA, 1997.
31. NCCLS Approved Standard M7-A, 37(2), Villanova, PA, 1997.
The minimal inhibitory concentration (MIC) values of the com-
pounds were determined against yeast-like fungi (C. albicans ATCC
90018, C. krusei ATCC 6258 and C. parapsilosis ATCC 22019), gram
positive bacteria (S. aureus ATCC 25923, E. faecalis ATCC 29212)
and gram negative bacteria (Escherichia coli ATCC 25922 and Pseu-
domonas aeruginosa ATCC 27853) by using broth microdilution
method.30,31 The tests were carried out using Mueller Hinton broth