Synthesis, biological evaluation and molecular docking studies of thiazole-based pyrrolidinones and isoindolinediones as anticonvulsant agents

Article abstract of DOI:10.1007/s00044-015-1371-3

A series of new 1-(thiazol-2-yl)pyrrolidin-2-one 5a-m and 2-(thiazol-2-yl)isoindoline-1,3-dione 6a-n derivatives were synthesized and evaluated for anticonvulsant activity. The activity was established in three seizure models: PTZ, picrotoxin and MES. Selected compounds were elected for neurotoxicity by the rotarod test. The most active compound of the series was 1-(4-(naphthalen-2-yl)thiazol-2-yl)pyrrolidin-2-one (5g), showing a PTZ effect dose (ED₅₀) value of 18.4 mg/kg in mice. The median toxic dose (TD₅₀) was 170.2 mg/kg, which provided a protection index (PI = TD₅₀/ED₅₀) of 9.2. A computational study was also carried out, including prediction of pharmacokinetic properties and docking studies. The structural assignments of the newly synthesized compounds were elucidated on the basis of spectroscopic data and single-crystal X-ray crystallography. Graphical Abstract: A series of new thiazole-based pyrrolidinones 5a-m and isoindolinediones 6a-l were synthesized and tested as anticonvulsant. The most active compound was 1-(4-(naphthalen-2-yl)thiazol-2-yl)pyrrolidin-2-one (5g), showing ED₅₀ value 18.4 mg/kg.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-015-1371-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1371-3
ORIGINAL RESEARCH
Synthesis, biological evaluation and molecular docking studies
of thiazole-based pyrrolidinones and isoindolinediones
as anticonvulsant agents
Hazem A. Ghabbour1,4
Adnan A. Kadi1 Kamal E. H. ElTahir2
•
•
•
Rihab F. Angawi3 Hussein I. El-Subbagh4
•
Received: 18 February 2015 / Accepted: 15 April 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of new 1-(thiazol-2-yl)pyrrolidin-2-one
5a–m and 2-(thiazol-2-yl)isoindoline-1,3-dione 6a–n deriva-
tives were synthesized and evaluated for anticonvulsant ac-
tivity. The activity was established in three seizure models:
PTZ, picrotoxin and MES. Selected compounds were elected
for neurotoxicity by the rotarod test. The most active com-
pound of the series was 1-(4-(naphthalen-2-yl)thiazol-2-
yl)pyrrolidin-2-one (5g), showing a PTZ effect dose (ED50)
value of 18.4 mg/kg in mice. The median toxic dose (TD50)
was 170.2 mg/kg, which provided a protection index
(PI = TD50/ED50) of 9.2. A computational study was also
carried out, including prediction of pharmacokinetic proper-
ties and docking studies. The structural assignments of the
newly synthesized compounds were elucidated on the basis of
spectroscopic data and single-crystal X-ray crystallography.
Graphical Abstract A series of new thiazole-based
pyrrolidinones 5a–m and isoindolinediones 6a–l were
synthesized and tested as anticonvulsant. The most active
compound was 1-(4-(naphthalen-2-yl)thiazol-2-yl)pyrro-
lidin-2-one (5g), showing ED50 value 18.4 mg/kg.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-015-1371-3) contains supplementary
material, which is available to authorized users.
& Hazem A. Ghabbour
ghabbourh@yahoo.com
1
Department of Pharmaceutical Chemistry, College
of Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia
2
Department of Pharmacology, College of Pharmacy,
King Saud University, Riyadh 11451, Saudi Arabia
3
Department of Chemistry, College of Science, King
Abdulaziz University, P.O. Box 54881, Jidda 21589,
Saudi Arabia
4
Department of Medicinal Chemistry, Faculty of Pharmacy,
Mansoura University, Mansoura 35516, Egypt
123

Med Chem Res
information on the cellular mechanism of human epilepsy
along with the complex mechanism of action of the ma-
jority of AEDs makes it difficult to use rational method-
ologies of discovery. Therefore, an alternative design of
new anticonvulsants is based on the different pharma-
cophores that were established through the analysis of
structural characteristics of clinically effective drugs as
well as other anticonvulsant active compounds (Alam
et al., 2010; Deng et al., 2010; Kaushik et al., 2010a, b).
Structure–activity relationship (SAR) studies of some
clinically available AEDs (e.g., phenytoin I, ethosuximide
II, levetiracetam III, brivaracetam IV) and other anticon-
vulsant compounds V–VII (Fig. 1) revealed that many of
these compounds possess five-membered cyclic imide
moieties in their structures (Bialer et al., 2007; Estrada and
Pena, 2000; Kenda et al., 2004; LeTiran et al., 2001; Ob-
niska et al., 2002; Ragavendran et al., 2007; Wong et al.,
1986). It is also well documented that nitrogen hetero-
atomic systems such as diazole, triazole, tetrazole, oxazole,
oxadiazole, thiazole, thiadiazole or benzothiazole are one
of the important core fragments that are incorporated in
many anticonvulsant agents (Amir et al., 2013; Kamboj
et al., 2015; Levandovskiy et al., 2011; Manna et al., 2014;
VandeVrede et al., 2014). Thiazole compounds are found
in many drug developments as antitumor (Gursoy and
Guzeldemirci, 2007; Wells et al., 2003), anticonvulsant
(Amin et al., 2008; Dawood et al., 2006; Koufaki et al.,
2007), anti-inflammatory (Rostom et al., 2009), antihy-
pertensive (Kashyap et al., 2012), antimicrobial (Bondock
et al., 2007, 2010, 2013; Guzeldemirci and Kucukbasmaci,
2010; Shiradkar et al., 2007), antioxidant (De et al., 2008;
Shih and Ke, 2004; Shih et al., 2007), antifungal (Narayana
Keywords 2-Aminothiazole Á Anticonvulsants Á
Neurotoxicity Á Molecular docking Á X-ray crystallography
Introduction
Epilepsyis a commondisordercharacterized byvariousforms
of seizure and results from episodic neural discharges. Nearly
all epileptic seizures are characterized by predominance of
excitation over inhibition either simultaneously in many brain
structures (primary, generalized convulsive seizures) or in a
part of the brain (partial, focal seizures). Epilepsy affects
0.5–1 % ofthe population(Hemming etal., 2008). Epilepsy is
treated mainly by drugs, and in severe cases, brain surgery can
be used. Current antiepileptic drugs (AEDs) are phenobarbi-
tal, phenytoin, carbamazepine, vigabatrin, valproate, felba-
mate and lamotrigine. They are effective in controlling
seizures in about 70 % of the patients, but their use is often
limited by side effects such as headache, nausea, anorexia,
ataxia, hepatotoxicity, drowsiness, gastrointestinal distur-
bance, gingival hyperplasia and hirsutism (Brodie and Kwan,
2012; Johannessen and Landmark, 2010). Thus, there is an
enormous need for the development of novel AEDs with
fewer side effects and increased effectiveness.
Currently used AEDs can be classified into four main
categories on the basis of molecular mechanisms of action.
These categories are as follows: (1) modulation of voltage-
dependent Na? and/or Ca2? channels, (2) enhancement of
the GABA-mediated effect or other effect on the GABA
system, (3) inhibition of synaptic excitation mediated by
ionotropic glutamate receptors and (4) modulation of sy-
naptic release (Pollard and French, 2006). The incomplete
123

Med Chem Res
O
O
O
O
O
NH
N
NH
O
O
N
N
N
H
N
O
O
H
O
NH2
NH2
I
II
III
IV
V
Cl
O
O
N
O
N
N
N
S
O
F
O
F
F
NH2
N
HN
O
Cl
VI
IX
VII
IIX
Fig. 1 Structures of some AEDs and anticonvulsant compounds incorporating a five-membered cyclic imide moiety
The design and synthesis of the titled compounds were
carried out with two objectives. The first was the molecular
hybridization of the pyrrolidinone moiety and thiazoles
(Fig. 2). The second was using different substitutions at
positions 4 and 5 of the thiazole ring which may improve
the anticonvulsant activity.
N
S
F
N
F
F
NH2
H2N
O
O
O
Riluzole
(IX)
Levetiracetam
(III)
The present work comprises the synthesis and anticon-
vulsant activity of 1-(thiazol-2-yl)pyrrolidin-2-one deriva-
tives 5a–m (Fig. 2) and 2-(thiazol-2-yl)isoindoline-1,3-
dione derivatives 6a–n (Scheme 1). Their chemical struc-
tures were identified using IR, 1H NMR, 13C NMR, HRMS
spectral analysis, molecular modeling studies and the pre-
diction of ADME (absorption, distribution, metabolism and
elimination) properties. In addition, a single-crystal X-ray
crystallography technique was performed for compounds
5a and 6e.
R
N
S
N
O
5a-m
Fig. 2 Design of the titled compounds 5a–m as anticonvulsants by
molecular hybridization of five-membered cyclic imide moiety and
thiazole ring
As in many classes of drugs, the preclinical discovery
and the development of a novel bioactive chemical entity
for the treatment of epilepsy rely heavily on the use of
predictable animal models. There are well documented
in vivo animal models that are routinely used by most
AEDs discovery programs. These include PTZ, picrotoxin
(PIC) and MES. The PTZ- and MES-induced seizure
models are recognized as the ‘‘gold standards’’ in the early
stages of testing and are most widely used in the search for
novel AEDs (White, 2003). These tests are designed to
detect new bioactive chemical entities affording protection
to generalized absence ‘‘petit mal’’ seizures and general-
ized tonic–clonic ‘‘grand mal’’ seizures (El-Behairy et al.,
2014). All the synthesized compounds 5a–m and 6a–n
were evaluated for their initial anticonvulsant activity.
et al., 2004), antischizophrenic agents (Yurttas et al.,
2013), anti-HIV agents (Zia et al., 2012), and also for the
treatment of pain (Thore et al., 2013) and as inhibitors of
bacterial DNA gyrase (Gursoy and Guzeldemirci, 2007;
Shiroya and Patel, 2013). For examples, chlormethiazole
IIX, a thiazole derivative obtained from thiamine mole-
cule, is used as a sedative or hypnotic and can also be used
intravenously in treating status epilepticus (Nair et al.,
2011; Shorvon, 2013). Riluzole IX is a potent neuropro-
tective drug with additional anticonvulsant activity (Cole-
man et al., 2015). Additionally, N-substituted phthalimides
have important biological activities including anticonvul-
sant activities (Fhid et al., 2014; Ragavendran et al., 2007;
Tiwari et al., 2014; Yadav et al., 2012).
123

