Synthesis, in vivo anticonvulsant testing, and molecular modeling studies of new nafimidone derivatives

Article abstract of DOI:10.1002/ddr.21538

An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anticonvulsant screening of new derivatives of nafimidone, a well-known member of (arylakyl)azole anticonvulsants. The compounds showed promising protection against maximal electroshock (MES)-induced seizures in mice and rats when administered via intraperitoneal (ip) and oral route. Especially, 5b, 5c, and 5i displayed outstanding activity in rats in MES test when given ip (ED₅₀: 16.0, 15.8, and 11.8 mg/kg, respectively). Additionally, 5l was active against 6 Hz and corneal-kindled mice models. Behavioral toxicity of the compounds was very low and their therapeutic indexes were high compared to some currently available AEDs. A number of pharmaceutically relevant descriptors and properties were predicted for the compounds in silico in comparison with a set of known drugs. Favorable results were obtained such as good blood–brain barrier permeability and high oral absorption, as well as drug-likeness. 5l was found to show affinity to the benzodiazepine binding site of A-type GABA receptor via molecular docking simulations.

Full text of DOI:10.1002/ddr.21538

Received: 26 December 2018
DOI: 10.1002/ddr.21538
Revised: 14 March 2019
Accepted: 1 April 2019
R E S E A R C H A R T I C L E
Synthesis, in vivo anticonvulsant testing, and molecular
modeling studies of new nafimidone derivatives
1,2
1
1
Mustafa F. Acar
| Suat Sari
| Sevim Dalkara
1
Faculty of Pharmacy, Department of
Pharmaceutical Chemistry, Hacettepe
University, Ankara, Turkey
Abstract
An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do
not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anti-
convulsant screening of new derivatives of nafimidone, a well-known member of
2
Server Gazi Pharmacy, Merkez Efendi,
Denizli, Turkey
Correspondence
(arylakyl)azole anticonvulsants. The compounds showed promising protection against
*
Suat Sari, Faculty of Pharmacy, Department
of Pharmaceutical Chemistry, Hacettepe
University, 06100 Ankara, Turkey.
Emails: suat.sari@hacettepe.edu.tr,
suat1039@gmail.com
maximal electroshock (MES)-induced seizures in mice and rats when administered via
intraperitoneal (ip) and oral route. Especially, 5b, 5c, and 5i displayed outstanding
activity in rats in MES test when given ip (ED50: 16.0, 15.8, and 11.8 mg/kg, respec-
tively). Additionally, 5l was active against 6 Hz and corneal-kindled mice models.
Behavioral toxicity of the compounds was very low and their therapeutic indexes
were high compared to some currently available AEDs. A number of pharmaceutically
relevant descriptors and properties were predicted for the compounds in silico in
comparison with a set of known drugs. Favorable results were obtained such as good
blood–brain barrier permeability and high oral absorption, as well as drug-likeness. 5l
was found to show affinity to the benzodiazepine binding site of A-type GABA
receptor via molecular docking simulations.
K E Y W O R D S
(arylalkyl)azole, esterification, molecular docking
1
| INTRODUCTION
small oxygen functional groups on this linker (Dalkara & Karakurt,
012; Robertson et al., 1986). Previously, some active ether and ester
2
Epilepsy, a common neurological disorder characterized by spontane-
ous and concurrent seizures, usually requires long-term use of anti-
epileptic drugs (AEDs), making toxicity a major issue. Also 1/3 of an
estimated 50 million patients are unresponsive to current AEDs
derivatives of AAAs were reported (Karakurt et al., 2006; Karakurt,
Özalp, I s¸ ık, Stables, & Dalkara, 2010; Sari et al., 2016, 2017; Sari,
Kaynak, & Dalkara, 2018). Herein, we present synthesis and anticon-
vulsant screening of new 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethanol
esters (5a-o). For anticonvulsant activity, acute (maximal electroshock
(
Dalkara & Karakurt, 2012).
Arylalkyl)azoles (AAAs) is an antiepileptic class with nafimidone
[MES], subcutaneous metrazol [SCM], 6 Hz psychomotor tests) and
(
chronic (corneal-kindled mice [CKM] and hippocampal kindling) in vivo
seizure models were used. Behavioral toxicity of the compounds was
evaluated by rotorod and minimal motor impairment tests.
and denzimol as known members (Figure 1; Nardi et al., 1981; Walker,
Wallach, & Hirschfeld, 1981). AAA scaffold comprises an aryl moiety,
an azole group, and an ethylene linker in between. Many AAAs include
Absorption, distribution, metabolism, excretion, and toxicity (ADMET)
is a crucial aspect of drug design (Rankovic, 2015). Thus, we evaluated
drug-likeness and certain ADMET properties of our compounds in silico.
We also performed docking studies to provide insights into binding prop-
Abbreviations: AAA, (arylalkyl)azole; ADMET, absorption, distribution, metabolism, excretion,
and toxicity; AED, antiepileptic drug; CBZ, carbamazepine; CKM, corneal-kindled mice; ETSP,
epilepsy therapy screening program; ip, intraperitoneal; MES, maximal electroshock; NIH,
National Institutes of Health; PHE, phenytoin; SCM, subcutaneous metrazol; TI, therapeutic
index.; TPE, time to peak effect; VPA, valproic acid.
A
erties of 5l to native (α1β2γ2) A-type GABA receptors (GABA Rs).
Drug Dev Res. 2019;1–11.
wileyonlinelibrary.com/journal/ddr
© 2019 Wiley Periodicals, Inc.
1

2
ACAR ET AL.
