β-naphthalene incorporated thiazole-5-carboxamides/thiazole -5- ketones: Design, synthesis and anticonvulsant screening against two seizure models

Article abstract of DOI:10.3844/ajptsp.2019.27.37

A bunch of β-naphthalene incorporated thiazole-5-carboxamides/thiazole -5- ketones (7a-7o& 8a-8e) were prepared by reacting 4-methyl-2-(naphthalen-2-yl)thiazole-5-carbonyl chloride with appropriate amines. Structures of all the compounds were explained by elemental analysis, FT-IR, 1H NMR and mass spectral data. The compounds were evaluated for their anticonvulsant activity employing MES and chemoshock (scPTZ) seizure tests. Neurotoxicity was also assessed. Majority of these compounds exhibited significant activity against both animal models; however, compounds 7e, 7j, 7n and 8c displayed promising activity and could be considered as leads for further investigations.

Full text of DOI:10.3844/ajptsp.2019.27.37

American Journal of Pharmacology and Toxicology
Original Research Paper
β-Naphthalene Incorporated Thiazole-5-
Carboxamides/Thiazole -5- Ketones: Design, Synthesis and
Anticonvulsant Screening against Two Seizure Models
1
2
1
Mohammed Faiz Arshad, Faisal Al-Otaibi, Gulam Mustafa,
3
4
Saad Shousha and Abdulrahman Alshahrani
1
2
3
4
Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Dawadmi, Kingdom of Saudi Arabia
Department of Clinical Pharmacy, College of Pharmacy, Shaqra University, Dawadmi, Kingdom of Saudi Arabia
Department of Physiology, Faculty of Veterinary Medicine, Benha University, 13736 Moshtohor, Egypt
College of Medicine, Shaqra, Shaqra University, Kingdom of Saudi Arabia
Article history
Abstract:
carboxamides/thiazole -5- ketones (7a-7o& 8a-8e) were prepared by reacting
-methyl-2-(naphthalen-2-yl)thiazole-5-carbonyl chloride with appropriate
amines. Structures of all the compounds were explained by elemental
analysis, FT-IR, 1H NMR and mass spectral data. The compounds were
evaluated for their anticonvulsant activity employing MES and chemoshock
A
bunch of β-naphthalene incorporated thiazole-5-
Received: 26-01-2019
Revised: 29-04-2019
Accepted: 28-08-2019
4
Corresponding Author:
Mohammed Faiz Arshad
Department of Pharmaceutical
Sciences, College of Pharmacy,
Shaqra University, Dawadmi,
Kingdom of Saudi Arabia
Tel: 00966594082153
(
scPTZ) seizure tests. Neurotoxicity was also assessed. Majority of these
compounds exhibited significant activity against both animal models;
however, compounds 7e, 7j, 7n and 8c displayed promising activity and
could be considered as leads for further investigations.
Email: drfaizarshad@gmail.com
Keywords: Thiazole, MES, scPTZ, Anticonvulsant Activity
accessible antiepileptic drugs have neurological toxicity
and idiosyncratic side effects (Brodie, 1990). The search
Introduction
Epilepsy is a group of neurological conditions which
has characteristics of epileptic seizures (Chang and
Lowenstein, 2003; Robert et al., 2014). Epileptic seizures
are episodes that can differ from brief and nearly
unnoticeable to long periods of forceful shaking. In the
brain, epilepsy causes unusual release of neurotransmitters
due to which the electrical working of brain gets disturbed
prompting muscle spasm, nausea, convulsions and loss of
consciousness (Al-Otaibi, 2019). It can be triggered by
brain injuries, tumours, high fevers or strokes. In a
substantial number of epilepsies, hereditary factor also
plays an important role in the development of seizures.
Approximately 65 million people in the world are
impacted by various types of epilepsy (Thurman et al.,
for new antiepileptic compounds with more selectivity
and lower toxicity is uninterruptedly an area of
investigation for medicinal chemists. The important and
highly effective approach to treat epilepsy is the
identification of new targets through better
understanding of molecular mechanisms of epilepsy.
In the last two decades, several new naphthalene
analogues were synthesized for antiepileptic screening. The
first naphthalene derivative developed as an antiepileptic
agent was nafimidone. Nafimidone, a derivative of
imidazole was discovered in early eighties, having
structurally different class with exclusive properties. Till
now, studies have revealed that nafimidone is a potent
anticonvulsant than phenytoin. But the problems with the
drug are huge in terms of its toxicity and low potency. The
drug inhibits carbamazepine and phenytoin metabolism
which in turn, leads to severe toxicity. Considering
nafimidone as lead, various analogues of nafimidone or
similar compounds were synthesized in recent years (Fig. 1;
I, II, III and IV) and promising anticonvulsant results were
observed with less toxicity (Karakurt et al., 2001; 2006;
2
011). The occurrence of epilepsy and other seizure related
disorders in Saudi population was assessed approximately
.65% (Al-Rajeh et al., 2001). The lacks of single
0
fundamental mechanism in case of epilepsy and, the multi-
factorial origin of the disease create much more difficulty in
developing new antiepileptic drugs. Furthermore, treatment
of various epilepsies and particularly the partial one, which
is the most common type, present a continuous headache to
the drug developers. The typical antiepileptic drugs
comprise phenobarbital, phenytoin, carbamazepine and
valproic acid have been existing in several European
countries since 1960s (Hess, 1985). All these currently
2010; 2012; Ozdemir et al., 2014). The optimization of
nafimidone is continued in the hope that the potent and less
toxic nafimidone derivative will usher a new era of
antiepileptic drug development.
©
2019 Mohammed Faiz Arshad, Faisal Al-Otaibi, Gulam Mustafa, Saad Shousha and Abdulrahman Alshahrani. This open
access article is distributed under a Creative Commons Attribution (CC-BY) 3.0 license.