Med Chem Res
R
X
5a C6H5
H
5b 4-CH3C6H4
5c 4-ClC6H4
5d 4-BrC6H4
5e 3,4-(OCH3)2C6H3
5f 4-C6H5C6H4
10H7
5h C6H5
5i 4-CH3C6H4
5j 4-ClC6H4
5k 4-BrC6H4
5l 3,4-(OCH3)2C6H3 Br
5m CH3CH2OCO
H
H
H
R
H
N
H
5g
C
H
X
N
S
Br
Br
Br
Br
O
5a-m
iv
Br
R
O
O
R
R1
H
O
Cl
Cl
Cl
Cl
N
Cl
6a C6H5
6b 4-CH3C6H4
6c 4-ClC6H4
6d 4-BrC6H4
6e 3,4-(OCH3)2C6H3
6f 4-C6H5C6H4
6g C10H7
6h C6H5
6i 4-CH3C6H4
6j 4-ClC6H4
H
iii
X
iii
S
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
4a-m
R
R
N
O
N
i
ii
Br
R
NH2
NH2
Br
S
6k 4-BrC6H4
6l 3,4-(OCH3)2C6H3
6m 4-C6H5C6H4
S
1a-h
2a-h
3a-f
6n
C10H7
R1
R1
R1
O
N
v
O
R
N
R1
R1
R
R1
R1
N
O
- H2O
R1
R1
NH
HO
S
O
O
S
R1
O
R1
O
R1
6a-n
Scheme 1 Synthetic route of the target compounds. Reagents and
conditions: i ethanol, reflux 30 h then stirring 12 h at RT, 68–90 %. ii
Glacial acetic acid, heating 90 min at 80 °C, 65–79 %. iii K2CO3,
CHCl3, stirring 48 h at RT, 55–85 %. iv Piperidine, toluene, reflux
24 h, 59–81 %. v Glacial acetic acid, anhydrous sodium acetate,
reflux 3 h, 74–90 % or fusion in oil bath for 2 h, 68–82 %
bath without solvent. Alternatively, refluxing 2-aminothia-
zoles 2a–g with phthalic anhydrides and anhydrous sodium
acetate in glacial acetic acid.
Results and discussion
Chemistry
The structural assignments of the new compounds 5a
1
and 6e were elucidated on the basis of IR, H NMR, 13C
The reaction sequence leading to the formation of the titled
compounds, 1-(thiazol-2-yl)pyrrolidin-2-ones 5a–m and
2-(thiazol-2-yl)isoindoline-1,3-diones 6a–n, is shown in
Scheme 1. The 2-aminothiazoles 2a–h were obtained by re-
acting 2-bromo-1-arylethanones 1a–h with thiourea in etha-
nol. The 5-bromothiazol-2-amine derivatives 3a–f were
prepared by bromination of 2-aminothiazoles 2a–f in glacial
acetic acid at room temperature. The N-(thiazol-2-yl)-4-
chlorobutanamides 4a–m were synthesized by reaction of
2-aminothiazoles 2a–h and 3a–f with 4-chlorobutyryl in
chloroform. The N-(thiazol-2-yl)-4-chlorobutanamides 4a–
m were refluxed in toluene in the presence of piperidine to
yield 1-(thiazol-2-yl)pyrrolidin-2-ones 5a–m. 2-(Thiazol-2-
yl)isoindoline-1,3-diones 6a–g were obtained directly by
heating phthalic anhydrides with 2-aminothiazoles 2a–g in oil
NMR, HRMS and single-crystal X-ray crystallography.
The formation of 5-bromothiazol-2-amine derivatives 3a–f
was confirmed by the absence of the singlet at dH 7.1 ppm
characterized for the thiazole H in 1H NMR spectrum. The
IR spectrum of the titled compound 5b showed a band at
1681 cm-1 characterized for amide C=O and CH3 band at
3099 cm-1. Its 1H NMR spectrum showed a multiplet at dH
2.18 ppm and two triplets at dH 2.64 and 4.14 ppm for the
pyrrolidinone protons. In addition, the spectrum showed a
singlet at dH 2.33 ppm for the CH3 protons, another singlet
at dH 7.63 ppm of the thiazol-H and two doublets at dH
7.24 and 7.83 ppm for the aromatic protons. Mass spectral
data have further confirmed its purity and molecular
weight.
123

Med Chem Res
Crystallography
Molecular modeling study
The crystallographic structures of 5a and 6e are repre-
sented in Fig. 3. The single-crystal X-ray study on both
derivatives unambiguously defines the exact structure. The
bond lengths and angles are in normal ranges (Allen et al.,
1987).
Molecular docking is a very popular method employed
to investigate molecular association. It is particularly
useful in the drug discovery arena to study the binding
of small molecules (ligands) to macromolecules (re-
ceptor or enzyme). Docking-based drug design by the
use of structural biology remains one of the most
logical and esthetically pleasing approaches in the drug
discovery process. The structured knowledge of the
binding capabilities of the active site residues to
specific groups on the agonist or antagonist leads to
various proposals for the synthesis of very specific
agents with a high probability of biological action
(Barril and Morley, 2005).
Pharmacology
In this study, three seizure models were used for pre-
liminary (phase I) screening of the synthesized compounds
5a–m and 6a–l, and the results are presented in Table 1.
The PTZ screen showed that compounds 5b, 5c, 5e, 5f, 5g,
5i, 5j, 5m, 6a, 6b, 6g, 6h, 6i, 6k and 6l were found to be
active after 0.5 or/and 4.0 h, and the other derivatives were
found to be devoid of anticonvulsant activity in the PTZ
model under specified conditions. The most active com-
pound was 5g, characterized by a low ED50 and a high PI.
The same pattern of activity of the investigated com-
pounds withdrawn from PTZ model was emphasized in the
PIC model (Table 1). Compounds 5e, 5h, 5i, 5l, 5m, 6f, 6k
and 6l proved to be the most active compounds in this
study with remarkable protection against PIC-induced
convulsions. This result suggests that the active compounds
may act directly as GABAA receptor agonist. The sug-
gested modes of action are either indirectly by increasing
GABA synthesis or its release as a brain inhibitory neu-
rotransmitter or that they may act by inhibiting the c-amino
butyrate aminotransferase (GABA-AT) enzyme. None of
the tested compounds prevented the convulsions induced
by maximal electric shock. In the neurotoxicity test, the
percentage of mice that dropped from the rod within 3 min
was calculated and converted into probit and plotted
against the log dose. The dose of the compound that im-
paired the staying of the animals on the rod and impaired
the motor coordination of the animals in the 50 % of tested
animals was labeled TD50. Potential compounds were also
subjected to quantification studies, and the corresponding
ED50, TD50 and PI are reported in Table 1.
GABA is a predominant inhibitory neurotransmitter
in mammalian central nervous system (CNS) modulat-
ing central inhibitory tone that acts via the activation of
ionotropic GABAA and GABAC receptors and G-pro-
tein-coupled GABAB receptors (Osolodkin et al., 2009).
GABA-AT catalyzes the degradation of GABA to
succinic semialdehyde. Depleted levels of GABA have
been shown to cause convulsions (Bansal et al., 2012).
Raising GABA levels in the brain has an anticonvulsive
effect (Madsen et al., 2011). GABA-AT is a validated
target for AEDs because its selective inhibition raises
GABA concentration in the brain (Bansal et al., 2013).
Docking with GABA-aminotransferase model
To compare the binding affinity of the newly synthe-
sized compounds, they were docked in the empty
binding site of GABA-AT (PDB entry 1OHV) (Storici
et al., 2004). Vigabatrin (standard drug) reveals Mol-
Dock score of -83.46 and forms three hydrogen bonds
between its carboxylic moiety and Ser 137 with a bond
˚
distance of 2.99 A and another two bonds with Thr 353
˚
with bond distances of 2.91 and 3.02 A (Fig. 4a).
Compounds 5a–m and 6a–n exhibited binding scores
ranging from -175.29 to -90.69. Compounds 5f and
Fig. 3 ORTEP drawings with atomic numbering scheme of the asymmetric units of 5a (left) and 6e (right) with displacement ellipsoids 40 %
probability level. The dashed line indicates intramolecular hydrogen bond between C1-H1AÁ Á ÁN2
123

Med Chem Res
Table 1 Anticonvulsant activity of the tested compounds
Compounds
R
X
R1
PTZ
Picrotoxin
0.5 h
ED50 (mg/kg)
TD50 (mg/kg)
PI
0.5 h
4.0 h
4.0 h
5a
5b
5c
5d
5e
5f
C6H5
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
–
–
–
–
–
–
–
4-CH3C6H4
4-ClC6H4
300
300
–
–
–
–
–
–
–
–
–
–
–
–
–
4-BrC6H4
–
–
–
–
–
–
3,4-(OCH3)2C6H3
4-C6H5C6H4
300
200
200
–
300
300
300
–
300
–
–
108.5
227.8
2.1
3.2
9.2
–
–
56.9
185.6
5g
5h
5i
C
10H7
–
–
18.4
170.2
C6H5
100
300
–
300
–
–
–
4-CH3C6H4
4-ClC6H4
300
300
–
–
–
–
–
5j
–
–
–
–
–
5k
5l
4-BrC6H4
–
–
–
–
–
–
3,4-(OCH3)2C6H3
CH3CH2OCO
C6H5
–
–
100
300
–
300
–
–
–
–
5m
6a
6b
6c
6d
6e
6f
300
300
300
–
–
129.6
259.2
2.0
1.9
3.1
–
H
300
300
–
–
110.2
209.4
4-CH3C6H4
4-ClC6H4
H
–
–
90.2
279.6
H
–
–
–
–
4-BrC6H4
H
–
–
–
–
–
–
–
3,4-(OCH3)2C6H3
4-C6H5C6H4
H
–
–
–
–
–
–
–
H
–
–
300
–
–
–
–
–
6g
6h
6i
C
10H7
H
300
300
300
–
–
–
–
–
–
C6H5
Cl
Cl
Cl
Cl
Cl
Cl
Cl
–
–
–
–
–
–
4-CH3C6H4
4-ClC6H4
300
–
–
–
122.1
–
276.4
–
2.26
–
6j
–
–
6k
6l
4-BrC6H4
300
300
–
300
–
300
100
–
–
138.0
111.3
–
276.0
189.2
–
2.0
1.7
–
3,4-(OCH3)2C6H3
4-C6H5C6H4
300
–
6m
6n
–
C
10H7
–
–
300
–
–
–
–
Doses of 100, 200 and 300 mg/kg were administered. The numbers in the table indicate the minimum dose whereby bioactivity was demon-
strated in half or more of the mice. The dash (–) indicates the absence of activity at maximum dose administered (300 mg/kg)
Docking with human GABAA homology model
5g have good MolDock scores, -155.36 and -163.80,
respectively, where they show the highest biological
activities. Compound 5g is the most active one among
the series. It forms two hydrogen bonds. One hydrogen
bond is between oxygen of pyrrolidin-2-one moiety
The GABAA receptor is a pentameric ligand-gated ion
channel (2a1, 2b2, 1c2). GABA binding site is the receptor
located between a and b subunits, and the benzodiazepine
(BDZ) binding site is located on the extracellular surface at
the interface of the a and c subunits (Fig. 6a) (Sigel, 2002).
Although several studies have made significant strides in
uncovering the specific amino acid residues that contribute
to the binding of classical BDZ, complete descriptions of
the residues that preferentially contribute to the binding of
non-BZD ligands and the orientation of these ligands
within the BZD site are relatively unknown (Sigel, 2002).
The results of docking studies of the reference drugs
(diazepam, flunitrazepam, eszopiclone and zolpidem) and
the tested compounds show good interactions with BZD
˚
with Glu 301 of distance 3.01 A. The other hydrogen
bond is between nitrogen of thiazole ring and Lys 329
˚
with bond distance 2.85 A and also the naphthyl moiety
located in the hydrophobic pocket Trp 354 and Phe
189. The position of thiazole derivatives 5g overlaps
well with vigabatrin (standard drug) (Figs. 4b, 5).
Lipophilicity appears to play crucial role in 5g in-
hibitory activity, as naphthyl moiety is properly ori-
ented to the more lipophilic area of GABA-AT binding
site and forms CH–p interaction with Phe 189 and Trp
354.
123