FIGURE 1 Nafimidone, denzimol, and
5a-o
2
| METHODS
.1 | Chemistry
(400 MHz, CDCl
CHCH ), 1.39–1.51 (m, H
2.40–2.49 (m, 1H, CHCH
AX = 7.2 Hz, JAY = 4.8, 1H, CHO), 7.08–9.57 (m, 10H, aromatic); IR
3
): δ = 0.76–0.82 (m, 3H, CH
, CH CH ), 1.56–1.70 (m, H
), 4.72–4.88 (m, 2H, CH N), 6.33 (dd,
2
CH
3
), 1.10 (d, 3H,
3
A
2
3
B
, CH CH ),
2
3
2
3
2
J
All chemicals were purchased from commercial suppliers. Melting points
mp) were determined with Thomas-Hoover capillary melting point
1
+
(
ATR): 3222, 1,738 cm− ; MS (ESI+) m/z: 346, 323 (100%) [M + H] ;
(
2 2
Anal. calcd. For C20H23ClN O : C 69.94, H 6.46, N 7.81, found: 66.48,
apparatus (Swedesboro, NJ, USA) and uncorrected. IR spectra were
H 6.67, N 7.65.
recorded with PerkinElmer FT-IR System Spectrum BX (Waltham, MA,
2-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl trimethylacetate hydro-
1
USA) with attenuated total reflection (ATR) sampling,
H
NMR
1
ꢀ
chloride 5c: White powder (0.86 g, 60%). Mp: 191–3 C; H NMR
13
(
400 MHz) and C NMR (150 MHz) spectra with Varian Mercury
00 FT (Palo Alto, CA, USA) and Bruker Avonce 600 Ultrashield™
Billerica, MA, ABD) NMR spectrometers, and mass spectra with Waters
(
3 3 2
400 MHz, CDCl ): δ = 1.11 (s, 9H, CH ), 4.72–4.88 (m, 2H, CH ), 6.28
4
(
dd, JAX = 7.2 Hz, JAY = 4.8, 1H, CHO), 7.55–9.22 (m, 10H, aromatic);
(
IR (ATR): 3088, 1,718 cm−1; MS (ESI+) m/z (%): 346 (23), 323 (100)
Micromass ZQ mass spectrometer (Milford, MA, USA) using
electrospray ionization (ESI+) method and MassLynx 4.1 software. Ele-
mental analyses were performed with LECO 932 CHNS apparatus (Saint
Joseph, MI, USA) and the results are reported as %. Compounds were
+
[
M + H] ; Anal. calcd. For C20
H
23ClN
2
O
2.1/2H
2
O: C 65.30, H 6.58, N
7
.62, found: 64.94, H 6.69, N 7.59.
2
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 2-methylpentanoate hydro-
ꢀ
1
chloride 5d: White powder (0.88 g, 59%). Mp: 168–70 C; H NMR
400 MHz, CDCl ): δ = 0.76–0.82 (m, 3H, CH CH ), 0.84–1.12 (m, 5H,
CHCH and CH CH ), 1.26–1.38 (m, H , CH CH ), 1.42–1.52 (m, H
CH CH ), 2.46–2.58 (m, 1H, COCH), 4.70–4.85 (m, 2H, CH N),
.29–6.35 (m, 1H, CHO), 7.54–9.24 (m, 10H, aromatic); IR (ATR): 3044,
3
dissolved in CDCl for NMR spectroscopy. The chemical shifts are
(
3
2
3
reported as δ (ppm) values using TMS as internal reference with splitting
3
2
3
A
2
2
B
,
patterns designated as s (singlet), d (doublet), t (triplet), q (quartet), m
2
2
2
(
multiplet), and dd (doublet of doublet).
6
1
,717 cm− ; MS (ESI+) m/z (%): 360 (25), 337 (100) [M + H] ; Anal. calcd.
1
+
For C21
2 2
H25ClN O : C 67.64, H 6.76, N 7.51, found: 67.30, H 6.70,
2
.1.1 | Synthesis of the compounds
N 7.47.
Compund 1 was purchased from commercial suppliers and 2-4 were syn-
thesized according to the literature methods (see Supporting Information
for details; Baji et al., 1995; Godefroi, Heeres, Van Cutsem, & Janssen,
2
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl but-2-enoate hydro-
ꢀ
1
chloride 5e: Off-white powder (0.70 g, 51%). Mp: 187–9 C; H NMR
400 MHz, CDCl ): δ = 1.91 (d, J = 5.6 Hz, 3H, CH ), 4.76 (dd,
AB = 14.4 Hz, JAX = 7.6 Hz, H , CH ), 4.87 (dd, JBA = 14.4 Hz,
BX = 4.0 Hz, H , CH ), 5.92 (d, J = 15.6 Hz, 1H, COCH), 6.38 (dd,
XA = 7.6 Hz, JXB = 3.6, H , CHO), 7.02–9.39 (m, 11H, CHCH , aro-
(
3
3
1969; Immediata & Day, 1940). 5a-o was afforded by Steglich esterifica-
J
J
J
A
2
0
tion (Neises & Steglich, 1978): A mixture of N,N -dicyclohexylcarbodiimide
B
2
(DCC; 4 mmol) and 4-dimethylaminopyridine (DMAP; 0.27 mmol) in dic-
X
3
hloromethane (DCM) was added dropwise to a mixture of 4 (4 mmol) and
matic); IR (ATR): 3002, 1,703 cm−1; MS (ESI+) m/z (%): 330 (22),
ꢀ
+
proper carboxylic acid (4 mmol) in DCM at 0–5 C. The mixture was stirred
3
07 (100) [M + H] ; Anal. calcd. For C19
2
H19ClN O
2 2
.1/3H O: C 65.42,
ꢀ
for 0.5 hr at 0–5 C then for 3–6 hr at room temperature. The precipitate
H 5.68, N 8.03, found: 65.46, H 5.70, N 7.86.
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 2-methylbut-2-enoate
hydrochloride 5f: White powder (0.81 g, 56%). Mp: 153–5 ꢀC; 1
NMR (400 MHz, CDCl ): δ = 1.77 (s, 3H, CCH ), 1.81 (d, J = 5.6 Hz,
was filtered off and the filtrate was evaporated to dryness. The residue
was purified via column chromatography (chloroform–methanol 90:10).
All the title compounds except 5a were converted to their hydrochloride
2
H
3
3
(HCl) salts using gaseous HCl.
3 AB A 2
3H, CHCH ), 4.78 (dd, J = 14.0 Hz, JAX = 8.4 Hz, H , CH ), 4.85 (dd,
2
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl acetate 5a: Off-white
B 2 XA
JBA = 14.4 Hz, JBX = 4.0 Hz, H , CH ), 6.34 (dd, J = 8.4 Hz, JXB = 4.0,
ꢀ
1
powder (0.50 g, 45%). Mp: 72–4 C; H NMR (400 MHz, CDCl
δ = 2.12 (s, 3H, CH ), 4.32 (dd, JAB = 14.4 Hz, JAX = 4.8, H , CH
.38 (dd, JBA = 14.4 Hz, JBX = 7.2, H , CH ), 6.11 (dd, JXB = 7.2 Hz,
3
):
X 3
H , CHO), 6.95–7.02 (m, 1H, CHCH ), 7.54–9.20 (m, 10H, aromatic);
IR (ATR): 3081, 1,693 cm− ; MS (ESI+) m/z (%): 344 (23), 321 (100)
1
3
A
2
),
+
4
B
2
[M + H] ; Anal. calcd. For C20H21ClN O2 C 67.32, H 5.93, N 7.85
2
J
XA = 4.8, H
X
, CHO), 6.80–7.86 (m, 10H, aromatic); IR (ATR): 3110,
found: 67.10, H 6.03, N 7.83.