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
Fig. 1: Recently synthesized promizing antiepileptic agents
In our study, β-naphthalene incorporated thiazole-5-
carboxamide derivatives were aimed on the basis of
structural similarities with nafimidone. Furthermore, the
imidazole moiety of nafimidone was replaced with
thiazole ring with the expectation to improve the
bioactivity since thiazole possessed neuroprotective as
well as antiseizure activity (Koufaki et al., 2007;
Amin et al., 2008). The presence of sulfur moiety in the
thiazole ring may facilitate the drugs to cross the Blood
Brain Barrier (BBB) due to lipophilic nature and exhibit
more anticonvulsant activity.
are not changed. Elemental analysis was performed on
a Vario-EL III CHNOS- Elemental analyzer and the
results were within ±0.4% of the theoretical values of
elements. The Fourier Transform Infrared (FTIR)
spectra were documented in KBr pellets on a Jasco
FT/IR 410 spectrometer and the values were attributed

1
1
in inverse centimeter (υmax-cm ). The H NMR
spectra were taken on a Bruker model dpx 300 (300
MHz) NMR spectrometer and chemical shifts (δ) are
presented in part per million (ppm) from the peak of
Tetramethylsilane (TMS) which is used as reference
standard. Mass spectra were taken on a Bruker Ion
trap (Esquire 3000) mass spectrophotometer. The
consistency of the compounds was checked by Thin
Layer Chromatography (TLC) on silica gel G (Merck)
coated plates by using toluene: Ethyl acetate: Formic
acid (5:4:1) as solvent system. The TLC spots were
visualized by using iodine chamber and UV lamp.
Lipophilicity (Log P) was measured using ACD lab
software version 12.0. The docking simulations study
of synthesized compounds was performed using
Maestro, version 9.4 implemented from Schrodinger
software suite. The protein structure for docking study
was obtained from protein data bank (PDB ID: 1OHW)
and prepared by eliminating solvent, adding hydrogen and
further energy minimization was achieved in the presence
of bound ligand using protein preparation software. The
ligands were sketched in 3D format using build panel and
To understand the possible mode of action of
substituted napthalenyl-thiazole derivatives at the
molecular level, we carried out molecular docking
simulations studies of synthesized molecules (7a-7o&8a-
8
e) at the GABA aminotransferase catalytic ligand
binding site. For the validation of docking parameters,
the rosmarinic acid, a well-known gamma amino butyric
acid (GABA) transaminase inhibitor was docked at the
catalytic site of protein and the root-mean-square
deviation (RMSD) between co-crystal and docked pose
was found to be 0.255 Å (less than 2 Å).
Experimental
Chemical Synthesis
The melting points were determined in open
capillary tubes in a Hicon melting point device and
2
8

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
were prepared for docking, making use of Ligprep
application. Docking of title compounds were performed
using Glide extra-precision (XP) mode, with up to three
poses saved per molecule.
4-Methyl-2-(Naphthalen-2-yl)
Carboxylic Acid (5)
Thiazole-5-
To a mixture of ethanol (25 m) and THF (05 ml)
containing ethyl 4-methyl-2-(naphthalen-2-yl)
Synthesis of Naphthalene-2-Carbonitrile (2)
thiazole-5-carboxylate (compound 4, 0.01 mol), 2 ml
of 1N NaOH was mixed and content was refluxed for
8 hr. After the reaction is complete the mixture was
checked by TLC, the solvent was removed under
evaporation and the residue was neutralized by 1N
HCl to pH 2-3. The precipitated solid was strained,
washed with water and crystal formation was done from
To a mixture of hydroxylamine hydrochloride
(
0.515 mol) and sodium formate (0.687 mol) in formic
acid (anhydrous, 300 mL), 2-naphthaldehyde (0.343
mol) was mixed and the reaction blend was heated to
1
00°C for almost eight hours. After completion of
reaction, the reaction mixture was cooled down to
about 40°C and water was mixed. The reaction blend was
cooled to about 25°C and agitated for about 1 h. The solid
precipitated was strained, washed with water and
dehydrated. The solid was then dissolved in acetone at
about 50°C and water was mixed slowly over a time of
about 30 min. The mixture was cooled to about 25°C and
again agitated for about 1 h. The solid thus collected was
strained, washed with acetone and water (1:1) mixture and
dehydrated to obtain the title product.
1
aqueous ethanol. Yield: 68%; m.p.: 154C; H-NMR (300
MHz, DMSO-d
6
): δ 2.65 (s, 3H, CH
3
), 7.65-7.68 (m, 2H,
Ar-H), 7.86-7.90 (m, 2H, Ar-H), 8.05-8.08 (m, 2H, Ar-H),
8
2
.35 (s, 1H, Ar-H), 10.56 (s, 1H, COOH); ESI-MS m/z
69.05 (M ), 253.92, 226.26.
+
Synthesis
of
4-Methyl-2-(Naphthalen-2-yl)
Thiazole-5-Carbonyl Chloride (6)
To mixture of 4-methyl-2-(naphthalen-2-yl)
a
Synthesis of Naphthalene-2-Carbothioamide (3)
thiazole-5-carboxylic acid (compound 5) (0.02 mol) in
dry toluene in 50 ml RBF, thionyl chloride (0.06 mol)
was added. The resulting blend was refluxed for about 4
hour. The status of the reaction was checked by TLC
using TEF as solvent system. At the end of the reaction
the extra thionyl chloride was eliminated by distillation
under low pressure. The crude acyl chloride was
obtained and crystal formation was done from ethanol.
To a suspension of sodium hydrosulfide (NaSH)
(hydrate, 70% w/w) (11.98 g, 0.150 mol) and
MgCl2.6 H2O (15.20 g, 0.075 mol) in DMF (100
mL), 2-nitrile naphthalene (0.075 mol) was added.
The reaction blend was agitated at 20°C for 18 h and
progress of reaction was checked on TLC. On
finishing point of the reaction, the mixture was added
in water (200 mL). The precipitated solid was washed
with water and then agitated in IN HCl (200 mL) for
1
Yield: 72%; m.p.: 174C, H-NMR (300 MHz, DMSO-
d
6
): δ 2.64 (s, 3H, CH ), 7.69-7.72 (m, 2H, Ar-H), 7.87-
3
2
0 min. After filtration and washing with water, the
7.91 (m, 2H, Ar-H), 8.02-8.06 (m, 2H, Ar-H), 8.30 (s,
1H, Ar-H); ESI-MS m/z 289.01 (M+2), 287.02 (M ),
254.15, 226.12.
+
product was crystallized from toluene and hexane,
obtaining the title compound, as a yellow solid. Yield:
7
9%, mp: 144C.
General Method for Synthesis of Compounds (7a-
Synthesis of Ethyl 4-Methyl-2-(Naphthalen-2-yl)
Thiazole-5-Carboxylate (4)
7o; 8a-8e)
To a solution of appropriate amine (52.0 mmol) in
dry pyridine (50 ml) at room temperature, a solution of
-methyl-2-(naphthalen-2-yl)thiazole-5-carbonyl
chloride (compound 6) (50.0 mmol) in dehydrated
acetone (50 mL) was mixed. After the addition, the
reaction blend was constantly agitated for 4-6 h. The
status of the reaction was checked by TLC using TEF
Naphthalene-2-carbothioamide (0.069 mol) was
dissolved in EtOH (130 mL) and to this, ethyl-2-
choroacetoacetate (9.5 mL, 11.30 g, 0.069 mol) was
added. The reaction blend was refluxed for 16 hours.
When the starting compound was completely finished,
the reaction blend was cooled to room temperature and
the product was strained. Crystal formation of
intermediate was done from ethanol, obtaining a white
4
(
5:4:1) as solvent system. At the end of the reaction,
crude mixture was added into ice water (100 mL). The
precipitate collected was agitated, washed with cold
water and dehydrated to obtain desired compound. The
crystal formation of the compound was done from
methanol or ethanol. Figure 2 describes the synthetic
scheme of the title compounds 7a-7o and 8a-8e.
solid at the bottom of the container. Yield: 71%; m.p.:
1
1
CH
7
8
2
85C, H-NMR (300 MHz, DMSO-d
6
): δ 2.66 (s, 3H,
), 4.32 (q, 2H, CH CH ),
.62-7.65 (m, 2H, Ar-H), 7.89-7.93 (m, 2H, Ar-H), 8.04-
3
), 1.34 (t, 3H, CH
2
CH
3
2
3
.07 (m, 2H, Ar-H), 8.32 (s, 1H, Ar-H); ESI-MS m/z
+
97.08 (M ), 253.98, 226.17
2
9