Med Chem Res
Fig. 4 a Vigabatrin with more hydrogen bonding to GABA-AT active site. b Interactions between compound 5g and GABA-AT active site
superimposed with standard inhibitor vigabatrin (red molecule) (Color figure online)
and -269.13, respectively. Taking into account the above
results, differences in binding to the GABAA receptor
within the two series 5a–m and 6a–n arise from the bal-
ancing of the H-bond network and internal energy which is
a result of the different orientations of molecules into the
same site of the receptor (Fig. 6d).
CONH2
Gln 301
HOOC
NH2
O
N
N
O
S
ADME properties
NH2
HO
NH2
COOH
Phe 189
H2N
A computational study for the prediction of the ADME
properties of the titled compounds was performed, and the
results are presented in Table 2. Topological polar surface
area (TPSA) is a descriptor that was shown to correlate
well with passive molecular transport through membranes
and, therefore, allows prediction of transport properties of
the drugs in the intestines and blood brain barrier (BBB)
crossing (Ertl et al., 2000). The percentage of absorption
(%ABS) was calculated using TPSA. The molecules have
ideal ADME properties, showing high percentage of in-
testinal absorption. Log P, number of rotatable bonds
(Veber et al., 2002) and violations of Lipinski’s rule of five
were calculated by using Molinspiration online property
calculation toolkit (‘‘Molinspiration Cheminformatics:
http://www.molinspiration.com/services/properties.html’’).
Calculated log P for synthesized compounds were then
compared with the experimental capacity factor K data of
these compounds.
Lys 329
HOOC
H2N
N
H
Trp 354
Fig. 5 Possible interactions between compound 5g and the active site
of GABA-AT enzyme
binding site residues. Eszopiclone makes nine hydrogen
bonds with amino acid residues: Ser 61, His 101, Arg 144
and Tyr 199, and reveals MolDock score of -293.75
(Fig. 6b). Compounds 5a–m have MolDock scores ranging
from -211.30 to -305.27. This range increases in com-
pounds 6a–g from -271.82 to -298.37 and reaches the
highest level in compounds 6h–n, from -299.05 to
-313.61. Compound 6l which has the highest MolDock
score in this experiment makes five hydrogen bonds with
amino acid residues: Asn 60, Ser 61, Arg 144, Trp 196 and
Trp 199 (Fig. 6c). Biologically, the most active com-
pounds, 5f and 5g, show good MolDock score, -305.27
From all these parameters, it can be observed that all the
titled compounds exhibited a great %ABS ranging from
84.7 to 97.5 % (Table 2). Furthermore, compounds 6k,
6l and 6m show violated two Lipinski’s parameters. All
the other compounds obey Lipinski’s parameters, making
them potentially promising agents for epilepsy therapy.
123

Med Chem Res
Fig. 6 a Homology model of the a1b2c2 GABAA receptor pentamer
as seen from the extracellular membrane surface. Arrows indicate that
GABA binds at the b2/a1 interfaces, whereas benzodiazepines
(BZDs) bind at the a1/c2 interface of the receptor. b Best pose of
eszopiclone (sticks): blue dashes represent H-bonds. c Best pose of
compound 6l (sticks): blue dashes represent H-bonds. d Poses of 5a
(red lines) and 6h (gray lines) in the BDZ binding site of GABAA
receptor, showing the inversion of the whole molecule leads to a
different binding mode (Color figure online)
Lipophilicity determination
leading and the most frequently used chromatographic
method for the routine lipophilicity determination. It enables
rapid, accurate and high-reproducibility analysis of
relatively large sets of samples. These experiments are
usually performed on reverse phase systems, where the
chromatographic retention behavior of an analyte is directly
related to its lipophilicity. The lipophilicity of the two series
5a–m and 6a–n of the anticonvulsant agents was determined
using HPLC analyses on the modern C18-monolithic sta-
tionary phase which seems to be a reasonable alternative to
the common stationary phase. Their higher permeability and
higher stability resulted from the nature of monoliths enable
the use of a fast flow. The experimental data (log K) and
calculated Clog P values by ChemBioDraw Ultra 11 soft-
ware were compared and are shown in Table 2.
The titled compounds showed dependence of biological
activity on lipophilic character in a congeneric series. In
particular, for drugs acting on central nervous system to be
potent, they have to cross BBB. Thus, potency has been
correlated with optimum lipophilicity (log P). The basic
experimental method for the determination of lipophilicity is
based on the partitioning of a molecule in a system of two
immiscible phases (aqueous and lipophilic ones). Practical-
ly, this is performed using traditional shake-flask procedure
with subsequent determination of the concentrations of the
compound in both phases. Although different solvents were
investigated for this purpose, octanol–water system remains
the most popular model (Valko, 2004). Unfortunately,
shake-flask method is extremely time-consuming and labor-
intensive. It requires a high purity of the tested substances
and often suffers from solubility and stability problems.
Hence, nowadays this complicated approach was almost
completely substituted by modern chromatographic tech-
niques (Gocan et al., 2006; Liu et al., 2005). Among them,
high-performance liquid chromatography (HPLC) is the
Conclusion
A series of 1-(thiazol-2-yl)pyrrolidin-2-one and 2-(thiazol-
2-yl)isoindoline-1,3-dione derivatives were designed and
synthesized. The anticonvulsant activity and the
123

Med Chem Res
Table 2 Pharmacokinetic parameters of the tested compounds
Compounds %ABS TPSA (A2) n-ROTB MW
MV
–
n-OHNH donors n-ON acceptors Lipinski’s violations Log K Clog
B1
Rule
–
–
–
\500
\5
\10
5a
5b
5c
5d
5e
5f
97.5
97.5
97.5
97.5
91.1
97.5
97.5
97.5
97.5
97.5
97.5
91.1
88.4
91.0
91.0
91.0
91.0
84.7
91.0
91.0
91.0
91.0
91.0
91.0
84.7
91.0
91.0
33.20
33.20
33.20
33.20
51.66
33.20
33.20
33.20
33.20
33.20
33.20
51.66
59.50
51.96
51.96
51.96
51.96
70.43
51.96
51.96
51.96
51.96
51.96
51.96
70.43
51.96
51.96
2
2
2
2
4
3
2
2
2
2
2
4
4
2
2
2
2
4
3
2
2
2
2
2
4
3
2
244.31 213.33
258.34 229.89
278.76 226.87
323.21 231.22
304.37 264.43
320.41 284.74
294.37 257.33
323.21 231.22
337.24 247.78
357.66 244.76
402.11 249.10
383.26 282.31
319.18 221.14
306.34 253.32
320.37 269.88
340.79 266.86
385.24 271.21
366.39 304.41
382.44 324.73
356.40 297.31
444.12 307.46
458.15 324.02
478.57 321.00
523.02 325.35
504.17 358.56
520.22 378.87
494.96 351.46
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3
3
3
3
5
3
3
3
3
3
3
5
5
4
4
4
4
6
4
4
4
4
4
4
6
4
4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
2
3
2
1
2.02
2.42
2.69
3.35
1.89
4.11
3.26
2.74
358
2.54
3.04
3.26
3.41
2.27
4.43
3.71
3.15
3.65
3.87
4.02
2.88
1.10
3.80
4.30
4.52
4.67
3.53
5.69
4.97
6.31
6.81
7.02
7.17
6.04
8.19
7.48
5g
5h
5i
5j
3.63
3.86
2.44
0.89
3.94
4.39
4.44
4.70
3.59
4.92
4.41
6.01
6.44
6.61
6.60
5.52
7.24
7.01
5k
5l
5m
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6 l
6m
6n
%ABS the percentage of absorption, TPSA (A2) topological polar surface area, n-ROTB number of rotatable bonds, MW molecular wight,
MV molecular volume, log K log capacity factor
neurotoxicity of the compounds were evaluated after in-
traperitoneal (i.p.) administration in three seizure models:
the PTZ, the PIC and the MES models. Computational
studies that cover prediction of the pharmacokinetic prop-
erties and docking studies were also performed. Compound
5g displayed significant protection and emerged as the lead
in this series. The results of the docking studies showed
that the compounds exhibited good binding properties of
GABAA to human homology model and GABA-AT en-
zyme. The data of docking studies strongly support the
assumption that these receptors may be involved in ob-
served anticonvulsant activity of 1-(thiazol-2-yl)pyrrolidin-
2-one and 2-(thiazol-2-yl)isoindoline-1,3-dione deriva-
tives. However, further studies need to be carried out to
ascertain the precise mechanism of action of anticonvulsant
activity of these molecules.
Experimental
Instrumentation and chemicals
Melting points (°C) were measured and uncorrected in open
glass capillaries using Branstead 9001 electrothermal melting
point apparatus. Infrared (IR) spectra were recorded in
potassium bromide (KBr) disks using Shimadzu FT-IR
spectrophotometer in the region 4000–400 cm-1
(500 MHz) and 13C (125 MHz) NMR spectra were obtained
¨
on Bruker AC 500 Ultra Shield spectrometer (Fallanden,
.
1H
Switzerland). High-resolution mass spectra (HRMS) were
measured with JEOL the Tandem MStation JMS-700. X-ray
data collection was carried out on Bruker SMART APEX II
CCD diffractometer, cell refinement: SAINT; data reduction:
SAINT; program used to solve structure: SHELXS; program
123