,729 cm− ; MS (ESI+) m/z: 304, 281 (100%) [M + H] ; Anal. calcd.
1
+
1
2-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl hexa-2,4-dienoate hydro-
ꢀ
1
For C17H N
16 2
N 9.87.
O
2
: C 72.84, H 5.75, N 9.99, found: 72.41, H 6.01,
chloride 5g: Pale yellow powder (0.70 g, 48%). Mp: 162–5 C; H NMR
(400 MHz, CDCl ): δ = 1.84 (d, J = 5.2 Hz, 3H, CH ), 4.79–4.81 (m, 2H,
3
3
2-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 2-methylbutanoate hydro-
2 3
CH ), 5.94 (d, 1H, J = 15.6 Hz, COCH), 6.25–6.41 (m, 3H, CHCHCH ,
ꢀ
1
13
chloride 5b: Off-white powder (0.73 g, 51%). Mp: 129–31 C; H NMR
and CHO), 7.50–9.08 (m, 11H, COCHCH, aromatic);
C NMR

ACAR ET AL.
3
(
3
400 MHz, CDCl ): δ = 18.5, 52.3, 73.2, 117.6, 119.6, 122.7, 123.8,
127.7, 127.9, 128.5, 128.5, 128.9130.8, 132.5, 132.8, 133.8, 133.9,
1
1
1
25.4, 126.6, 126.6, 127.6, 127.9, 128.5, 129.5, 132.5, 132.8, 134.0,
36.0, 141.2, 146.4, 165.1; IR (ATR): 3022, 1,706 cm−1; MS (ESI+) m/z
136.1, 145.8, 165.0; IR (ATR): 3000, 1,716 cm− ; MS (ESI+) m/z (%):
+
392 (26), 369 (100) [M + H] ; Anal. calcd. For C24
H21ClN
2
O
2
.1/2H
2
O
+
(
%): 356 (24), 333 (100) [M + H] ; Anal. calcd. For C21
H
21ClN
2
O
2 2
.H O C
C 69.64, H 5.36, N 6.67 found: C 69.70, H 5.65, N 6.68.
2-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 3-benzoylpropanoate hydro-
6
5.20, H 5.99, N 7.24 found: 64.66, H 5.70, N 7.25.
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 4-oxopentanoate hydrochlo-
ꢀ
1
2
chloride 5m: White powder (0.79 g, 46%). Mp: 184–6 C; H NMR
(400 MHz, CDCl ): δ = 2.72–2.96 (m, 2H, COCH CH COC ),
3.24–3.50 (m, 2H, COCH CH COC ), 4.67 (dd, AB = 14.4 Hz,
AX = 6.0 Hz, H , CH N), 4.89 (dd, JBA = 14.4 Hz, JBX = 2.8 Hz, H , CH N),
6.41 (dd, JXA = 5.8 Hz, JXB = 2.8, H , CHO), 7.04–9.20 (m, 15H, aromatic);
ꢀ
1
ride 5h: White powder (0.79 g, 53%). Mp: 195–7 C; H NMR (400 MHz,
CDCl ): δ = 2.19 (s, 3H, CH ), 2.52–2.88 (m, 4H, CH CH ), 4.66 (dd,
AB = 14.4 Hz, JAX = 6.0 Hz, H , CH N), 4.84 (dd, JBA = 14.4 Hz,
BX = 3.2 Hz, H , CH N), 6.37 (dd, JXA = 5.6 Hz, JXB = 3.2, H , CHO),
.97–9.20 (m, 10H, aromatic); C NMR (400 MHz, CDCl ): δ = 28.3, 29.9,
3
2
2
6 5
H
3
3
2
2
2
2
6
H
5
J
J
A
2
J
A
2
B
2
J
B
2
X
X
13
IR (ATR): 3077, 1,722 cm−1; MS (ESI+) m/z (%): 422 (27), 399 (100) [M
6
3
1
1
3
+
8.2, 53.6, 73.7, 119.6, 122.1, 123.4, 125.9, 127.0, 127.0, 128.0, 128.4,
29.3, 132.5, 133.2, 133.5, 136.0, 171.8, 207.2; IR (ATR): 3029,
,728 cm− ; MS (ESI+) m/z (%): 360 (22), 337 (100) [M + H] ; Anal. calcd.
+ H] ; Anal. calcd. For C25
2 2
H23ClN O C 69.04, H 5.33, N 6.44 found: C
68.77, H 5.27, N 6.49.
1
+
2-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl diphenylacetate hydro-
ꢀ
1
For C20
H
21ClN
2
O
3
.1/2H
2
O C 62.91, H 5.81, N 7.34 found: 62.99, H 6.01,
chloride 5n: Pale yellow powder (1.23 g, 66%). Mp: 182–4 C;
H
N 7.44.
NMR (400 MHz, CDCl ): δ = 4.70–4.83 (m, 2H, CH ), 5.13 (s, 1H,
3
2
2
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl cyclohexanecarboxylate
COCH), 6.31–6.37 (m, 1H, CHO), 6.51 (m, 20H, aromatic); IR (ATR):
3033, 1,729 cm−1; MS (ESI+) m/z (%): 456 (32), 433 (100) [M + H]+;
ꢀ
1
hydrochloride 5i: White powder (1.02 g, 66%). Mp: 138–40 C;
NMR (400 MHz, CDCl ): δ = 1.09–2.50 (m, 11H, cyclohexane),
N), 6.31 (dd, JAX = 7.8 Hz, JAY = 4.4, 1H, CHO),
H
3
Anal. calcd. For C29
found: C 73.01, H 5.99, N 5.75.
2-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 4-phenylbenzoate hydro-
2 2 2
H25ClN O .1/2H O C 72.87, H 5.48, N 5.86
4
7
2
1
3
.70–4.83 (m, 2H, CH
2
13
.52–9.20 (m, 10H, aromatic); C NMR (400 MHz, CDCl
3
): δ = 24.6,
ꢀ
1
4.6, 25.1, 28.3, 41.9, 52.2, 73.0, 119.6, 122.7, 123.8, 125.4, 126.6,
27.6, 127.9, 128.5, 132.5, 132.8, 134.0, 135.9, 173.8; IR (ATR):
chloride 5o: Pale yellow powder (0.77 g, 42%). Mp: 151–3 C; H NMR
(400 MHz, CDCl ): δ = 4.88–5.04 (m, 2H, CH ), 6.55–6.62 (m, 1H, CHO),
3
2
022, 1,719 cm− ; MS (ESI+) m/z (%): 372 (23), 349 (100) [M + H] ;
25ClN .1/2H O C 67.08, H 6.65, N 7.11
found: 67.28, H 6.54, N 7.18.