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
Fig. 2: Synthesis of the title compounds (7a-o & 8a-e); Reagents and conditions: [a] NH
MgCl , [c] CH COCHClCOOC /ethanol [d] THF/C OH, NaOH/HCl, [e] SOCl2, [f] ArNH2/Pyridine [g] HNC4H8X 7a: R =
, 7b: R = 4CH -C -, 7c: R = 4Cl -C -, 7d: R = 4F -C -, 7e: R = 4Br -C -, 7f: R = 4NO -C -, 7g: R = 4OCH
-, 7h: R = 4OH-C -, 7i: R = 3Cl,4F-C -, 7j: R = 3,4-diCl-C -, 7k: R = 2OH-C -, 7l: R = 2F-C -, 7m: R = 2CH
-, 7n: R = 4NH SO -C -, 7o: R = Cyclohexyl-, 8a: X = CH , 8b:X = O, 8c: X = S, 8d: X = NCH , 8e: X = NCH Cl
2
OH, HCl, HCOONa/HCOOH, [b] NaSH,
2
3
H
2 5
2 5
H
C
6
H
5
3
6 4
H
6
H
4
H
6 4
6
H
4
3
H
6 4
3
-
C
C
6
6
H
H
4
6
H
2
4
6
H
3
6 3
H
H
6 4
6
H
4
3
-
4
2
H
6 4
2
3
2
4
-Methyl-2-(Naphthalen-2-yl)-N-Phenylthiazole-5-
(s,3H, CH
3
), 7.42 (d, 2H, Ar-H, J = Hz), 7.57-7.60 (m, 2H,
Ar-H), 7.74-7.73 (m, 2H, Ar-H, J = Hz), 7.85-7.90 (m,
Carboxamide (7a)
2
1
H, Ar-H), 8.10-8.13 (m, 2H, Ar-H), 8.36 (s, 1H, Ar-H),
Yield: 65%; mp: 157C, LogP: 5.33, FT-IR νmax
2.57(s, 1H, CONH); ESI-MS m/z 380.09 (M+2), 378.06

1
+
(cm , KBr pellets): 3378 (NH), 1687 (C = O), 1623 (C
(M ), 254.09, 226.69. Anal. Calcd for C H ClN OS: C,
21
15
2
1
=
2
C), 1590 (C = N). H-NMR (300 MHz, DMSO-d
.64 (s, 3H, CH ), 7.08-7.11 (m, 1H, Ar-H), 7.51 (d, 2H,
Ar-H, J = Hz), 7.58-7.62 (m, 4H, Ar-H), 7.87-7.91 (m,
6
): δ
6
6.57; H, 3.99; N, 7.39. Found: C, 67.73; H, 7.97; N, 7.43.
3
N-(4-Fluorophenyl)-4-Methyl-2-(Naphthalen-2-yl)
Thiazole-5-Carboxamide (7d)
2
1
2
H, Ar-H), 8.05-8.08 (m, 2H, Ar-H), 8.34 (s, 1H, Ar-H),
2.67 (s, 1H, CONH); ESI-MS m/z 344.10, 253.95,
26.19. Anal. Calcd for C21
Yield: 72%; mp: 140C, LogP: 5.78, FT-IR νmax
cm , KBr pellets): 3370 (NH), 1690 (C = O), 1628 (C
H
16
2
N OS: C, 73.23; H, 4.68;

1
(
N, 8.13. Found: C, 73.44, H, 4.69; N, 8.17.
1
=
C), 1596 (C = N). H-NMR (300 MHz, DMSO-d
2.65 (s, 3H, CH ), 7.26 (d, 2H, Ar-H, J = Hz), 7.57-7.64
m, 4H, Ar-H), 7.87-7.92 (m, 2H, Ar-H), 8.06-8.10 (m,
H, Ar-H), 8.33 (s, 1H, Ar-H), 12.51 (s, 1H, CONH);
ESI-MS m/z 362.09, 254.15, 226.30 Anal. Calcd for
OS: C, 69.59; H, 4.17; N, 7.73. Found: C,
9.33; H, 4.19; N, 7.77.
6
): δ
4
-Methyl-2-(Naphthalen-2-yl)-N-p-Tolylthiazole-5-
3
(
2
Carboxamide (7b)
Yield: 59%; mp: 174C, LogP: 5.79, FT-IR νmax