Med Chem Res
(DMSO-d6) d: 7.12 (brs, 2H, NH2), 7.62 (m, 2H, Ar-H),
7.76 (m, 2H, Ar-H). 13C NMR (DMSO-d6) d: 87.7 (C-Br),
121.0, 129.8, 131.1, 132.8 (Ar-C), 145.8 (thiazole C), 167.0
(C-NH2).
used to refine structure: SHELXL; molecular graphics:
SHELXTL; software used to prepare material for publication:
SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2009).
Synthesis
Bromo-4-(3,4-dimethoxyphenyl)thiazol-2-amine (3e)
(Shetty et al., 2010) Mp: 128–130 °C, yield = 65 %.
1
FT-IR (KBr, cm-1): 3386, 3274 (NH2), 3110 (Ar CH). H
General procedure of 2-aminothiazole derivatives 2a–h
NMR (DMSO-d6) d: 3.72 (s, 6H, OCH3), 6.84 (d, 1H,
J = 8 Hz, Ar-H), 6.92 (d, 1H, J = 8 Hz, Ar-H), 7.2 (s, 2H,
NH2), 7.41 (s, 1H, Ar-H). 13C NMR (DMSO-d6) d: 63.4
(OCH3), 101.2 (thiazole C-Br), 124.8, 125.2, 127.4, 127.9,
139.2, 139.8 (Ar-C), 147.1 (thiazole C), 168.8 (C-NH2).
2-Bromo-1-arylethanones (0.015 mol) were added to a
solution of thiourea (1.5 g, 0.02 mol) in ethanol (50 mL).
The mixture was reflux for 8 h and then cooled down to
room temperature. The solvent was removed to half its
volume in vacuum. The residue was brought to about pH 9
using ammonia. The mixture was extracted by EtOAc, and
the extract was washed with saturated NaCl solution and
dried over anhydrous Na2SO4. The solvent was removed in
vacuum to give a precipitate which was crystallized from
ethanol to afford the target compounds 2a–h.
Ethyl 2-amino-5-bromothiazole-4-carboxylate (3f) Mp:
115–117 °C, yield = 79 %. 1H NMR (DMSO-d6) d: 1.26 (t,
3H, J = 6 Hz, CH3), 4.21 (q, 2H, J = 7 Hz, OCH2), 7.46 (s,
2H, NH2). 13C NMR (DMSO-d6) d: 14.0 (CH3), 60.4
(OCH2), 101.3, 138.8 (thiazole C) 160.6 (C-NH2), 166.7
(C=O).
General procedure of 5-bromothiazol-2-amine derivatives
General procedure of N-(thiazol-2-yl)-4-chlorobutanamide
3a–f
derivatives 4a–m
2-Aminothiazoles (0.1 mol) were dissolved in the least
amount of glacial acetic acid, and then bromine (0.11 mol)
was added drop-wise with continuous stirring at room
temperature. The mixture was heated at 80 °C for 90 min
then stirred at room temperature for 12 h. The mixture was
filtered and washed with water. The precipitate was heated
in water, and the aqueous solution was alkalized by am-
monia, filtered, washed with water and then dried. Crystals
were formed from ethanol/water to give the 5-bromothia-
zol-2-amine compounds 3a–f.
A mixture of 2-aminothiazole derivatives 2a–h and 3a–e
(1.0 mmol) and K2CO3 (4.0 mmol) was stirred at room
temperature with drop-wise addition of 4-chlorobutyryl
chloride (4.0 mmol) in chloroform for 48 h. The reaction
mixture was monitored by TLC (using chloroform/ethyl
acetate 9:1). Ammoniated water was added, and the or-
ganic layer was separated and dried over anhydrous Na2-
SO4, and the solvent was removed in vacuum. The
resulting precipitate was crystallized from ethanol to give
crystals of pure N-(thiazole-2-yl)-4-chlorobutanamide
derivatives.
5-Bromo-4-phenylthiazol-2-amine (3a) (Sadigova, 2008) Mp:
1
155–156 °C, yield = 65 %. H NMR (DMSO-d6) d: 7.76
N-(4-phenylthiazol-2-yl)-4-chlorobutanamide (4a) Mp:
158–161 °C, yield = 55 %. FT-IR (KBr, cm-1): 3434
(m, 5H, Ar-H), 13.2 (brs, 2H, NH2). 13C NMR (DMSO-d6) d:
87.6 (C-Br), 128.6, 129.2, 132.1, 135.1 145.8 (Ar-C), 166.0
(C-NH2).
1
(NH), 1683 (C=O). H NMR (DMSO-d6) d: 2.01–2.12 (m,
2H, –CH2–CH2–CH2–Cl), 2.64 (t, 2H, J = 8 Hz, –CH2–
CH2–CH2–Cl), 3.71 (t, 2H, J = 5.5 Hz, –CH2–CH2–CH2–
Cl), 7.33 (d, 1H, J = 7 Hz, Ar-H), 7.43 (t, 2H, J = 6 Hz,
Ar-H), 7.61 (s, 1H, thiazole H), 7.90 (d, 2H, J = 7 Hz, Ar-
H), 12.32 (s, 1H, NH). 13C NMR (DMSO-d6) d: 27.4, 32.0,
44.7 (butamide C), 107.9 (thiazole C), 125.6, 127.7, 128.6,
134.2 (Ar-C), 148.7, 157.8 (thiazole C), 170.5 (C=O).
5-Bromo-4-p-tolylthiazol-2-amine (3b) (Nath et al.,
1981) Mp: 192–195 °C, yield = 75 %. 1H NMR
(DMSO-d6) d: 2.51 (s, 3H, CH3), 7.37 (d, 2H, Ar-H,
J = 8 Hz), 7.85 (d, 2H, Ar-H, J = 8 Hz), 12.8 (brs, 2H,
NH2). 13C NMR (DMSO-d6) d: 20.3 (CH3-C), 88.5 (C-Br),
126.2, 129.3, 130.7, 134.1 145.3 (Ar-C), 167.2 (C-NH2).
N-(4-p-tolylthiazol-2-yl)-4-chlorobutanamide (4b) Mp:
185–187 °C, yield = 67 %. 1H NMR (CDCl3) d:
2.02–2.09 (m, 2H, –CH2–CH2–CH2–Cl), 2.25 (t, 2H,
J = 7 Hz, –CH2–CH2–CH2–Cl), 2.53 (s, 3H, CH3), 3.44 (t,
2H, J = 6.5 Hz, –CH2–CH2–CH2–Cl), 7.23 (s, 1H, thia-
zole H), 7.37 (d, 2H, J = 8 Hz, Ar-H), 7.85 (d, 2H,
J = 8 Hz, Ar-H), 11.58 (s, 1H, NH). 13C NMR (CDCl3) d:
20.3 (CH3-C), 26.4, 31.5, 42.7 (butamide C), 106.3
5-Bromo-4-(4-chlorophenyl)thiazol-2-amine(3c)(Nathetal.,
1981) Mp: 157–159 °C, yield = 73 %. 1H NMR (DMSO-
d6) d: 4.54 (brs, 2H, NH2), 7.41 (m, 2H, Ar-H), 7.64 (m, 2H,
Ar-H). 13C NMR (DMSO-d6) d: 87.8 (C-Br), 128.2, 129.5,
132.1, 132.5 (Ar-C), 145.2 (thiazole C), 167.1 (C-NH2).
5-Bromo-4-(4-bromophenyl)thiazol-2-amine (3d) (Nath
1
et al., 1981) Mp: 173–175 °C, yield = 67 %. H NMR
123