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl phenylacetate hydro-
1
+
7.08–9.51 (m, 19H, aromatic); IR (ATR): 3002, 1,713 cm−1; MS (ESI+) m/z
+
Anal. calcd. For C22
H
2
O
2
2
(%): 442 (31), 419 (100) [M + H] ; Anal. calcd. For C28
H
23ClN
2
O
2
.1/2H
2
O
C 72.49, H 5.21, N 6.04 found: C 72.84, H 5.18, N 6.17.
2
ꢀ
1
chloride 5j: White powder (0.78 g, 50%). Mp: 185–7 C; H NMR
400 MHz, CDCl ): δ = 3.70 (s, 3H, COCH ), 4.56 (dd, JAB = 14.4 Hz,
, CH N), 4.78 (dd, JBA = 14.4 Hz, JBX = 3.6 Hz, H
N), 6.30 (dd, JXA = 7.6 Hz, JXB = 3.2, H , CHO), 6.56–9.28 (m,
2
.2 | Pharmacology
(
3
2
J
AX = 7.2 Hz, H
A
2
B
,
All the in vivo tests were performed by The epilepsy therapy screen-
ing program (ETSP) of the National Institutes of Health (NIH) in com-
pliance with compliance with the U.S. National Research Council's
Guide for the Care and Use of Laboratory Animals, the U.S. Public
Health Service's Policy on Humane Care and Use of Laboratory Ani-
mals, and Guide for the Care and Use of Laboratory Animals.
CH
2
X
1
3
5H, aromatic); IR (ATR): 3027, 1,731 cm− ; MS (ESI+) m/z (%):
1
+
80 (26), 357 (100) [M + H] ; Anal. calcd. For C23
2
H21ClN O
2 2
.1/2H O
C 67.23, H 5.64, N 6.82 found: C 67.28, H 5.95, N 6.77.
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 4-phenylbutanoate hydro-
2
ꢀ
1
chloride 5k: White powder (0.83 g, 49%). Mp: 131–3 C; H NMR
400 MHz, CDCl ): δ = 1.87–1.94 (m, 2H, COCH CH ), 2.40 (t,
= 7.6 Hz, J = 7.2 Hz, 2H, CH ), 2.58 (t, J = 8 Hz, J = 7.2 Hz,
H, COCH ), 4.70 (dd, JAB = 14.4 Hz, JAX = 7.6 Hz, H , CH N), 4.85 (dd,
BA = 14.6 Hz, JBX = 4.0 Hz, H , CH N), 6.33 (dd, JXA = 7.2 Hz, JXB = 4.0,
, CHO), 6.96–9.60 (m, 15H, aromatic); C NMR (400 MHz, CDCl
δ = 26.0, 32.8, 34.1, 51.0, 73.3, 120.5, 122.4, 123.9, 125.5, 125.9, 126.6,
(
3
2
2
2
.2.1 | MES test
J
1
2
2
C
6
H
5
1
2
2
2
A
2
Each compound was given at default doses (30, 100, and 300 mg/kg)
to adult male CF1 mice (18–25 g) or Sprague–Dawley rats via ip or
oral route. After predetermined time points, the animals were treated
with ocular 0.5% tetracaine and delivered 60 Hz corneal stimulation
at 50 mA (mice) or 150 mA (rats) for 0.2 s, which typically induces a
tonic seizure (rapid spams or jerky movements of the limbs) followed
by a clonic phase. Compounds were considered active upon abolition
of the hind limb tonic extensor component of the seizure (Castel-
Branco, Alves, Figueiredo, Falcao, & Caramona, 2009).
J
B
2
13
H
X
3
):
1
1
3
6
27.6, 127.9, 128.2, 128.3, 128.4, 132.5, 132.8, 133.9, 136.1, 141.1,
71.7; IR (ATR): 3044, 1,720 cm−1; MS (ESI+) m/z (%): 308 (26),
+
85 (100) [M + H] ; Anal. calcd. For C25
H
25ClN
2
O
2
C 71.33, H 5.99, N
.66 found: C 71.34, H 6.16, N 6.65.
2
-(1H-Imidazol-1-yl)-1-(2-naphthyl)ethyl 3-phenylprop-2-enoate
ꢀ
1
hydrochloride 5l: White powder (0.87 g, 54%). Mp: 190–2 C;
NMR (400 MHz, CDCl ): δ = 4.81 (dd, JAB = 14.4 Hz, JAX = 7.2 Hz, H
CH N), 4.92 (dd, JBA = 14.4 Hz, JBX = 3.6 Hz, H , CH N), 6.47 (dd,
XA = 7.6 Hz, JXB = 3.6, H , CHO), 6.52 (d, J = 16 Hz, 1H, COCH),
.06–9.54 (m, 16H, CHC
CDCl ): δ = 52.4, 73.5, 117.2, 119.6, 122.8, 123.9, 125.4, 126.6,
H
3
A
,
2
.2.2 | SCM test
2
B
2
J
X
Each compound was given at default doses (30, 100, and 300 mg/kg)
to adult male CF1 mice (18–25 g) and Sprague–Dawley rats via ip or
oral route. After the determined amount of time 85 mg/kg (mice) or
13
7
6 5
H and aromatic); C NMR (400 MHz,
3

4
ACAR ET AL.
5
6.4 mg/kg (rats) metrazol was injected subcutaneously in the midline
The animals with compound were monitored for indications of
ataxia (circular or zigzag gait, abnormal body posture and spreading
legs, tremor, hyperactivity, lack of exploratory behavior, somnolence,
stupor, catalepsy, loss of righting reflex, and changes in muscle tone).
Animals showing at least two of these indications were considered
intoxicated by the compound (Stables & Kupferberg, 1997).
of the neck, which triggers clonic seizures characterized by spasms of
the fore and/or hind limbs, jaws, or vibrissae. The animals were
observed for the next 30 min and those without these symptoms
were considered protected by the compound (Swinyard, 1989).