1
(cm , KBr pellets): 3367 (NH), 1680 (C = O), 1626 (C
C
6
21
H15FN
2
1
=
C), 1593 (C = N). H-NMR (300 MHz, DMSO-d
6
): δ
2
.25 (s, 3H, CH ), 2.66 (s, 3H, CH ), 7.25 (d, 2H, Ar-H,
3
3
N-(4-Bromophenyl)-4-Methyl-2-(Naphthalen-2-yl)
Thiazole-5-Carboxamide (7e)
J = Hz), 7.54-7.59 (m, 4H, Ar-H), 7.89-7.92 (m, 2H, Ar-
H), 8.09-8.11 (m, 2H, Ar-H), 8.30 (s, 1H, Ar-H), 12.44
(
s, 1H, CONH); ESI-MS m/z 358.11, 253.91, Anal.
Yield: 66%; mp: 159C, LogP: 6.50,FT-IR νmax
cm , KBr pellets): 3368 (NH), 1683 (C = O), 1620 (C
Calcd for C22 OS: C, 73.71; H, 5.06; N, 7.82.
Found: C, 73.50; H, 5.08; N, 7.87.
H
18
N
2
1
(
=
2
(
1
C), 1592 (C = N). H-NMR (300 MHz, DMSO-d
.66 (s, 3H, CH ), 7.32 (d, 2H, Ar-H, J = Hz), 7.62-7.67
m, 4H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.06-8.10 (m,
H, Ar-H), 8.36 (s, 1H, Ar-H), 12.62 (s, 1H, CONH);
6
): δ
N-(4-Chlorophenyl)-4-Methyl-2-(Naphthalen-2-yl)
Thiazole-5-Carboxamide (7c)
3
2
1
+
Yield: 68%; mp: 168C, LogP: 6.12, FT-IR νmax (cm ,
ESI-MS m/z 424.04 (M+2), 422.01 (M ), 253.86,
226.08. Anal. Calcd for C H BrN OS: C, 59.58; H,
KBr pellets): 3363 (NH), 1688 (C = O), 1623 (C = C),
1
2
1
15
2
1
589 (C = N). H-NMR (300 MHz, DMSO-d
6
): δ 2.66
3.57; N, 6.62. Found: C, 59.76; H, 3.59; N, 6.60.
3
0

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
4
-Methyl–2-(Naphthalene-2-yl)-N-(4-Nitrophenyl)
(m, 2H, Ar-H), 8.00-8.06 (m, 3H, Ar-H), 8.34 (s, 1H,
Ar-H), 12.60 (s, 1H, CONH); ESI-MS m/z 416.05
Thiazole-5-Carboxamide (7f)
+
(
M+4), 414.07 (M+2) 412.02 (M ), 253.90, 226.25 Anal.
Yield: 70%; mp: 175C, LogP: 5.42,FT-IR νmax
Calcd for C21
H14Cl
2
2
N OS: C, 61.02; H, 3.41; N, 6.78.

1
(cm , KBr pellets): 3370 (NH), 1679 (C = O), 1618 (C
Found: C, 61.25 H, 3.42; N, 6.83.
1
=
2
(
C), 1596 (C = N). H-NMR (300 MHz, DMSO-d
.67 (s, 3H, CH ), 7.62-7.68 (m, 4H, Ar-H), 7.86-7.93
m, 2H, Ar-H), 8.05-8.12 (m, 4H, Ar-H), 8.34 (s, 1H,
Ar-H), 12.60 (s, 1H, CONH); ESI-MS m/z 389.08,
54.20, 226.22. Anal. Calcd for C21 S: C, 64.77;
6
): δ
N-(2-Hydroxyphenyl)-4-Methyl-2-(Naphthalen-2-
yl) Thiazole-5-Carboxamide (7k)
3
Yield: 61%; mp: 163C, LogP: 5.34, FT-IR νmax
2
H
15
N
3
O
3

1
(
=
cm , KBr pellets): 3368 (NH), 1687 (C = O), 1623 (C
H, 3.88; N, 10.79. Found: C, 64.48; H, 3.89; N, 10.85.
1
C), 1597 (C = N). H-NMR (300 MHz, DMSO-d6): δ
2.64 (s, 3H, CH ), 7.09-7.15 (m, 3H, Ar-H), 7.64-7.73
m, 4H, Ar-H), 7.86-7.90 (m, 2H, Ar-H), 8.03-8.07 (m,
N-(4-Methoxyphenyl)-4-Methyl-2-(Naphthalen-2-
yl) Thiazole-5-Carboxamide (7g)
3
(
2
H, Ar-H), 8.36 (s, 1H, Ar-H), 12.64 (s, 1H, CONH);
Yield: 59%; mp: 180C, LogP: 5.28,FT-IR νmax
ESI-MS m/z 360.07, 254.31, 226.10. Anal. Calcd for
S: C, 69.98; H, 4.47; N, 7.77. Found: C,
9.76; H, 4.49; N, 7.72.

1
(cm , KBr pellets): 3362 (NH), 1683 (C = O), 1622 (C
C
21
H
16
N
2
O
2
1
=
2
C), 1591 (C = N). H-NMR (300 MHz, DMSO-d
.65 (s, 3H, CH ), 3.89 (s, 3H, CH ), 7.05-7.08 (d, 2H,
Ar-H, J = Hz), 7.67-7.72 (m, 4H, Ar-H), 7.83-7.86 (m,
6
): δ
6
3
3
N-(2-Fluorophenyl)-4-Methyl-2-(Naphthalen-2-yl)
Thiazole-5-Carboxamide (7l)
2
1
H, Ar-H), 8.09-8.12 (m, 2H, Ar-H), 8.36 (s, 1H, Ar-H),
2.63 (s, 1H, CONH); ESI-MS m/z 374.11, 226.30.
o
Yield: 69%; mp: 145 C, LogP: 5.30, FT-IR νmax
Anal. Calcd for C22
H
18
N
2
2
O S: C, 70.57; H, 4.85; N,

1
(
=
2
(
cm , KBr pellets): 3373 (NH), 1689 (C = O), 1629 (C
7
.48. Found: C, 70.72; H, 4.86; N, 7.53.
1
C), 1607 (C = N). H-NMR (300 MHz, DMSO-d
.67 (s, 3H, CH ), 7.12-7.19 (m, 3H, Ar-H), 7.67-7.70
m, 2H, Ar-H), 7.86-7.92 (m, 3H, Ar-H), 8.09-8.12 (m,
H, Ar-H), 8.35 (s, 1H, Ar-H), 12.60 (s, 1H, CONH);
6
): δ
N-(4-Hydroxyphenyl)-4-Methyl-2-(Naphthalen-2-
yl) Thiazole-5-Carboxamide (7h)
3
2
Yield: 62%; mp: 149C, LogP: 4.59,FT-IR νmax
ESI-MS m/z 362.09, 253.99, 226.14. Anal. Calcd for