Med Chem Res
(thiazole C), 125.3, 128.7, 130.7, 137.4 (Ar-C), 148.7,
158.3 (thiazole C), 169.2 (C=O).
NH). 13C NMR (DMSO-d6) d: 27.4, 32.0, 44.7 (butamide
C), 108.6 (thiazole C), 123.9, 124.1, 126.1, 126.4, 127.5,
128.1, 128.2, 131.7, 132.4, 133.1 (Ar-C), 148.6, 157.9
(thiazole C), 170.6 (C=O).
N-(4-(4-chlorophenyl)thiazol-2-yl)-4-chlorobutanamide
(4c) Mp: 163–165 °C, yield = 85 %. FT-IR (KBr,
1
cm-1): 3253 (NH), 1672 (C=O). H NMR (DMSO-d6) d:
N-(5-bromo-4-phenylthiazol-2-yl)-4-chlorobutanamide
1
(4h) Mp: 147–149 °C, yield = 67 %. H NMR (DMSO-
2.05–2.14 (m, 2H, –CH2–CH2–CH2–Cl), 2.67 (t, 2H,
J = 7.5 Hz, –CH2–CH2–CH2–Cl), 3.74 (t, 2H, J = 6.5 Hz,
–CH2–CH2–CH2–Cl), 7.52 (d, 2H, J = 8.5 Hz, Ar-H), 7.70
(s, 1H, thiazole H), 7.94 (d, 2H, J = 8.5 Hz, Ar-H), 12.37
(s, 1H, NH). 13C NMR (DMSO-d6) d: 27.3, 32.0, 44.7
(butamide C), 108.6 (thiazole C), 127.3, 128.7, 132.1,
133.1(Ar-C), 147.4, 157.9 (thiazole C), 170.6 (C=O).
d6) d: 2.04–2.12 (m, 2H, –CH2–CH2–CH2–Cl), 2.60 (t, 2H,
J = 8 Hz, –CH2–CH2–CH2–Cl), 3.75 (t, 2H, J = 6.5 Hz,
–CH2–CH2–CH2–Cl), 7.39 (d, 1H, J = 7 Hz, Ar-H), 7.44
(t, 2H, J = 6 Hz, Ar-H), 7.87 (d, 2H, J = 7 Hz, Ar-H),
12.31 (s, 1H, NH). 13C NMR (DMSO-d6) d: 27.3, 32.4,
44.1 (butamide C), 107.8 (thiazole C), 125.5, 128.1, 128.5,
134.2 (Ar-C), 148.8, 157.4 (thiazole C), 170.7 (C=O).
N-(4-(4-bromophenyl)thiazol-2-yl)-4-chlorobutanamide
(4d) Mp: 157–159 °C, yield = 60 %. FT-IR (KBr,
N-(5-bromo-4-p-tolylthiazol-2-yl)-4-chlorobutanamide
(4i) Mp: 163–165 °C, yield = 74 %. FT-IR (KBr,
1
cm-1): 3247 (NH), 1670 (C=O). H NMR (DMSO-d6) d:
1
2.01–2.12 (m, 2H, –CH2–CH2–CH2–Cl), 2.63 (t, 2H,
J = 7 Hz, –CH2–CH2–CH2–Cl), 3.70 (t, 2H, J = 6.5 Hz,
–CH2–CH2–CH2–Cl), 7.62 (d, 2H, J = 8.5 Hz, Ar-H), 7.69
(s, 1H, thiazole H), 7.84 (d, 2H, J = 8.5 Hz, Ar-H), 12.34
(s, 1H, NH). 13C NMR (DMSO-d6) d: 27.3, 32.1, 44.1
(butamide C), 108.7 (thiazole C),120.7, 127.6, 131.6,
133.4(Ar-C), 147.5, 157.9 (thiazole C), 170.6 (C=O).
cm-1): 3224 (NH), 1649 (C=O). H NMR (DMSO-d6) d:
2.03–2.12 (m, 2H, –CH2–CH2–CH2–Cl), 2.30 (s, 3H, CH3),
2.60–2.68 (m, 2H, –CH2–CH2–CH2–Cl), 3.68 (t, 2H,
J = 6 Hz, –CH2–CH2–CH2–Cl), 7.27 (d, 2H, Ar-H,
J = 8 Hz), 7.75 (d, 2H, J = 8 Hz, Ar-H), 12.55 (s, 1H,
NH). 13C NMR (DMSO-d6) d: 20.8 (CH3 - C), 27.2, 31.8,
44.6 (butamide C), 96.2 (thiazole C), 127.7, 128.9, 130.4,
137.7 (Ar-C), 145.7, 156.7 (thiazole C), 171.0 (C=O).
N-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)-4-chlorobutanamide
1
(4e) Mp: 132–135 °C, yield = 69 %. H NMR (DMSO-
N-(5-bromo-4-(4-chlorophenyl)thiazol-2-yl)-4-chlorobu-
tanamide (4j) Mp: 166–168 °C, yield = 58 %. 1H NMR
(DMSO-d6) d: 2.03–2.09 (m, 2H, –CH2–CH2–CH2–Cl),
2.69 (t, 2H, –CH2–CH2–CH2–Cl), 3.72 (t, 2H, –CH2–CH2–
CH2–Cl), 7.72 (d, 2H, J = 8.5 Hz, Ar-H), 7.84 (d, 2H,
J = 8.5 Hz, Ar-H), 12.65 (s, 1H, NH). 13C NMR (DMSO-
d6) d: 27.2, 31.9, 44.6 (butamide C), 97.0 (thiazole C),
122.0, 129.8, 131.4, 132.3 (Ar-C), 144.0, 157.0 (thiazole
C), 171.2 (C=O).
d6) d: 2.04–2.15 (m, 2H, –CH2–CH2–CH2–Cl), 2.65 (t, 2H,
J = 7 Hz, –CH2–CH2–CH2–Cl), 3.74 (t, 2H, J = 6.5 Hz,
–CH2–CH2–CH2–Cl), 3.78 (s, 6H, OCH3, 7.60 (d, 1H,
J = 8.5 Hz, Ar-H), 7.67 (s, 1H, thiazole H), 7.84 (d, 1H,
J = 8.5 Hz, Ar-H), 7.88 (s, 1H, Ar-H), 12.25 (s, 1H, NH).
13C NMR (DMSO-d6) d: 26.8, 31.7, 45.1(butamide C),62.7
(OCH3),108.2 (thiazole C), 120.8, 127.1, 132.6, 133.4,
135.4 (Ar-C), 146.9, 157.2 (thiazole C), 170.1 (C=O).
N-(4-(biphenyl-4-yl)thiazol-2-yl)-4-chlorobutanamide
(4f) Mp: 182–185 °C, yield = 71 %. FT-IR (KBr,
N-(5-bromo-4-(4-bromophenyl)thiazol-2-yl)-4-chlorobu-
tanamide (4k) Mp: 173–175 °C, yield = 63 %. FT-IR
1
1
cm-1): 3369 (NH), 1658 (C=O). H NMR (DMSO-d6) d:
(KBr, cm-1): 3226 (NH), 1652 (C=O). H NMR (DMSO-
2.02–2.11 (m, 2H, –CH2–CH2–CH2–Cl), 2.63 (m, 2H,
–CH2–CH2–CH2–Cl), 3.70 (t, 2H, J = 6.5 Hz, –CH2–
CH2–CH2–Cl), 7.38 (d, 1H, J = 7 Hz, Ar-H), 7.48 (m, 2H,
Ar-H), 7.72 (m, 5H, Ar-H), 7.98 (d, 2H, J = 8 Hz, Ar-H),
12.35 (s, 1H, NH). 13C NMR (DMSO-d6) d: 27.2, 32.0,
44.7 (butamide C), 108.1 (thiazole C), 126.1, 126.4, 126.9,
127.4, 128.9, 139.2 (Ar-C), 148.3, 157.8 (thiazole C), 170.5
(C=O).
d6) d: 2.02–2.10 (m, 2H, –CH2–CH2–CH2–Cl), 2.63 (t, 2H,
–CH2–CH2–CH2–Cl), 3.70 (t, 2H, –CH2–CH2–CH2–Cl),
7.70 (d, 2H, Ar-H, J = 8.5 Hz), 7.82 (d, 2H, Ar-H,
J = 8.5 Hz), 12.62 (s, 1H, NH). 13C NMR (DMSO-d6) d:
27.2, 31.9, 44.6 (butamide C), 97.0 (thiazole C), 122.0,
129.8, 131.4, 132.3 (Ar-C), 144.0, 157.0 (thiazole C), 171.2
(C=O).
N-(5-bromo-4-(3,4-dimethoxyphenyl)thiazol-2-yl)-4-chlorobu-
1
tanamide (4l) Mp: 157–160 °C, yield = 52 %. H NMR
N-(4-(naphthalen-2-yl)thiazol-2-yl)-4-chlorobutanamide
1
(4g) Mp: 175–177 °C, yield = 58 %. H NMR (DMSO-
d6) d: 2.00–2.10 (m, 2H, –CH2–CH2–CH2–Cl), 2.64 (t, 2H,
J = 6.5 Hz, –CH2–CH2–CH2–Cl), 3.71 (t, 2H, J = 6.5 Hz,
–CH2–CH2–CH2–Cl), 7.53 (d, 2H, J = 6.5 Hz, Ar-H), 7.76
(s, 1H, Ar-H), 7.94 (m, 3H, Ar-H), 8.04 (d, 1H,
J = 8.5 Hz, Ar-H), 8.42 (s, 1H, thiazole H), 12.41 (s, 1H,
(DMSO-d6) d: 2.06–2.14 (m, 2H, –CH2–CH2–CH2–Cl),
2.61 (t, 2H, J = 7 Hz, –CH2–CH2–CH2–Cl), 3.71 (t, 2H,
J = 6.5 Hz, –CH2–CH2–CH2–Cl), 3.77 (s, 6H, OCH3, 7.60
(d, 1H, J = 8.5 Hz, Ar-H), 7.84 (d, 1H, J = 8.5 Hz, Ar-
H), 7.88 (s, 1H, Ar-H), 12.48 (s, 1H, NH). 13C NMR
(DMSO-d6) d: 26.9, 31.7, 45.5 (butamide C), 62.1 (OCH3),
123