2
.2.3 | Six hertz psychomotor test
2
.2.7 | Quantification studies
Each compound was given at default doses (30, 100, and 300 mg/kg)
to adult male CF1 mice (18–25 g) via ip route. After predetermined
time points, the mice were treated with ocular 0.5% tetracaine and
delivered 6 Hz corneal stimulation at 32 or 44 mA for 3 s, which
induces a seizure with a minimal clonic phase followed by stereo-
typed, automatistic behaviors including twitching of the vibrissae and
Straub-tail. The mice not displaying these behaviors were considered
protected by the compound (Barton, Klein, Wolf, & White, 2001).
Quantification of effective and toxic doses (ED50 and TD50) was per-
formed at the TPE of each compound in a given test, animal, and
route. For TPE determination, animals were tested at 0.25, 0.5, 1.0,
2.0, and 4.0 hr at a given dose to determine the TPE. To obtain biolog-
ical response data, groups of animals were tested at various doses at
the TPE until at least two points were established between 0 and full
protection. By applying Probit analysis the ED50 and TD50, 95% confi-
dence interval, slope of the regression line, and SE were calculated.
2
.2.4 | CKM test
2
.3 | Molecular modeling
Adult male CF-1 mice were kindled until each animal underwent five
consecutive Stage 5 seizures (fully kindled). The kindling procedure
consists of corneal stimulations of 3 mA and 60 Hz for 3 s twice a
day. Eight mice were used for each dose (42.5, 85, and 170 mg/kg) at
the time to peak effect (TPE) and the behavioral seizure scores (BSS)
were rated for each when stimulated in the presence of 5l (see
Table S3 for the scoring criteria; Racine, 1972).
Ligands were modeled and prepared using LigPrep (Schrödinger release
2018-4, LLC, New York, NY 2018), MacroModel (Schrödinger release
2018-4, LLC), and OPLS_2005 force field on Maestro (Schrödinger
release 2018-4, LLC; Banks et al., 2005). Their descriptors and proper-
ties were calculated using QikProp (Schrödinger release 2018-4, LLC).
The GABA
loaded from the RCSB protein databank (www.rcsb.org; Berman et al.,
000) and prepared for docking using the Protein Preparation Wizard of
A
R structure (PDB ID: 6D6T; Zhu et al., 2018) was down-
2
2
.2.5 | Hippocampal kindling test
Maestro (Sastry, Adzhigirey, Day, Annabhimoju, & Sherman, 2013) by
treating hydrogens and charges. For receptor grid, the central coordi-
nates of the cocrystallized flumazenil was taken and 5l was docked
Adult male Sprague–Dawley rats (275–300 g) were surgically
implanted with bipolar electrodes into the ventral hippocampus under
ketamine–xylazine anesthesia and allowed to recover for 1 week
before the rapid hippocampal kindling procedure (Lothman, Perlin, &
Salerno, 1988; Lothman, Salerno, Perlin, & Kaiser, 1988), which con-
sists of applying a repeated stimulation regimen on alternating days
for a total of five stimulus days (Lothman & Williamson, 1994). During
the stimulation regimen, a 50 Hz, 10 s train of 1 ms biphasic 200 μA
pulses were delivered every 30 min for 6 hr, thereby giving 12 stimula-
tions per stimulus day. Two rats, which were kindled to display a
Stage 5 behavioral seizure, that is, fully kindled, were administered
with a nontoxic dose of the test compound to evaluate its ability to
modify the fully expressed kindled seizure and afterdischarge duration
after a 1-week, stimulation-free period. Each kindled rat was given
the kindled stimulation at 15, 45, 75, 105, 135, 165, and 195 min fol-
lowing drug administration. The rats were allowed at least 5 days
between tests to “washout” any investigational compound after test-
ing. (The BSS were rated according to the criteria in Table S3.)
A
50 times flexibly to GABA R using Glide (Schrödinger release 2018-4,
LLC) at extra precision (Friesner et al., 2004, 2006; Halgren et al., 2004).
To confirm the accuracy of the docking protocol, the cocrystallized
flumazenil was re-docked to GABA
A
R and the obtained binding mode
for flumazenil was close to its original conformation (RMSD 0.62 Å).
3
3
| RESULTS AND DISCUSSION
.1 | Chemistry
1-(2-naphthyl)ethanone (1) was brominated using bromine (Br
2
) and
bromic acid (HBrO ) to obtain 2-bromo-1-(2-naphthyl)ethanone (2)
3
with which imidazole was alkylated using its excess as base in N,N-
dimethylformamide (DMF) to afford 2-(1H-iImidazol-1-yl)-1-(2-
naphthyl)ethanone (3). Then, 3 was reduced using sodium borohydride
4
(NaBH ) to yield 4. Compounds 2-4 were previously reported in the
literature (Tajana, Portioli, Subissi, & Nardi, 1981). 5a-o were synthe-
sized by esterification of 4 with various carboxylic acids in the pres-
ence of an acyl transfer and dehydration catalyst (DMAP and DCC)
and converted to their HCl salts to further purify and improve their
aqueous solubility (Scheme 1). Their structures and purity were con-
firmed by spectral and elemental analyses.
2
.2.6 | Rotorod and minimal motor impairment tests
The mice with compound were placed on a rod rotating at 6 rpm. Any
mouse that fell off the rod three times in a minute was considered
intoxicated by the compound (Stables & Kupferberg, 1997).

ACAR ET AL.