1
(cm , KBr pellets): 3366 (NH), 1689 (C = O), 1620 (C
C H FN OS: C, 69.59; H, 4.17; N, 7.73. Found: C,
2
1
15
2
1
=
2
7
C), 1597 (C = N). H-NMR (300 MHz, DMSO-d
.64 (s, 3H, CH ), 7.00-7.03 (d, 2H, Ar-H, J = Hz), 7.64-
.70 (m, 3H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.03-8.06
6
): δ
69.74; H, 4.18; N, 7.78.
3
4-Methyl-2-(Naphthalen-2-yl)-N-o-Tolylthiazole-5-
Carboxamide (7m)
(m, 2H, Ar-H), 8.32 (s, 1H, Ar-H), 9.30 (s, 1H, OH),
1
2
2.69 (s, 1H, CONH); ESI-MS m/z 360.09, 254.12,
26.34 Anal. Calcd for C21 S: C, 69.98; H, 4.47;
Yield: 64%; mp: 139C, LogP: 5.79, FT-IR νmax
H
16
N
2
O
2

1
(
cm , KBr pellets): 3361 (NH), 1684 (C = O), 1620 (C =
N, 7.77. Found: C, 69.70; H, 4.45; N, 7.81.
1
C), 1595 (C = N). H-NMR (300 MHz, DMSO-d
s, 3H, CH ), 2.64 (s, 3H, CH ), 7.08-7.10 (m, 1H, Ar-H),
.35-7.41 (m, 3H, Ar-H), 7.64-7.68 (m, 2H, Ar-H), 7.84-
.87 (m, 2H, Ar-H), 8.05-8.09 (m, 2H, Ar-H), 8.37 (s, 1H,
6
): δ 2.24
(
7
7
3
3
N-(3-Chloro-4-Fluorophenyl)-4-Methyl-2-
(Naphthalen-2-yl) Thiazole-5-Carboxamide (7i)
Yield: 75%; mp: 188C, LogP: 7.02, FT-IR νmax
Ar-H), 12.68 (s, 1H, CONH); ESI-MS m/z 358.11,
253.68, 226.47. Anal. Calcd for C H N OS: C, 73.71; H,

1
(cm , KBr pellets): 3373 (NH), 1684 (C = O), 1619 (C
22
18
2
1
=
2
(
2
C), 1594 (C = N). H-NMR (300 MHz, DMSO-d
.65 (s, 3H, CH ), 7.44-7.49 (m, 2H, Ar-H), 7.63-7.66
m, 2H, Ar-H), 7.85-7.90 (m, 3H, Ar-H), 8.06-8.09 (m,
H, Ar-H), 8.37 (s, 1H, Ar-H), 12.58 (s, 1H, CONH);
6
): δ
5.06; N, 7.82. Found: C, 73.85; H, 5.04; N, 7.88.
3
4
-Methyl-2-(Naphthalen-2-yl)-N-(4-Sulfamoyl-
Phenyl) Thiazole-5-Carboxamide (7n)
+
ESI-MS m/z 398.02 (M+2), 396.05 (M ), 254.04,
2
3
Yield: 76%; mp: 201C, LogP: 4.14, FT-IR νmax
26.15. Anal. Calcd for C21
H14ClFN
2
OS: C, 63.55; H,
1
(
=
cm , KBr pellets):3373 (NH), 1692 (C = O), 1625 (C
.56; N, 7.06. Found: C, 63.74; H, 3.58; N, 7.13.
1
C), 1570 (C = N). H-NMR (300 MHz, DMSO-d6):
δ 2.02 (s, 2H, NH ), 2.48 (s, 3H, CH ), 7.37-7.39 (d,
H, Ar-H, J = Hz), 7.62-7.64 (d, 2H, Ar-H, J = Hz),
.80-7.93 (m, 4H, Ar-H), 7.98-8.0 (d, 2H, Ar-H, J =
2
3
N-(3, 4-Dichlorophenyl)-4-Methyl-2-(Naphthalen-
2
2
7
-yl) Thiazole-5-Carboxamide (7j)
Hz), 8.27 (s, 1H, Ar-H), 9.30 (s, 1H, CONH); ESI-MS
m/z 423.50, 254.28, 226.33. Anal. Calcd for
Yield: 73%; mp: 195C, LogP: 7.13, FT-IR νmax

1
(
(
2
cm , KBr pellets): 3370 (NH), 1681 (C=O), 1622
1
C H N O S : C, 59.56; H, 4.05; N, 9.92. Found: C,
C=C), 1592 (C=N). H-NMR (300 MHz, DMSO-d
6
): δ
21 17
3
3 2
5
9.43; H, 4.03; N, 9.96.
.67 (s, 3H, CH ), 7.59-7.67 (m, 4H, Ar-H), 7.83-7.87
3
3
1

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
N-(Cyclohexyl)–4–Methyl–2-(Naphthalene–2-yl)
Thiazole-5-Carboxamide (7o)
Anal. Calcd for C2O
H
21
N OS: C, 68.35; H, 6.02; N,
3
1
1.96. Found: C, 68.41; H, 6.08; N, 11.91.
[
4-Methyl-2-(Naphthalen-2-yl) Thiazol-5-yl)](4-
Yield: 67%; mp: 178C, LogP: 5.63, FT-IR νmax

1
Chloromethylpiperazin-1-yl) Methanone (8e)
(
=
1
2
(
cm , KBr pellets): 3365 (NH), 1680 (C = O), 1623 (C
1
C), 1598 (C = N). H-NMR (300 MHz, DMSO-d
.39-1.45 (m, 6H, 2xCH ), 1.81-1.89 (m, 4H, 2xCH
.66 (s, 3H, CH ), 7.66-7.69 (m, 2H, Ar-H), 7.82-7.89
6
): δ
Yield: 85%; mp: 148C, LogP: 3.45, FT-IR νmax
2
2
),