Med Chem Res
108.2 (thiazole C), 118.3, 127.7, 131.6, 132.5, 133.1, 135.4
(Ar-C), 146.9, 157.2 (thiazole C), 170.7 (C=O).
1-(4-(4-Chlorophenyl)thiazol-2-yl)pyrrolidin-2-one (5c)
(Uehara et al., 2013) Mp: 205–208 °C, yield = 68 %.
1
FT-IR (KBr, cm-1): 3099 (Ar CH), 1691 (C=O). H NMR
Ethyl 5-bromo-2-(4-chlorobutanamido)thiazole-4-carboxy-
late (4m) Mp: 177–179 °C, yield = 78 %. FT-IR (KBr,
cm-1): 3267 (NH), 1708 (ester C=O), 1689 (amide C=O).
1H NMR (CDCl3) d: 1.34 (t, 3H, J = 7 Hz, CH3)
2.05–2.14 (m, 2H, –CH2–CH2–CH2–Cl), 2.59 (t, 2H,
J = 7 Hz, –CH2–CH2–CH2–Cl), 3.56 (t, 2H, J = 6 Hz,
–CH2–CH2–CH2–Cl), 3.33 (q, 2H, J = 7 Hz, O–CH2–CH3),
10.1 (s, 1H, NH). 13C NMR (CDCl3) d: 14.2 (CH3), 27.2,
32.5, 43.8 (butamide C),61.8 (OCH2), 112.1, 137.7, 157.0
(thiazole C), 161.0 (O-C=O) 170.6 (N–C=O). HRMS m/z:
Calcd. for C10H12BrClN2O3S: 353.9440; found, 353.9681.
(DMSO-d6) d: 2.11–2.20 (m, 2H, –CH2–CH2–CH2–N),
2.65 (t, 2H, J = 8 Hz, –CH2–CH2–CH2–N), 4.14 (t, 2H,
J = 7 Hz, –CH2–CH2–CH2–N), 7.50 (d, 2H, J = 8.5 Hz,
Ar-H), 7.78 (s, 1H, thiazole H), 7.96 (d, 2H, J = 8.5 Hz,
Ar-H). 13C NMR (DMSO-d6) d: 17.6, 31.2, 47.7 (pyrro-
lidinone C), 109.0 (thiazole C), 127.4, 128.6, 132.2, 132.9
(Ar-C), 147.3, 157.0 (thiazole C), 173.9 (C=O). HRMS m/
z: Calcd. for C13H11ClN2OS: 278.0281; found, 277.9900.
1-(4-(4-Bromophenyl)thiazol-2-yl)pyrrolidin-2-one (5d) Mp:
215–217 °C, yield = 71 %. 1H NMR (DMSO-d6) d:
2.12–2.21 (m, 2H, –CH2–CH2–CH2–N), 2.65 (t, 2H,
J = 8 Hz, –CH2–CH2–CH2–N), 4.13 (t, 2H, J = 7 Hz,
–CH2–CH2–CH2–N), 7.63 (d, 1H, J = 8.5 Hz, Ar-H), 7.80
(s, 1H, thiazole H), 7.90 (d, 2H, J = 7.5 Hz, Ar-H,). 13C
NMR (DMSO-d6) d: 17.6, 31.2, 47.7 (pyrrolidinone C),
109.0 (thiazole C), 120.8, 127.7, 131.6, 133.2 (Ar-C),
147.3, 157.0 (thiazole C), 173.9(C=O). HRMS m/z: Calcd.
for C13H11BrN2OS: 321.9775; found, 321.9917.
General procedure of 1-(thiazol-2-yl)pyrrolidin-2-one
derivatives 5a–m
A mixture of 4-chloro-N-(thiazol-2-yl)butanamide deriva-
tives 4a–m (4 mmol) and piperidine (0.8 mL, 8 mmol) in
toluene (50 mL) was heated under reflux for 24 h. The
reaction mixture was cooled, poured into ammoniated
water and stirred. Toluene was then separated, dried over
anhydrous Na2SO4 and finally evaporated to give a crude
product. This product was purified by Chromatotron silica
plate with 1 cm thickness using CHCl3/EtOAc (95:5 v/v)
as eluting system. The solid obtained was recrystallized to
give the required products.
1-(4-(3,4-Dimethoxyphenyl)thiazol-2-yl)pyrrolidin-2-one
1
(5e) Mp: 167–169 °C, yield = 65 %. H NMR (DMSO-
d6) d: 2.09–2.17 (m, 2H, –CH2–CH2–CH2–N), 2.64 (t, 2H,
J = 7 Hz, –CH2–CH2–CH2–N), 4.11 (t, 2H, J = 6.5 Hz,
–CH2–CH2–CH2–N), 3.77 (s, 6H, OCH3, 7.61 (d, 1H,
J = 8.5 Hz, Ar-H), 7.65 (s, 1H, thiazole H), 7.88 (d, 1H,
J = 8.5 Hz, Ar-H), 7.93 (s, 1H, Ar-H). 13C NMR (DMSO-
d6) d:21.8, 31.7, 47.1 (pyrrolidinone C),62.5 (OCH3),
108.1 (thiazole C), 120.7, 127.3, 132.6, 132.9, 133.4, 135.4
(Ar-C), 146.9, 157.1 (thiazole C), 170.9 (C=O). HRMS m/
z: Calcd. for C15H16N2O3S: 304.0882; found, 303.9683.
1-(4-Phenylthiazol-2-yl)pyrrolidin-2-one (5a) (Paul et al.,
1982) Mp: 163–164 °C, yield = 72 %. FT-IR (KBr,
1
cm-1): 3078 (Ar CH), 1697 (C=O). H NMR (DMSO-d6)
d: 2.01–2.12 (m, 2H, –CH2–CH2–CH2–N), 2.64 (t, 2H,
J = 8 Hz, –CH2–CH2–CH2–N), 4.14 (t, 2H, J = 7 Hz,
–CH2–CH2–CH2–N), 7.30–7.38 (m, 1H, Ar-H), 7.41–7.49
(m, 2H, Ar-H), 7.71 (s, 1H, thiazole H), 7.94 (d, 2H,
J = 7 Hz, Ar-H). 13C NMR (DMSO-d6) d: 17.5, 31.2, 47.7
(pyrrolidinone C), 108.3 (thiazole C), 125.7, 127.8, 128.6,
134.0(Ar-C), 148.5, 156.8 (thiazole C), 173.8 (C=O).
HRMS m/z: Calcd. for C13H12N2OS: 244.0670; found,
244.0639.
1-(4-(Biphenyl-4-yl)thiazol-2-yl)pyrrolidin-2-one (5f) Mp:
210–212 °C, yield = 77 %. FT-IR (KBr, cm-1): 3109 (Ar
1
CH), 1681 (C=O). H NMR (DMSO-d6) d: 2.15–2.24 (m,
2H, –CH2–CH2–CH2–N), 2.66 (t, 2H, J = 8 Hz, –CH2–
CH2–CH2–N), 4.11–4.20 (m, 2H, –CH2–CH2–CH2–N),
7.39 (s, 1H, thiazole H), 7.44–7.51 (m, 2H, Ar-H), 7.71-
.7.79 (m, 5H, Ar-H), 8.00–8.07 (m, 2H, Ar-H,). 13C NMR
(DMSO-d6) d: 21.5, 31.2, 47.4 (pyrrolidinone C), 107.0
(thiazole C), 126.3, 126.5, 126.9, 127.4, 128.9, 132.2,
132.9 (Ar-C), 141.2, 147.5 (thiazole C), 173.2 (C=O).
HRMS m/z: Calcd. for C19H16N2OS: 320.0983; found,
319.9664.
1-(4-p-Tolylthiazol-2-yl)pyrrolidin-2-one (5b) (Uehara
et al., 2013) Mp: 163–165 °C, yield = 75 %. FT-IR
(KBr, cm-1): 3099 (CH3), 1681 (C=O). 1H NMR (DMSO-
d6) d: 2.11–2.20 (m, 2H, –CH2–CH2–CH2–N), 2.33 (s, 3H,
CH3), 2.64 (t, 2H, J = 7.5 Hz, –CH2–CH2–CH2–N), 4.14
(t, 2H, J = 7 Hz, –CH2–CH2–CH2–N), 7.24 (d, 2H,
J = 7.5 Hz, Ar-H), 7.63 (s, 1H, thiazole H), 7.83 (d, 2H,
J = 8 Hz, Ar-H). 13C NMR (DMSO-d6) d: 17.6 (CH3),
20.7, 31.2, 47.7 (pyrrolidinone C), 107.4 (thiazole C),
125.6, 129.2, 131.4, 137.1 (Ar-C), 148.6, 156.7 (thiazole
C), 173.8(C=O). HRMS m/z: Calcd. for C14H14N2OS:
258.0827; found, 258.0823.
1-(4-(Naphthalen-2-yl)thiazol-2-yl)pyrrolidin-2-one (5g) Mp:
162–165 °C, yield = 72 %. 1H NMR (DMSO-d6) d:
2.16–2.22 (m, 2H, J = 7 Hz, –CH2–CH2–CH2-N), 2.67 (t,
2H, J = 7.5 Hz, –CH2–CH2–CH2–N), 4.22 (t, 2H,
J = 6.5 Hz, –CH2–CH2–CH2–N), 7.49–7.54 (m, 2H, Ar-
H), 7.87 (s, 1H, thiazole H), 7.92 (d, 1H, Ar-H, J = 7 Hz),
7.94–8.02 (m, 2H, J = 7 Hz, Ar-H), 8.08 (d, 1H,
123

Med Chem Res
J = 7 Hz, Ar-H) 8.48 (s, 1H, Ar-H). 13C NMR (DMSO-d6)
d: 17.6, 31.2, 47.8 (pyrrolidinone C),109.0 (thiazole C),
124.0, 124.2, 126.1, 126.5, 127.5, 128.1, 128.2, 131.5,
132.5, 133.1 (Ar-C), 148.5, 157.0 (thiazole C), 173.9
(C=O). HRMS m/z: Calcd. for C17H14N2OS: 294.0827;
found, 293.9884.
(DMSO-d6) d: 2.08–2.16 (m, 2H, –CH2–CH2–CH2–N),
2.71 (t, 2H, J = 7 Hz, –CH2–CH2–CH2–N), 4.21 (t, 2H,
J = 6.5 Hz, –CH2–CH2–CH2–N), 3.79 (s, 6H, OCH3, 7.62
(d, 1H, J = 8.5 Hz, Ar-H), 7.85 (d, 1H, J = 8.5 Hz, Ar-
H), 7.91 (s, 1H, Ar-H). 13C NMR (DMSO-d6) d: 21.7, 31.6,
47.1 (pyrrolidinone C), 62.7 (OCH3),108.4 (thiazole C),
121.5, 127.2, 132.3, 132.9, 133.1, 135.2 (Ar-C), 147.0,
157.2 (thiazole C), 170.8 (C=O). HRMS m/z: Calcd. for
C15H15BrN2O3S: 381.9987; found, 381.9905.
1-(5-Bromo-4-phenylthiazol-2-yl)pyrrolidin-2-one (5h) Mp:
158–160 °C, yield = 75 %. FT-IR (KBr, cm-1):1695
1
(C=O). H NMR (DMSO-d6) d: 2.14–2.19 (m, 2H, –CH2–
CH2–CH2–N), 2.65 (t, 2H, J = 7.5 Hz, –CH2–CH2–CH2–
N), 4.06 (t, 2H, J = 7.0 Hz, –CH2–CH2–CH2–N), 7.44 (d,
1H, J = 7.5 Hz, Ar-H), 7.50 (t, 2H, J = 7.5 Hz, Ar-H),
7.90 (d, 2H, J = 7.0 Hz, Ar-H). 13C NMR (DMSO-d6) d:
17.6, 30.9, 47.1(pyrrolidinone C), 97.4 (thiazole C-Br),
127.9, 128.3, 128.4, 133.0 (Ar-C), 145.6, 155.6 (thiazole
C), 174.5 (C=O). HRMS m/z: Calcd. for C13H11BrN2OS:
321.9775; found, 321.9766.
Ethyl 5-bromo-2-(2-oxopyrrolidin-1-yl)thiazole-4-car-
boxylate (5m) Mp: 161–163 °C, yield = 61 %. FT-IR
1
(KBr, cm-1): 1706 (ester C=O), 1693 (amide C=O). H
NMR (DMSO-d6) d: 1.32 (t, 3H, J = 7 Hz, CH3)
2.11–2.20 (m, 2H, –CH2–CH2–CH2–N), 2.65 (t, 2H,
J = 8 Hz, –CH2–CH2–CH2–N), 4.02 (t, 2H, J = 7.5 Hz,
–CH2–CH2–CH2–N), 4.32 (q, 2H, J = 7 Hz, O–CH2–
CH3). 13C NMR (DMSO-d6) d: 14.0 (CH3), 17.6, 30.8, 47.2
(pyrrolidinone C), 61.0 (OCH2), 110.8, 137.6, 155.6
(thiazole C), 160.4 (O-C=O) 175.0 (N–C=O). HRMS m/z:
Calcd. for C10H11BrN2O3S: 317.9674; found, 317.9789.
1-(5-Bromo-4-p-tolylthiazol-2-yl)pyrrolidin-2-one (5i) Mp:
1
165–167 °C, yield = 59 %. H NMR (CDCl3) d: 2.43 (s,
3H, CH3), 2.75–2.81 (m, 2H, –CH2–CH2–CH2–N), 3.01 (t,
2H, J = 7.0 Hz, –CH2–CH2–CH2–N), 4.40 (t, 2H,
J = 6.5 Hz, –CH2–CH2–CH2–N), 7.28 (s, 2H, Ar-H), 7.80
(s, 2H, Ar-H). 13C NMR (CDCl3) d: 17.2 (CH3), 20.6, 30.1,
47.5 (pyrrolidinone C), 97.4 (thiazole C), 128.6, 129.2,
131.3, 137.5 (Ar-C), 147.6, 156.2 (thiazole C),
173.2(C=O). HRMS m/z: Calcd. for C14H13BrN2OS:
335.9932; found, 336.0088.
General procedure of 2-(thiazol-2-yl)isoindoline-1,3-dione
derivatives 6a–g
2-Aminothiazole derivatives 2a–g (0.01 mol) were
triturated and mixed with phthalic anhydride (1.48 g,
0.01 mol). The mixture was heated on an oil bath with
occasional stirring for 2 h. The crude product was dis-
solved in hot EtOAc and filtered to remove any undis-
solved particles, and the 2-(thiazole-2-yl)isoindoline-1,3-
dione derivatives were precipitated by cooling.
1-(5-Bromo-4-(4-chlorophenyl)thiazol-2-yl)pyrrolidin-2-
one (5j) Mp: 184–186 °C, yield = 64 %. FT-IR (KBr,
1
cm-1): 3098 (Ar CH), 1692 (C=O). H NMR (DMSO-d6)
d: 2.12–2.19 (m, 2H, –CH2–CH2–CH2–N), 2.67 (t, 2H,
J = 8 Hz, –CH2–CH2–CH2–N), 4.12 (t, 2H, J = 7 Hz,
–CH2–CH2–CH2–N), 7.52 (d, 2H, J = 8.5 Hz, Ar-H), 7.92
(d, 2H, J = 8.5 Hz, Ar-H). 13C NMR (DMSO-d6) d: 17.6,
31.2, 47.7 (pyrrolidinone C), 109.1 (thiazole C), 127.4,
128.6, 132.2, 132.9 (Ar-C), 147.3, 157.1 (thiazole C),
173.7(C=O). HRMS m/z: Calcd. for C13H10BrClN2OS:
355.9386; found, 355.9301.
2-(4-Phenylthiazol-2-yl)isoindoline-1,3-dione (6a) (Ra-
jpurohit and Sah, 2005) Mp: 127–129 °C, yield = 68 %.
FT-IR (KBr, cm-1): 3093 (Ar CH), 1728, 1716 (2 C=O).
1H NMR (DMSO-d6) d: 7.31–7.37 (m, 1H, Ar-H), 7.55 (d,
2H, J = 7.5 Hz, Ar-H), 7.92–7.97 (m, 2H, Ar-H),
8.02–8.07 (m, 4H, Ar-H), 8.22 (s, 1H, thiazole H). 13C
NMR (DMSO-d6) d: 114.0 (thiazole C), 123.9, 127.5,
128.8, 131.0, 132.5, 132.7, 135.3 (Ar-C), 149.5, 151.9
(thiazole C), 164.8 (C=O). HRMS m/z: Calcd. for C17
H10N2O2S: 306.0463; found, 305.9941.
1-(5-Bromo-4-(4-bromophenyl)thiazol-2-yl)pyrrolidin-2-
one (5k) Mp: 195–197 °C, yield = 70 %. 1H NMR
(DMSO-d6) d: 2.17–2.23 (m, 2H, –CH2–CH2–CH2–N),
2.67 (t, 2H, J = 8 Hz, –CH2–CH2–CH2–N), 4.19 (t, 2H,
J = 7 Hz, –CH2–CH2–CH2–N), 7.66 (d, 1H, J = 8.5 Hz,
Ar-H), 7.90 (d, 2H, J = 7.5 Hz, Ar-H). 13C NMR (DMSO-
d6) d: 17.6, 31.2, 47.7 (pyrrolidinone C), 109.1 (thiazole
C), 120.8, 127.7, 131.7, 133.2 (Ar-C), 147.3, 157.7 (thia-
zole C), 173.(C=O). HRMS m/z: Calcd. for C13H10Br2N2-
OS: 399.8881; found, 399.8867.
2-(4-p-Tolylthiazol-2-yl)isoindoline-1,3-dione (6b) Mp:
171–173 °C, yield = 79 %. FT-IR (KBr, cm-1): 3107 (Ar
CH), 1750, 1731 (2 C=O). 1H NMR (DMSO-d6) d: 2.32 (s,
3H, CH3), 7.29 (d, 2H, J = 7 Hz, Ar-H), 7.85–7.94 (m,
2H, Ar-H), 7.92 (s, 2H, Ar-H), 8.03 (s, 2H, Ar-H), 8.09 (s,
1H, thiazole H). 13C NMR (DMSO-d6) d: 20.8 (CH3),
112.7 (thiazole C), 123.9, 125.8, 129.3, 131.0, 131.1,
135.2, 137.6 (Ar-C), 150.9, 151.5 (thiazole C), 164.9
(C=O). HRMS m/z: Calcd. for C17H10N2O2S: 320.0619;
found, 319.9996.
1-(5-Bromo-4-(3,4-dimethoxyphenyl)thiazol-2-yl)pyrrolid-
1
in-2-one (5l) Mp: 170–172 °C, yield = 71 %. H NMR
123