5
SCHEME 1 Synthesis and
molecular structure of 5a-o
TABLE 1 Anticonvulsant identification results of 5a, 5d-f, 5h-m, and 5o in mice via ip route
Compound
Test
Time (hr)
Dose (mg/kg)
5a
5d
5e
5f
5h
0/1
2/2
-
5i
5j
5k
5l
5m
5o
PHE
1/1
1/1
1/1
1/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/4
3/4
4/4
0/2
2/2
2/2
CBZ
1/1
1/1
1/1
0/1
1/1
1/1
0/1
1/1
1/1
0/1
0/1
1/1
0/4
4/4
4/4
0/2
0/2
2/2
VPA
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/4
0/4
0/4
0/2
0/2
0/2
MES
0.5
30
0/1
3/3
1/1
0/1
2/3
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
2/2
0/2
0/4
0/2
0/1
3/3
1/1
0/1
3/3
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
2/2
0/2
0/4
2/2
0/1
3/3
0/3
0/1
0/3
1/1
0/1
0/1
-
0/1
2/3
0/3
0/1
1/3
0/1
0/1
0/1
-
0/1
3/3
1/1
0/1
2/3
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
2/2
0/2
0/4
2/2
0/1
3/3
1/1
0/1
2/3
-
0/1
3/3
1/1
0/1
1/3
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
2/2
0/2
0/4
0/2
0/1
3/3
1/1
0/1
2/3
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
2/2
0/2
0/4
2/2
0/1
3/3
1/1
0/1
1/3
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
2/2
0/2
0/4
0/2
0/1
0/3
1/1
0/1
1/3
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
0/2
0/2
0/4
0/2
1
00
00
30
00
00
30
00
00
30
00
00
30
00
00
30
00
00
a
a
3
4
0/1
1/1
-
1
3
SCM
0.5
4
0/1
0/1
-
0/1
0/1
-
1
3
0/1
0/1
-
0/1
0/1
-
0/1
0/1
-
0/1
0/1
-
1
3
Toxicity
0.5
4
0/2
0/4
-
0/2
0/4
-
0/2
0/3
-
0/2
0/4
1/1
0/2
0/4
-
1
3
b
b
b
b
b
b
0/2
0/4
0/1
0/2
0/4
0/1
0/2
0/2
-
1
3
Note. “-” not determined. Results are expressed as the number of animals active/toxic over tested. Data indicating at least 50% activity (or toxicity) is
highlighted as bold.
a
Death.
b
Clonic seizures.

6
ACAR ET AL.
3
.2 | Pharmacology
phenytoin (PHE), carbamazepine (CBZ), and valproic acid (VPA)
obtained from the PANAChE (Public Access to Neuroactive & Anti-
convulsant Chemical Evaluations) database of the NIH, the com-
pounds' activity profile was similar to PHE.
Oral and ip MES, SCM, and 6 Hz psychomotor tests were used in anti-
convulsant identification studies in mice and rats. MES, a model for
generalized tonic–clonic seizures, tests a compound's ability to pre-
vent seizure spread (Swinyard, 1989; White, Johnson, Wolf, &
Kupferberg, 1995; White, Woodhead, & Franklin, 1995). SCM, a
model for human clonic, forebrain seizures, tests a compound's ability
to raise seizure threshold (Snead, 1992; Swinyard, 1989). Siz hertz
psychomotor test is a model for human partial seizures and tests the
5a, 5b, 5d, 5f, 5g, 5i, and 5j-n were tested in rats using the MES
test at time points from 0.25 to 4 hr. Unlike in mice, these compounds
were active at 30 mg/kg, except 5f and 5n (Table 2). 5b was active up
to 1 hr via ip route and 5i, 5j, and 5l up to 4 hr orally. None of the
compounds manifested toxicity in this test.
Furthermore, 5g, 5i, 5k, 5l, and 5o were tested ip in mice using
ability of
et al., 2001).
a, 5d-f, 5h-m, and 5o were tested ip in mice; all the compounds,
a compound to block psychomotor seizures (Barton
6
0
Hz psychomotor test at 75, 100, or 200 mg/kg at time points from
.25 to 4 hr. 5l was active up to 2 hr at 200 mg/kg at 32 mA but inac-
5
tive at 44 mA. 5i showed protection at the same dose up to 2 hr at
except 5f, were protective in the MES test at one of the doses and
one of the time points at least (Table 1). No protection was observed
at 30 mg/kg, but the compounds were active up to 4 hr except 5f and
44 mA (Table 3). These compounds did not display toxicity, either.
Quantification studies were performed for 5b, 5c, 5g, 5i, and 5l
using various tests at their TPE, the time point of the highest activity
or toxicity. The results are presented in Table 4 along with the
5
i. All but 5o were protective at 100 mg/kg without neurotoxicity.
None was active in the SCM test. According to the activity data of
TABLE 2 Anticonvulsant identification results of 5a, 5b, 5d, 5f, 5g, 5i, and 5j-n using MES test in rats via ip and oral route
Compound
a
b
a
a
b
a
a
b
a
b
a
a
b
Test
Dose (mg/kg)
Time (hr)
5a
5b
5d
5f
5g
5i
5j
5k
5l
5l
5m
5n
5n
MES
30
0.25
2/4
2/4
2/4
2/4
1/4
0/4
0/4
0/4
0/4
0/4
4/4
4/4
3/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
2/4
2/4
0/4
0/4
0/4
0/4
0/4
0/4
1/4
1/4
0/4
1/4
1/4
0/4
0/4
0/4
0/4
0/4
3/4
4/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
2/4
2/4
3/4
3/4
3/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
2/4
0/4
3/4
0/4
0/4
0/4
0/4
0/4
2/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
1/4
2/4
2/4
4/4
2/4
0/4
0/4
0/4
0/4
0/4
2/4
2/4
1/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
2/4
2/4
1/4
1/4
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
1
2
4
.5
Tox.
30
0.25
0
1
2
4
.5
Note. Tox., toxicity. Data indicating at least 50% activity (or toxicity) is highlighted as bold.
a
Oral route.
b
Ip route.
TABLE 3 Anticonvulsant identification results of 5g, 5i, 5k, 5l, and 5o using 6 Hz psychomotor test in mice via ip route
2 mA 44 mA
3
Test
Hz
Time (hr)
Dose (mg/kg)
5g
5k
Dose (mg/kg)
5l
Dose (mg/kg)
5o
Dose (mg/kg)
5i
5l
6
0.25
100
1/4
2/4
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
200
3/4
3/4
2/4
2/4
0/4
0/4
0/4
0/4
0/4
0/4
75
0/4
0/4
2/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
200
1/4
3/4
2/4
2/4
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
1
2
4
.5
Tox.
0.25
100
200
75
200
0
1
2
4
.5
Note. Data indicating at least 50% activity (or toxicity) is highlighted as bold.

ACAR ET AL.
7
TABLE 4 ED50, TD50, and TI values of 5b, 5c, 5g, 5i, and 5l
a
b
c
Compounds
Test
MES
Tox.
MES
Tox.
MES
Tox.
MES
Tox.
MES
Tox.
MES
Tox.
MES
Tox.