1
(
(
(
7
8
3
cm , KBr pellets): 1680 (C = O), 1621 (C = C), 1591
3
1
C = N). H-NMR (300 MHz, DMSO-d
m, 7H, CH3 and 2xCH ), 3.22-3.29 (m, 4H, 2XCH
.56-7.71 (m, 2H, Ar-H), 7.79-7.96 (m, 2H, Ar-H), 8.03-
6
): δ 2.45-2.53
m, 4H, Ar-H), 8.04-8.07 (m, 2H, Ar-H), 8.36 (s, 1H,
Ar-H), 12.61 (s, 1H, CONH); ESI-MS m/z 350.15,
53.89, 226.40. Anal. Calcd for C20 OS: C, 71.97;
H, 6.33; N, 7.99. Found: C, 71.76; H, 6.35; N, 8.04.
2
2
),
2
H
20
N
2
.10 (m, 2H, Ar-H), 8.33 (s, 1H, Ar-H); ESI-MS m/z
+
24.14 (M+2), 322.11 (M ), 253.91, 226.13. Anal. Calcd
for C20
C, 62.19; H, 5.29; N, 10.94.
H
20ClN OS: C, 62.25; H, 5.22; N, 10.89. Found:
3
4
–Methyl–2-(Naphthalene–2-yl) Thiazol-5-yl)
(Piperidin-1-yl) Methanone (8a)
1
Anticonvulsant Screening
Yield: 80%; mp: 170C, LogP: 4.15, FT-IR νmax (cm ,
KBr pellets): 1677 (C = O), 1624 (C = C), 1589 (C = N).
The pharmacological screening of all the title
compounds was performed according to the standard
procedure specified by the epilepsy branch of the
National Institute of Neurological Disorders and Stroke
1
6
H-NMR (300 MHz, DMSO-d ): δ 1.65-1.72 (m, 6H,
3
7
8
3
7
xCH
2
), 2.64 (s, 3H, CH
3
), 3.68-3.72 (m, 4H, 2xCH ),
2
.68-7.70 (m, 2H, Ar-H), 7.88-7.91 (m, 2H, Ar-H), 8.07-
.10 (m, 2H, Ar-H), 8.38 (s, 1H, Ar-H); ESI-MS m/z
36.13, 254.21, 225.97. Anal. Calcd for C20
(Kupferberg, 2001).
H
20
2
N OS: C,
Male albino mice (Swiss) of 25-30 g were used as
1.40; H, 5.99; N, 8.33. Found: C, 71.52; H, 5.95; N, 8.37.
investigational animal. Title compounds were suspended
in PEG 200 for MES and scPTZ evaluation. The animals
were kept at an ambient temperature 22±1°C, in groups
of six per cage under standard laboratory condition and
permitted to free access to food and water (Krall et al.,
1978; Clark et al., 1984).
[
4-Methyl-2-(Naphthalen-2-yl) Thiazol-5-
yl](Morpholin-4-yl) Methanone (8b)
1
Yield: 78%; mp: 183C, LogP: 2.60, FT-IR νmax (cm ,
KBr pellets): 1679 (C = O), 1621 (C = C), 1592 (C = N).
1
H-NMR (300 MHz, DMSO-d
6
): δ 2.64 (s, 3H, CH
3
),
),
Maximal Electroshock Seizure Test (MES Test)
3
7
8
3
6
2
.62-3.65 (m, 4H, 2xCH ), 3.70-3.76 (m, 4H, 2xCH
2
.65-7.68 (m, 2H, Ar-H), 7.86-7.90 (m, 2H, Ar-H), 8.10-
.13 (m, 2H, Ar-H), 8.35 (s, 1H, Ar-H); ESI-MS m/z
38.11, 253.91, 226.09. Anal. Calcd for C19
Test compounds were delivered as an intraperitoneal
(i.p.) injection at dose of 30, 100 and 300 mg/kg body
weight and the anticonvulsant potential was measured
after 0.5 h and 4 h intervals of administration. Maximal
electroshock seizures were caused in mice by delivering
H N
18 2
2
O S: C,
7.43; H, 5.36; N, 8.28. Found: C, 67.48; H, 5.39; N, 8.32.
[
4-Methyl-2-(Naphthalen-2-yl) Thiazol-5-
6
0Hz, 50 mA electrical stimuli for 0.2 s via ear clip
yl](Thiomorpholin-4-yl)Methanone (8c)
electrodes. Abolition of hind limb tonic extensor
component of the seizure in half or more of the animals
is termed as protection.
1
Yield: 83%; mp: 191C, LogP: 3.48, FT-IR νmax (cm ,
KBr pellets): 1685 (C = O), 1626 (C = C), 1600 (C = N).
1
H-NMR (300 MHz, DMSO-d
6
): δ 2.64 (s, 3H, CH
3
),
),
Subcutaneous Pentylenetetrazole Seizure Test
3
7
8
3
6
2
.62-3.65 (m, 4H, 2xCH ), 3.70-3.76 (m, 4H, 2xCH
2
(scPTZ)
.65-7.68 (m, 2H, Ar-H), 7.86-7.90 (m, 2H, Ar-H), 8.10-
.13 (m, 2H, Ar-H), 8.35 (s, 1H, Ar-H); ESI-MS m/z
54.12, 254.21, 226.09. Anal. Calcd for C19
The scPTZ primarily pinpoints compounds that
H N
18 2
2
OS : C,
elevate seizure threshold. The sc PTZ test employs a
dose of pentylenetetrazol (85 mg/kg). This yields clonic
seizures lasting for a period of at least five seconds in 97
percent (CD97) of animals tested. Solutions of test
compounds were administered intraperitoneally at dose
level of 30, 100 and 300 mg/kg. At the estimated time of
testing (0.5 h and 4.0 h), the convulsant (PTZ) was
administered subcutaneously and animals were observed
over a 30 min period. Abolition of clonic seizure in half
or more of the animals in the observed time period
designated a compound’s ability to eliminate the effect
of pentylenetetrazol on seizure threshold.
4.38; H, 5.12; N, 7.90. Found: C, 64.45; H, 5.18; N, 7.95.
[
4-Methyl-2-(Naphthalen-2-yl) Thiazol-5-yl)](4-
Methylpiperazin-1-yl) Methanone (8d)
Yield: 76%; mp: 136C, LogP: 3.06, FT-IR νmax