Med Chem Res
2-(4-(4-Chlorophenyl)thiazol-2-yl)isoindoline-1,3-dione
(6c) Mp: 197–199 °C, yield = 81 %. FT-IR (KBr,
cm-1): 3095 (Ar CH), 1782, 1728 (2 C=O). 1H NMR
(DMSO-d6) d: 7.55 (d, 2H, J = 7.5 Hz, Ar-H), 7.92–7.98
(m, 2H, Ar-H), 8.02–8.10 (m, 4H, Ar-H), 8.22 (s, 1H,
thiazole H). 13C NMR (DMSO-d6) d: 114.0 (thiazole C),
123.9, 127.5, 128.8, 131.0, 132.5, 132.7, 135.3 (Ar-C),
149.5, 151.9 (thiazole C), 164.8 (C=O). HRMS m/z: Calcd.
for C17H9ClN2O2S: 340.0073; found, 339.9948.
glacial acetic acid (50 mL) under reflux for 3 h. On cooling, the
separated solid was filtered, washed with water (20 mL), dried
and crystallized from ethanol to yield the title compounds.
2-(4-Phenylthiazol-2-yl)4,5,6,7-tetrachloroisoindoline-1,3-
dione (6h) Mp: 255–257 °C, yield = 85 %. 1H NMR
(DMSO-d6) d: 7.37–7.42 (m, 1H, Ar-H), 7.47–7.51 (m, 2H,
Ar-H), 7.92–8.01 (m, 2H, Ar-H), 8.24 (s, 1H, thiazole H).
13C NMR (DMSO-d6) d: 114.2 (thiazole C), 124.4, 126.3,
127.2, 127.5, 128.3, 128.7, 128.9, 131.5, 132.2, 133.8 (Ar-
C), 149.5, 150.4 (thiazole C), 161.4 (C=O). HRMS m/z:
Calcd. for C17H6Cl4N2O2S: 441.8904; found, 441.8900.
2-(4-(4-Bromophenyl)thiazol-2-yl)isoindoline-1,3-dione
(6d) Mp: 186–188 °C, yield = 82 %. FT-IR (KBr,
cm-1): 3120 (Ar CH), 1739, 1679 (2 C=O). 1H NMR
(DMSO-d6) d: 7.68 (d, 2H, J = 8.5 Hz, Ar-H), 7.84–7.89
(m, 6H, Ar-H), 8.23 (s, 1H, thiazole H). 13C NMR (DMSO-
d6) d: 114.1 (thiazole C), 121.3, 123.9, 127.8, 131.0, 131.7,
132.9, 135.3 (Ar-C), 149.5, 151.9 (thiazole C), 164.8
(C=O). HRMS m/z: Calcd. for C17H9BrN2O2S: 383.9568;
found, 383.9553.
2-(4-p-Tolylthiazol-2-yl)4,5,6,7-tetrachloroisoindoline-1,3-
dione (6i) Mp: 266–268 °C, yield = 89 %. FT-IR (KBr,
cm-1): 3120 (Ar CH), 1795, 1731 (2 C=O). 1H NMR
(DMSO-d6) d: 2.5 (s, 3H, CH3), 7.34 (d, 2H, J = 8 Hz, Ar-
H), 7.88 (d, 2H, J = 8 Hz, Ar-H), 8.16 (s, 1H, thiazole H).
13C NMR (DMSO-d6) d: 114.2 (thiazole C), 125.8, 128.0,
128.3, 128.7, 128.8, 138.8 (Ar-C), 149.5, 150.4 (thiazole
C), 160.6 (C=O). HRMS m/z: Calcd. for C18H8Cl4N2O2S:
455.9061; found, 455.9042.
2-(4-(3,4-Dimethoxyphenyl)thiazol-2-yl)isoindoline-1,3-dione
(6e) Mp: 195–198 °C, yield = 71 %. FT-IR (KBr,
cm-1): 3101 (Ar CH), 1758, 1728 (2 C=O). 1H NMR
(DMSO-d6) d: 3.81 (s, 6H, OCH3), 7.06 (d, 1H, J = 8 Hz,
Ar-H), 7.55 (d, 2H, J = 7.5 Hz, Ar-H), 7.96 (s, 2H, Ar-H),
8.03 (s, 2H, Ar-H), 8.07 (s, 1H, thiazole H). 13C NMR
(DMSO-d6) d: 55.5 (OCH3), 109.4 (thiazole C), 111.8,
112.0, 118.5, 123.9, 126.7, 131.1, 135.2, 148.8, 148.9 (Ar-
C), 151.0, 151.3 (thiazole C), 165.0 (C=O). HRMS m/z:
Calcd. for C19H14N2O4S: 366.0674; found, 366.0632.
2-(4-(4-Chlorophenyl)thiazol-2-yl)4,5,6,7-tetrachloroisoin-
doline-1,3-dione (6j) Mp: 294–296 °C, yield = 78 %.
FT-IR (KBr, cm-1): 3120 (Ar CH), 1793, 1728 (2 C=O).
1H NMR (DMSO-d6) d: 7.56 (d, 2H, J = 8 Hz, Ar-H),
8.02 (d, 2H, J = 8 Hz, Ar-H), 8.29 (s, 1H, thiazole H). 13
C
NMR (DMSO-d6) d: 114.2 (thiazole C), 126.7, 128.2,
128.4, 128.9, 129.5, 129.9, 131.5, 132.5, 132.7 (Ar-C),
149.1, 151.4 (thiazole C), 160.4 (C=O). HRMS m/z: Calcd.
for C17H5Cl5N2O2S: 475.8514; found, 475.8501.
2-(4-(Biphenyl-4-yl)thiazol-2-yl)isoindoline-1,3-dione
1
(6f) Mp: 202–205 °C, yield = 78 %. H NMR (DMSO-
2-(4-(4-Bromophenyl)thiazol-2-yl)-4,5,6,7-tetrachloroisoin-
doline-1,3-dione (6k) Mp: 276–278 °C, yield = 90 %.
1H NMR (DMSO-d6) d: 7.69 (d, 2H, J = 8.5 Hz, Ar-H),
d6) d: 7.55 (d, 2H, J = 7.5 Hz, Ar-H), 7.72–7.79 (m, 6H,
Ar-H), 8.01–8.13 (m, 5H, Ar-H), 8.29 (s, 1H, thiazole H).
13C NMR (DMSO-d6) d: 114.0 (thiazole C), 123.9, 127.5,
128.8, 131.0, 132.5, 132.7, 135.3, 137.2, 137.9 (Ar-C),
149.5, 151.7 (thiazole C), 164.7 (C=O). HRMS m/z: Calcd.
for C23H14N2O2S: 382.0776; found, 381.9953.
7.95 (d, 2H, J = 8 Hz, Ar-H), 8.30 (s, 1H, thiazole H). 13
C
NMR (DMSO-d6) d: 114.4 (thiazole C), 126.4, 126.5,
127.2, 127.6, 128.0, 128.7, 128.9, 132.8, 133.4, 139.8 (Ar-
C), 150.5, 150.8 (thiazole C), 161.5 (C=O). HRMS m/z:
Calcd. for C17H5BrCl4N2O2S: 519.8009; found, 519.5808.
2-(4-(Naphthalen-2-yl)thiazol-2-yl)isoindoline-1,3-dione
(6g) Mp: 215–217 °C, yield = 69 %.1H NMR (DMSO-
d6): d 7.47–4.50 (m, 4H, Ar-H), 7.66–7.69 (m, 6H, Ar-H),
8.02 (s, 1H, thiazole H), 8.15 (s, 1H, Ar-H). 13C NMR: d
114.3 (thiazole C), 122.8, 127.0, 127.8, 128.7, 130.5,
132.4, 132.8, 134.3, 136.3, 137.9 (Ar-C), 149.9, 151.5
(thiazole C), 164.9 (C=O). HR-EI-MS m/z: 356.0622 (M?),
Calcd. for C23H14N2O2S: 356.0619.
2-(4-(3,4-Dimethoxyphenyl)thiazol-2-yl)4,5,6,7-tetra-
chloroisoindoline-1,3-dione (6 l) Mp: 265–268 °C,
yield = 74 %. FT-IR (KBr, cm-1): 3112 (Ar CH), 1797,
1726 (2 C=O). 1H NMR (DMSO-d6) d: 1.9 (s, 6H, OCH3),
7.06 (d, 1H, J = 7.5 Hz, Ar-H), 7.55 (d, 2H, J = 8.5 Hz,
Ar-H), 8.14 (s, 1H, thiazole H). 13C NMR (DMSO-d6) d:
61.2 (OCH3), 114.2 (thiazole C), 124.5, 125.4, 126.5,
127.1, 127.6, 128.2, 128.7, 128.9, 132.8, 133.4 (Ar-C),
149.1, 150.3 (thiazole C), 161.7 (C=O). HRMS m/z: Calcd.
for C19H10Cl4N2O4S: 501.9115; found, 501.9719.
General procedure of 2-(thiazol-2-yl)4,5,6,7-
tetrachloroisoindoline-1,3-dione derivatives 6h–n
A mixture of 2-aminothiazole derivatives 2a–g (0.01 mol),
anhydrous sodium acetate (0.8 g, 0.01 mol) and 4,5,6,7-tetra-
chlorophthalic anhydride (2.8 g, 0.01 mol) was heated in
2-(4-(Biphenyl-4-yl)thiazol-2-yl)-4,5,6,7-tetrachloroisoin-
doline-1,3-dione (6m) Mp: 277–279 °C, yield = 80 %.
1H NMR (DMSO-d6) d: 7.37–7.42 (m, 1H, Ar-H),
123