MES
Time (hr)
0.25
0.25
0.25
0.25
0.25
0.25
1
Animal
Rat
Route
Ip
ED50 or TD50 (mg/kg)
16.01
>85
95% CI
Slope
11.89
–
SE
TI
5b
5c
5g
8.26–18.99
–
5.51
–
>5.3
N/A
4.9
Rat
Ip
Rat
Ip
15.82
76.95
51.58
257.20
36.12
>500
11.61–21.0
67.82–85.06
41.65–59.14
246.06–309.72
18.30–57.55
–
4.47
13.12
8.60
13.23
2.25
–
1.29
3.59
2.51
4.30
0.62
–
Rat
Ip
N/A
5.0
Mouse
Mouse
Rat
Ip
Ip
N/A
>13.8
N/A
5.2
Oral
Oral
Ip
1
Rat
5
i
0.25
0.25
0.25
0.25
1
Mouse
Mouse
Rat
38.07
198.38
11.76
>250
31.32–49.06
157.63–229.47
6.50–17.97
–
5.13
8.64
2.92
–
1.52
2.40
0.92
–
Ip
N/A
>21.3
N/A
>9.8
N/A
8.2
Ip
Rat
Ip
Rat
Oral
Oral
Ip
50.89
>500
26.74–102.11
–
1.58
–
0.47
–
1
Rat
5
l
0.5
0.5
0.5
1
Mouse
Mouse
Mouse
Mouse
Rat
51.86
170.39
77.44
426.55
79.20
>500
37.90–66.73
135.94–206.34
52.52–109.91
308.40–527.37
44.36–180.6
–
5.83
7.16
5.31
7.11
1.75
–
1.94
2.16
1.72
2.36
0.51
–
d
6
Hz
Ip
2.5
CKM
Tox.
MES
Tox.
MES
Tox.
MES
Tox.
MES
Tox.
MES
Tox.
Ip
5.5
Ip
N/A
>6.3
N/A
6.1
2
Oral
Oral
Ip
2
Rat
PHE
1
Mouse
Mouse
Mouse
Mouse
Rat
6.71
5.38–8.37
39.0–42.89
7.19–9.09
80.39–98.52
1.38–3.67
11.92–19.22
20.73–35.20
–
11.05
32.85
13.21
18.37
3.05
7.55
4.95
–
3.29
8.96
4.16
6.49
0.92
2.59
1.38
–
1
Ip
40.63
8.59
N/A
10.3
N/A
6.4
4
Oral
Oral
Ip
2
88.62
2.39
0.25
0.5
2
Rat
Ip
15.21
28.11
>1,000
47.91
45.36
N/A
>35.6
N/A
0.95
N/A
Rat
Oral
Oral
Ip
2
Rat
d
CBZ
6 Hz
Tox.
0.25
0.25
Mouse
Mouse
27.39–94.16
32.87–54.37
1.88
6.84
0.69
2.05
Ip
Note. TD50 values are showed at the intersection of “ED50 or TD50” column and “Tox.” row highlighted in gray. Data indicating at least 50% activity (or
toxicity) is highlighted as bold.
a
Confidence interval.
b
Standard error.
c
Calculated according to formula: TD50/ED50
.
d
3
2 mA, N/A, not applicable.
therapeutic index (TI) values, as an important indicator of safe dose
interval.
5l was tested and found active (ED50: 77.44 mg/kg) in the CKM
test, a chronic seizure model of human partial seizures for identifying
potential compounds, such as levetiracetam (Table 4; Matagne &
Klitgaard, 1998; Rogawski, 2006; Rowley & White, 2010). Considering
the TD50 and the TI value (5.5), 5l was quite promising compared to
VPA (ED50: 174.39 mg/kg and TI: 2.3; CKM quantification for PHE
and CBZ is unavailable).
5
b, 5c, and 5i showed outstanding anti-MES profile in rats ip
ED50: 16.01, 15.82, and 11.76 mg/kg; TI: >5.3, 4.9, >21.3, respec-
tively). 5l showed moderate anti-6 Hz activity and toxicity (ED50
70.39 mg/kg, TI: 2.5), which was also promising considering that
PHE is inactive in 6 Hz model and CBZ's effective dose is not safe (TI:
.95). The compounds were more active in rats and the peak effect
(
:
1
0
5i and 5l were tested and failed in hippocampal kindling test in rats,
a model for human focal seizures testing compounds' ability to block
behavioral seizures and/or decrease the afterdischarge duration (see
Supporting Information for details; Lothman, Salerno, et al., 1988).
was observed later when given orally. 5i's ED50 increased threefold
orally compared to ip. This was more than 10-fold in the case of PHE,
thus we can suggest that our compounds had good oral bioavailability.

8
ACAR ET AL.

ACAR ET AL.
9
A
FIGURE 2 Superposition of flumazenil (green) and 5l (orange) in the BZD binding site of GABA R (color ribbons; a), key interactions of 5l
(
residues are showed as gray sticks, H bonds as yellow and π–π interactions as blue dashes; b), and 2D interaction diagram of 5l with GABA
A
R (c)
A
TABLE 6 Docking scores (kcal/mol) of 5a-o in the BZD binding site of GABA R
Compounds
Docking score
−5.97
Compounds
Docking score
−7.24
Compounds
Docking score
−6.63
5a
5b
5c
5d
5e
5f
5g
5h
5i
5k
5L
5m
5n
5o
−7.43
−6.63
−6.75
−5.34
−6.70
−6.77
−7.60
−7.70
−6.60
−7.00
5j
−6.01
−5.80
3
.3 | Prediction of ADMET and drug-likeness
3.4 | Molecular docking
According to QikProp, a software that predicts pharmaceutically rele-
vant descriptors and properties of organic molecules in comparison
with a known-drug set, 5a-o were in accordance with orally available
and blood–brain barrier-permeating chemical space with minor excep-
tions (Table 5; Kelder, Grootenhuis, Bayada, Delbressine, & Ploemen,
Anti-6 Hz and anti-kindling activity is connected with benzodiazepine
(BZD)-type allosteric activation of GABA R (Albertson, Stark, &
A
Derlet, 1990; Kaminski, Livingood, & Rogawski, 2004; Monaghan,
McAuley, & Data, 1999). We previously reported some AAAs with
anti-6 Hz and anti-CKM activity to show high affinity to BZD binding
1
999; Lipinski, Lombardo, Dominy, & Feeney, 2001; Mikitsh &
A
site of GABA R (Sari et al., 2017). We docked the title compounds to
Chacko, 2014). Favorable ADMET properties were predicted for most
compounds except 5n and 5o, which showed high lipophilicity and
low water solubility apparently due to the extra phenyl ring in their
ester moieties. These two compounds were among the derivatives
with low anticonvulsant activity. QikProp calculated aqueous solubil-
ity, high oral absorption, and gut–blood barrier permeability for the
compounds (see Supporting Information for details).