1
(
(
cm , KBr pellets): 1684 (C = O), 1624 (C = C), 1597
1
C = N). H-NMR (300 MHz, DMSO-d
), 2.35-3.38 (m, 4H, 2xCH ), 2.64 (s, 3H, CH
.36-3.39 (m, 4H, 2xCH ),7.66-7.69 (m, 2H, Ar-H),
.84-7.87 (m, 2H, Ar-H), 8.06-8.09 (m, 2H, Ar-H), 8.33
6
): δ 2.28 (s, 3H,
NCH
3
2
3
),
3
7
2
(s, 1H, Ar-H); ESI-MS m/z 351.14, 254.16, 225.90.
3
2

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
In vitro GABA-Transaminase Inhibition Assay
and 300 mg/kg body weight of the animals. Phenytoin
and carbamazepine were used as the standard drugs for
the comparison.
As docking study demonstrated that these
compounds are binding with gamma aminotransferase
enzyme, the most active compounds were screened in
vitro against the γ-amino Butyric Acid-Transaminase
The synthesized compounds 7e, 7j, 7n and 8c
showed anticonvulsant potential at the dose level of 30
mg/kg after 0.5 h against the seizure spread indicating
rapid onset but shorter duration of action except 8c.
Compound 8c displayed protection after 0.5 h and 4 h
signifying quick onset and long duration of action.
Moreover, compounds 7b, 7d, 7g, 7h, 7k and 8d
exhibited MES protection at the dose level 100 mg/kg at
(
GABA-T) enzyme and the inhibitory activity was
evaluated. The GABA-T enzyme was isolated from
Pseudomonas fluorescens using a method described
previously (Scott and Jakoby, 1958). The assay was
performed for a 4 h time period according to the
standard procedure (Lippert et al., 1977).
0
.5 h, but after 4 h these analogues had displayed
protection at dose level 300 mg/kg indicating rapid onset
and short duration of action. The other compounds either
did not exhibit any protection or showed activity at a
dose of 300 mg/kg which is not significant enough to
consider them for other future investigations. As
previously discussed only those analogues were selected
for anti PTZ screening which had displayed a significant
anti MES activity. Therefore, compounds 7b, 7d, 7e, 7g,
7h, 7i, 7j, 7k, 7n and 8d were screened for anti PTZ
activity. Analogues 7h, 7i, 7j and 8c showed potential at
100 mg/kg dose after 0.5 h. Out of these, two analogues
notably 7h and 7i showed potential even after 4 h at an
increased dose of 300 mg/kg. The overall outcomes
suggested the quick onset of these analogues and short
duration of action in anti PTZ potential. A few
compounds for example 7b, 7d and 7g showed very less
anti PTZ activity and therefore, insignificant to mention.
When we correlate anticonvulsant data with
lipophilicity (log P) data, it is quite obvious that the
lipophilicity is not the only factor which diktats the
anticonvulsant activity. Therefore, compound 7e (log P =
Neurotoxicity Screening
The minimal motor damage was measured in mice by
the rotarod test. The mice were skilled to hold on
speeding up rotarod of diameter 3.2 cm that rotates at 10
Revolutions Per Minute (RPM). Neurotoxicity was
designated by the inability of the animal to withstand
equilibration on the rod for at least one minute in each of
the three experiments. The dose at which 50% of the
animals qualified to balance themselves and fell off the
rotating rod was determined (Dunham and Miya, 1957).
Ethanol Potentiation Test
Mice were subjected with the minimum test compound
(
30 mg/kg body weight) and 1 h later with ethanol 2.5 g

1
kg ip. This dose of ethanol did not bring lateral position
in the control animals. The number of animals that were in
the lateral position after getting ethanol in each group was
determined (Clerici and Pocar, 2001).
Results and Discussion
Chemistry
6
.50) and 7j (log P = 7.13) showed high activity against
MES. But the other two highly active compounds 7n and
8
3
c showed low lipophilicity (log P values are 4.14 and
.4 respectively). Log P values of the titled analogues are
The structures of synthesized analogues were
identified by elemental analysis, FT-IR, H NMR and
mass spectral data. FT-IR spectrum revealed four bands
1
shown in supplementary material.
The four most active compounds (7e, 7j, 7n and 8c)
were subjected to in vitro GABA-T inhibition assay to
establish the mechanism involved in the anticonvulsant
potential of the title analogues. The GABA-transaminase
enzyme has been found to be accountable for the
metabolism of GABA and therefore, inhibition of the
enzyme will cause in an elevated amount of GABA in
various brain parts. The results of the assay are offered in

1
for NH, C = O and C = C and C = N at 3378-3348 cm ,

1
1
1
1
692-1677 cm , 1629-1618 cm and 1607-1570 cm
1
respectively. The H NMR of 7a-7o confirmed presence
of NHC = O group exhibiting chemical shift (δ) in the
range of 12.69-9.30 with broad singlet shape and
splitting, exchangeable with D O while the same peak
2
was found absent in the compounds 8a-8e. The physical
and chemical data for newly synthesized analogues are
presented supplementary material.
“
Table 2”. All four analogues were observed to inhibit
the GABA-T enzyme at the 4 h time period. Compound
d was found to inhibit GABA-T almost throughout the
7
Anticonvulsant Activity
time periods, but the full inhibition shown by 7d was
20% at 4 h. Compound 7n inhibited the enzyme at 1 h
and maximum inhibition (12%) was detected at 4 h.
Compound 7j demonstrated second maximum inhibition
amongst these compounds. It displayed inhibition at 2 h
and continued to inhibit the enzyme considerably
throughout the time periods. Compound 8cexhibited less
enzyme inhibition and maximum inhibition was
witnessed at 4 h (11%).
The preliminary evaluation of the titled compounds
a-7o and 8a-8e were evaluated for anticonvulsant
7
activity utilizing the predictable animal models and the
neurotoxicity was assessed by rotorod test method. Of
these, the MES and scPTZ seizure models exemplify the
most widely used screening models in the search for new
anticonvulsant agents. Data are presented “Table 1” after
the 0.5 and 4 h time intervals at the dose level of 30, 100
3
3