Med Chem Res
7.48–7.56 (m, 2H, Ar-H), 7.75 (d, 2H, J = 7 Hz, Ar-H),
7.81 (d, 2H, J = 7.5 Hz, Ar-H), 8.09 (d, 2H, J = 8 Hz, Ar-
H), 8.29 (s, 1H, thiazole H). 13C NMR (DMSO-d6) d: 114.2
(thiazole C), 125.5, 126.7, 127.4, 128.1, 128.5, 129.2,
129.9, 131.0, 132.3, 132.9 (Ar-C), 149.5, 151.6 (thiazole
C), 163.4 (C=O). HRMS m/z: Calcd. for C23H10Cl4N2O2S:
517.9217; found, 517.9846.
All the atom types, charges and bond hybridization were
carefully checked. The MolDock score (GRID) and MolDock
Optimizer routines as implemented in Molegro Virtual
Docker (MVD version 2013.6.0.0). The non-bonded oxygen
atoms of waters present in the crystal structure were removed.
ChemBio3D Ultra 10(Kerwin, 2010) was usedto drawthe 3D
structures of different ligands. Ligands were further pre-op-
timized using free version of Marvinsketch 4.1.13 from
Chemaxon Ltd (‘‘Marvinsketch, version 6.1.0, Chemaxon
company cheminformatics technology products services,
2013 http://www.chemaxon.com,’’ 2013) with MM force
field and saved in Tripos mol2 file format. MolDock score
2-(4-(Naphthalen-2-yl)thiazol-2-yl)-4,5,6,7-tetrachloroisoin-
doline-1,3-dione (6n) Mp: 260–263 °C, yield = 75 %. 1H
NMR (DMSO-d6): d 7.50–7.58 (m, 6H, Ar-H), 7.81(s, 1H,
thiazole H), 8.29 (s, 1H, Ar-H). 13C NMR: d 114.4 (thiazole
C), 126.5, 126.9, 127.8, 129.2, 129.5, 129.9, 131.4, 132.6,
132.9 (Ar-C), 148.5, 151.8 (thiazole C), 164.2 (C=O). HR-
EI-MS m/z: (M?) 491.9088, (M? ? 2) 493.9073, (M? ? 4)
495.9114, (M? ? 6) 497.9098, (M? ? 8) 499.9174. Calcd.
for C23H10Cl4N2O2S: 491.9061.
˚
functions were used with a 0.3 A grid resolution. Prior to the
calculationsofthesubjectcompounds,theMVDsoftwarewas
benchmarked docking the vigabatrin in case of GABA-TA
andeszopiclone, zolpidem, diazepamandflunitrazepaminthe
homology model of GABAA receptor (Hanson et al., 2008).
Crystallography
Anticonvulsant activity
Crystals of compounds 5a and 6e were obtained by slow
evaporation from solutions of ethanol/DMF and ethanol,
respectively. The measurements of the crystals were per-
formed on a Bruker SMART APEX II CCD diffractome-
ter with graphite-monochromated Cu Ka radiation
The anticonvulsant activity was carried out on Swiss albino
mice (25–30 g) of both sexes as experimental animals. The
animals were housed under standard conditions and allowed
free access to standard pellet diet and water (ab libitum).
The first group of animals were administered 0.5 % methyl
cellulose/water mixture which served as negative control.
The second group of animals were treated with phenytoin
sodium (25 mg/kg, i.p.) which served as positive control.
The tested compounds were suspended in 0.5 % methyl
cellulose/water mixture. In the preliminary screening tests
by MES, PTZ and PIC, each compound was administered as
an i.p. injection at three dose levels (100, 200 and 300 mg/
kg), and anticonvulsant and neurotoxic effects were assessed
at 30-min and 4-h intervals after administration in mice.
˚
(k = 1.54178 A) at room temperature. The structures were
solved by direct method and refined with SHELXTL
(Sheldrick, 2008). E-maps provided the positions of all the
non-H-atoms. The full-matrix least-squares refinement was
carried out on F2 using anisotropic temperature factors for
all non-H-atoms. Crystallographic data for the structure
reported in this paper have been deposited at the Cam-
bridge Crystallographic Data Center and allocated with the
deposition numbers: CCDC 963827 and 945621 for com-
pounds 5a and 6e, respectively. Copies of data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EW, UK (Fax: Int. code (1223)
336-033; E-mail: deposit@ccdc.cam.ac.uk).
Pentylenetetrazole-induced convulsion test in mice
Pentylenetetrazole dissolved in 0.9 % sodium chloride
solution (80 mg/kg) was administered in the posterior
midline of the mice, and the onset and severity of con-
vulsion was noted for the control group. The test group was
administered with the selected compounds 0.5, 4 h prior to
the administration of PTZ. The animals are placed in iso-
lation cage to minimize stress and observed for the next
30 min to see the absence of seizure. An episode of clonic
spasms was approximately 3–5 s of the fore and/or hind
limbs. Animals which did not meet this criterion were
considered protected (Wang et al., 2012).
Molecular modeling
All the modeling studies were carried out on a desktop PC,
IntelÒ CoreTM 2 Duo CPU E8200 @ 2.66 GHz, RAM 4 GB
operating under Windows 7 professional. It consists of several
steps. First, the 3D crystal structures of GABA-AT with PDB
code 1OHV (Storici et al., 2004) were downloaded from
Brookhaven Protein Data Bank (PDB; http://www.rcsb.org/
pdb) and human GABAA homology model (Berezhnoy et al.,
2009) loaded to Molegro Virtual Docker (MVD 2013.6.0.0
[Win32]) program fully functional free trial version with
time limiting license (‘‘Molegro Virtual Docker (MVD
2013.6.0.0), Molegro bioinformatics solutions, Danish, 2013
http://www.molegro.com’’;Thomsen and Christensen, 2006).
Picrotoxin-induced convulsion test in mice
Tested compounds in different doses were i.p. injected to
mice, 0.5, 4 h later, animals were injected i.p. with PIC
123

Med Chem Res
(10 mg/kg) and observed for 30 min, and the percentage of
anticonvulsant activity of the tested compounds was cal-
culated (Hasan et al., 2014).
was used in this experiment. The mixture of acetonitrile
(HPLC grade) (60 %) and 5 mmol ammonium formate
buffer (40 %) was used as a mobile phase. The total flow of
the column was 0.9 mL/min, injection volume was 10 lL,
and column temperature was 25 °C. The acetic acid solu-
tion was used for dead time (t0) determination. Retention
times (tR) were measured in minutes. The capacity factors
k were calculated according to the formula k = (tR - t0)/
t0, where tR is for the solute and t0 denotes the dead time
MES-induced convulsions in mice
The MES is one of the electrical tests used to evaluate an-
ticonvulsant activity. In this test, MES that induced 100 %
maximal seizures was found to be 50 mA alternating current
of 60 Hz frequency for 0.2 s, using ECT UNIT (model
number 7801, UGO Basile, Varese, Italy). 100, 200 mg/kg
of the test compounds were injected i.p. Thirty minutes later,
mice were restrained by hand and subjected to electric shock
through their ears. They were released immediately fol-
lowing the electrical stimulation to permit observation of the
maximal seizure. The maximal seizure typically consists of
a short period of initial tonic flexion and a prolonged period
of tonic extension (especially the hind limb). Protection was
defined as complete absence of hind limb tonic extension
(Lotarski et al., 2014).
ˇ
´
obtained via an unretained analyte (Mrkvickova et al.,
2008). The log k values of the individual compounds are
shown in Table 2.
Acknowledgments Authors would like to thank the Deanship of
Scientific Research and the Research Center, College of Pharmacy,
King Saud University.
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