A
the BZD binding site of GABA R, which lies at the interface of the
extracellular domains of α1 and γ2− and beneath loop C of α1
(Figure 2a). The compounds assumed a common binding orientation
with the naphthalene ring parallel to the central pore and close to α1
His102, the imidazole close to loop C and the ester portion reaching
to the γ2 subunit. 5l, active in 6 Hz and CKM tests, bound to the
receptor with good affinity making interactions with the key residues
+

1
0
ACAR ET AL.
(
Table 6). The naphthalene was in π–π interactions with His102 and the
Medicinal Chemistry, 30(7), 617–626. https://doi.org/10.1016/0223-5234
(
96)88277-8
imidazole with Tyr160 of α1 (Figure 2b). The latter donated H bond to
Ala161. 5l made van der Waals interactions with residues from both
subunits (Figure 2c). 5i, another derivative with potent anti-6 Hz activity,
also made similar interactions, in addition to an H bond with Thr207 of
loop C (see Figure S7). Most of these residues were reported to deter-
mine binding affinities of BZD-type ligands in alanine scanning, muta-
genesis, and related experimental studies (please note that the residue
numbering of the α1 subunit of the receptor 6D6T is one higher than
the original sequence; Bergmann, Kongsbak, Sørensen, Sander, & Balle,
Banks, J. L., Beard, H. S., Cao, Y., Cho, A. E., Damm, W., Farid, R., …
Levy, R. M. (2005). Integrated modeling program, applied chemical the-
ory (IMPACT). Journal of Computational Chemistry, 26(16), 1752–1780.
https://doi.org/10.1002/jcc.20292
Barton, M. E., Klein, B. D., Wolf, H. H., & White, H. S. (2001). Pharmaco-
logical characterization of the 6 Hz psychomotor seizure model of par-
tial epilepsy. Epilepsy Research, 47(3), 217–227. https://doi.org/10.
1
016/S0920-1211(01)00302-3
Bergmann, R., Kongsbak, K., Sørensen, P. L., Sander, T., & Balle, T. (2013).
A unified model of the GABA A receptor comprising agonist and ben-
zodiazepine binding sites. PLoS One, 8(1), e52323. https://doi.org/10.
2013). Similar interactions were also observed between the receptor
1
371/journal.pone.0052323
and co-crystallized flumazenil (Zhu et al., 2018).
Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N.,
Weissig, H., … Bourne, P. E. (2000). The protein data bank. Nucleic
Acids Research, 28(1), 235–242. https://doi.org/10.1093/nar/28.1.235
Castel-Branco, M. M., Alves, G. L., Figueiredo, I. V., Falcao, A. C., &
Caramona, M. M. (2009). The maximal electroshock seizure (MES)
model in the preclinical assessment of potential new antiepileptic
drugs. Methods and Findings in Experimental and Clinical Pharmacology,
4
| CONCLUSION
5
a-e and 5f-l emerged as promising compounds with anticonvulsant
activity. Especially, 5b, 5c, and 5i showed outstanding protection in
the MES test in rats. Also, 5l was protective against 6 Hz psychomotor
and CKM models. No protection was observed in the SCM and hippo-
campal kindling tests. The active compounds showed minimal behav-
ioral toxicity, thus had high TI values. These results suggest that our
compounds possess potential against generalized tonic–clonic and
partial seizures with a wide safe dosage range.
3
1(2), 101–106. https://doi.org/10.1358/mf.2009.31.2.1338414
Dalkara, S., & Karakurt, A. (2012). Recent progress in anticonvulsant drug
research: Strategies for anticonvulsant drug development and applica-
tions of antiepileptic drugs for non-epileptic central nervous system
disorders. Current Topics in Medicinal Chemistry, 12(9), 1033–1071.
https://doi.org/10.2174/156802612800229215
Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J.,
Mainz, D. T., … Shenkin, P. S. (2004). Glide: A new approach for rapid,
accurate docking and scoring. 1. Method and assessment of docking
accuracy. Journal of Medicinal Chemistry, 47(7), 1739–1749. https://
doi.org/10.1021/jm0306430
The compounds were predicted to have favorable ADMET proper-
ties and comply with the drug-like chemical space except 5n and 5o,
which were too lipophilic due to the double phenyl ring on their ester
moieties and which showed limited anticonvulsant activity. 5l showed
Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R.,
Halgren, T. A., … Mainz, D. T. (2006). Extra precision glide: Docking
and scoring incorporating a model of hydrophobic enclosure for
protein-ligand complexes. Journal of Medicinal Chemistry, 49(21),
high affinity to the BZD binding site residues of GABA
ment with its activity profile, making it likely to exert an BZD-type
activation of GABA R, although anticonvulsants are known to act
A
R in agree-
6
177–6196. https://doi.org/10.1021/jm051256o
A
Godefroi, E. F., Heeres, J., Van Cutsem, J., & Janssen, P. A. (1969). The
preparation and antimycotic properties of derivatives of
through multiple pathways.
1
-phenethylimidazole. Journal of Medicinal Chemistry, 12(5), 784–791.
https://doi.org/10.1021/jm00305a014
ACKNOWLEDGMENTS
Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L.,
Pollard, W. T., & Banks, J. L. (2004). Glide: A new approach for rapid,
accurate docking and scoring. 2. Enrichment factors in database
screening. Journal of Medicinal Chemistry, 47(7), 1750–1759. https://
doi.org/10.1021/jm030644s
The authors are grateful to the ETSP team for conducting biological
experiments and to Prof. Dr. Erhan Palaska for providing the mass data.
Immediata, T., & Day, A. R. (1940). β-Naphthyl derivatives of ethanolamine
and n-substituted ethanolamines. Journal of Organic Chemistry, 5(5),
CONFLICT OF INTEREST
5
12–527. https://doi.org/10.1021/jo01211a005
The authors declare no conflict of interest.
Kaminski, R. M., Livingood, M. R., & Rogawski, M. A. (2004). All-
opregnanolone analogs that positively modulate GABA receptors pro-
tect against partial seizures induced by 6-Hz electrical stimulation in
mice. Epilepsia, 45(7), 864–867. https://doi.org/10.1111/j.0013-9580.
ORCID
2
004.04504.x
Suat Sari
https://orcid.org/0000-0002-8248-4218
Karakurt, A., Aytemir, M. D., Stables, J. P., Özalp, M., Betül Kaynak, F.,
Özbey, S., & Dalkara, S. (2006). Synthesis of some Oxime ether deriva-
tives of 1-(2-Naphthyl)-2-(1, 2, 4-triazol-1-yl) ethanone and their anti-
convulsant and antimicrobial activities. Archiv der Pharmazie, 339(9),
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