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
Table 1: Anticonvulsant and neurotoxicity screen data of compounds (7a-o; 8a-e)
MES screening
--------------------------
scPTZ screening
----------------------------
Neurotoxicity screen
---------------------------
-
aEthanol
0.5 h
4.0 h
0.5 h
4.0 h
0.5 h
4.0 h
Potentiation
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
8
8
8
8
8
a
b
c
d
e
f
g
h
i
300
100
(—)
100
30
300
100
100
100
30
100
(—)
(—)
30
(—)
(—)
300
30
(—)
300
300
300
100
(—)
300
300
(—)
300
300
300
(—)
300
300
(—)
(—)
30
X
300
X
(—)
300
X
300
100
100
100
(—)
(—)
(—)
(—)
(—)
X
X
(—)
X
300
(—)
X
(—)
300
300
(—)
(—)
(—)
300
(—)
(—)
X
X
(—)
X
X
(—)
X
X
(—)
X
(—)
100
X
(—)
(—)
300
(—)
(—)
X
X
(—)
X
X
X
(—)
300
X
(—)
(—)
(—)
(—)
(—)
X
X
(—)
X
X
X
(—)
(+)
X
(—)
(—)
(+)
(—)
(—)
X
X
(—)
X
X
X
j
k
l
m
n
o
a
b
c
d
e
X
X
100
(—)
X
(—)
100
(—)
300
X
(—)
300
(—)
(—)
X
100
100
(—)
(—)
X
100
300
(—)
(+)
X
X
X
100
300
30
300
300
30
Phenytoin
Carbamazepine
30
100
3
0, 100 and 300 mg/kg body weight doses of the title analogues were delivered and the protection and neurotoxicity were estimated
after 0.5 and 4h. The figures pointed out the lowest dose required to show protection or neurotoxicity in 50% or more of the animals.
a
The dash (—) represents the absence of anticonvulsant potential or neuro-motor impairment. X represents not tested. Ethanol
potentiation test: (+), half or more animals passed the test; (–), half or more animals failed the test. X represents not tested.
Table 2: In vitro GABA-transaminase inhibition evaluation of selected compounds
a
Percentage inhibition of GABA-T
------------------------------------------------------------------------------------------------------------------------------
Compd. No.
Control
0.5 h
1.0 h
──
08
──
5
──
2.0 h
3.0 h
4.0 h
──
──
──
──
──
──
12
9
8
──
──
15
13
10
7`
──
20
18
12
11
7
7
7
8
a
e
j
n
c
In vitro enzyme inhibition was performed at a dose of 500 μM for each compounds
Fig. 3: Highest ligand scoring compound with catalytic domain of GABA aminotransferase protein
3
4

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
Fig. 4: Lig-plot: Highest ligand scoring compound 7k with catalytic domain of GABA aminotransferase protein
Fig. 5: Binding pose of rosmarinic acid (standard) with GABA aminotransferase protein
Fig. 6: Superimposition of rosmarinic acid (cyan) with highest ligand scoring compound (grey).
3
5

Mohammed Faiz Arshad et al. / American Journal of Pharmacology and Toxicology 2019, Volume 14: 27.37
DOI: 10.3844/ajptsp.2019.27.37
Only those compounds were selected for
neurotoxicity screening, which had shown good to
moderate anticonvulsant activity.
Majority of these compounds exhibited significant
activity against both animal models; however,
compounds 7e, 7j, 7n and 8c emerged as highly
active. These highly potent analogues did not show
any sign of neuromotor impairment when they were
subjected to rotorod and ethanol potentiation tests.
Docking analysis and GABA-transaminase inhibitory
assay suggested the mechanism of action of these
analogues. All these experimental data revealed that
these compounds might serve as lead candidates for
further design and development of anticonvulsant agents
with low toxicity and high efficacy.
Compound 7e showed considerable neuro-motor
impairment at a dose of 100 mg/kg in the rotorod test,
whereas compound 7i showed neurotoxicity at an
increased dose of 300 mg/kg. The rest of the compounds
did not show any neuro-motor impairment in rotorod test.
Compounds 7e, 7i and 8d showed an interaction with
motor system, due to which they potentiated the effect of
ethanol inducing the lateral position to the animals. The
rest of the analogues did not display any interaction with
ethanol at minimum dose of 30 mg/kg (Table 1).
We performed molecular docking on synthesized
Acknowledgement
compounds 7a-7o
&
8a-8e against GABA
The authors appreciate Shaqra University (KSA) for
providing various facilities to conduct this research work.
aminotransferase and the docking studies revealed a
common binding orientation of all the synthesized
compounds in the catalytic binding pocket of GABA
aminotransferase. Figure 3 shows highest ligand scoring
compound with catalytic domain of GABA
aminotransferase protein.
Log plot of highest ligand scoring analogue 7k with
catalytic domain of GABA aminotransferase protein is
offered in Fig. 4.
Author’s Contributions
Mohammed Faiz Arshad: Designed the concept of
this work and contributed in all sections.
Faisal Al-Otaibi: Performed antiepileptic activity of
the title compounds.
Binding pose of rosmarinic acid (standard) with
GABA aminotranseferase protein has been presented in
Fig. 5. Figure 6 shows superimposition of rosmarinic acid
Gulam Mustafa: Performed docking studies and
partly contributed in synthesis of the title compounds.
Saad Shousha: Contributed in toxicity evaluation.
(cyan) with highest ligand scoring compound (grey).
Abdulrahman
Alshahrani:
Contributed
in
The binding pose of compound (7k) has been
characterization of the title compounds and also
contributed in synthetic work.
compared with the standard co-crystal ligand which is
bonded with GABA aminotransferase protein. The
thiazole moiety of the compound indirectly plays a
significant role in binding with the amino acid. The
nitrogen atom of amino group is involved in hydrogen
bonding interactions with amino acid residue Glu270 and 2-
hydroxy substitution on phenyl ring forms hydrogen
bonding with Glu270 at the catalytic site (Fig. 3-6).
Hydrophobic amino acids Gly438, Cys439, Arg445, Ile72,
Phe189, Glu265, Gln301, Asp298, His190, Asn140 and
Val300 appeared as a cup like structure (Fig. 3-6). In
addition, the naphthalene moiety shows hydrophobic
interaction with GABA amino transferase protein
PHE189, VAL300, HIS190 and GLN301 amino acid
residues. It was also observed that ortho substitution in
phenyl moiety of 7k gives better interaction with
backbone of GABA aminotransferase protein. The
hydrogen bonding interaction may probably cause the
inhibition of GABA aminotransferase enzyme.
Conflict of Interest
The authors affirm that there is no conflict of interest
concerning the publication of this work.
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