Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant agents

Article abstract of DOI:10.1016/j.bmcl.2014.11.016

Herewith, we report the design and synthesis of a series of N-(2-oxo-2((4-oxo-2-substituted thiazolidin-3yl)amino)ethyl) benzamide derivatives 7(a-j) under microwave irradiation, based on four component pharmacophoric model to get structural prerequisite indispensable for anticonvulsant activity. The synthesized derivatives were investigated in maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (sc-PTZ) induced seizure and neurotoxicity screening. All the test compounds were administered at a dose of 30, 100 and 300 mg/kg body weight at the time interval of 0.5 h and 4 h. The compounds were also evaluated for behavioral activity and toxicity study. The compound 7h was found to be most active in MES model. The anticonvulsant screening data shows that 65% of the compounds were found active against MES model when compared to 35% sc-PTZ model. The computational parameter such as docking study, log P determination and ADME prediction were performed to exploit the results.

Full text of DOI:10.1016/j.bmcl.2014.11.016

Accepted Manuscript
Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-sub-
stituted thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant
agents
Anna Pratima G. Nikalje, Arfat N. Shaikh, Sameer I. Shaikh, Firoz A. Kalam
Khan, Jaiprakash N. Sangshetti, Devanand B. Shinde
PII:
S0960-894X(14)01187-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.11.016
BMCL 22171
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 August 2014
3 November 2014
5 November 2014
Please cite this article as: Nikalje, A.P.G., Shaikh, A.N., Shaikh, S.I., Kalam Khan, F.A., Sangshetti, J.N., Shinde,
D.B., Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted
thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant agents, Bioorganic & Medicinal Chemistry
Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.11.016
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Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted
thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant agents
Anna Pratima G. Nikalje a,*, Arfat N. Shaikh a, Sameer I. Shaikh a, Firoz A. Kalam Khan a,
Jaiprakash N. Sangshetti a, Devanand B. Shinde b
a Department of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr. Rafiq
Zakaria Campus, Rauza Bagh, P.B. No. 33, Aurangabad 431001 (M.S.), India
b Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431004 (M.S.), India
* Corresponding author. Tel.: +91 9823619992; Fax: +91 0240 2381129.
E-mail address: annapratimanikalje@gmail.com (A.P.G. Nikalje).
Abstract
Herewith, we report the design and synthesis of a series of N-(2-oxo-2((4-oxo-2-substituted
thiazolidin-3yl) amino) ethyl) benzamide derivatives 7(a-j) under microwave irradiation,
based on four component pharmacophoric model to get structural prerequisite indispensable
for anticonvulsant activity. The synthesized derivatives were investigated in maximal
electroshock seizure (MES), subcutaneous pentylenetetrazole (sc-PTZ) induced seizure and
neurotoxicity screening. All the test compounds were administered at a dose of 30, 100 and
300 mg/kg body weight at the time interval of 0.5 h and 4 h. The compounds were also
evaluated for behavioral activity and toxicity study. The compound 7h was found to be most
active in MES model. The anticonvulsant screening data shows that 65% of the compounds
were found active against MES model when compared to 35% sc-PTZ model. The
computational parameter such as docking study, log P determination and ADME prediction
were performed to exploit the results.
Keywords: Benzamide, Thiazolidinone, Microwave irradiation, Anticonvulsant evaluation,
Computational studies.
1

Epilepsy is a common neurological condition, affecting 0.5-1% of the population
worldwide.1, 2 Current drug treatments for epilepsy suffers from a number of disadvantages
including the convulsions of approximately 25% of epileptics that are not controlled by
medication.3 In recent years, the field of antiepileptic drug development has become quite
dynamic, providing many promising research opportunities.4 The search for new
anticonvulsant drugs continues to be an active area of investigation in medicinal chemistry.
Benzamide derivatives and related compounds constitute an important class of compounds
and are known to possess a wide range of biological activities such as muscle relaxant,
antiarrhythmic, antiemetic and antipsychotic.5-6 Several patents and articles reported the
anticonvulsant activity of benzamide containing compounds.7-12 On the other side,
thiazolidinone nucleus is also a potential candidate for anticonvulsant activity and is
contained in Ralitoline Fig. 1(8). Ralitoline is found to be effective in preclinical
anticonvulsant evaluation. Various research groups have reported the anticonvulsant activity
of thiazolidinone and its mechanism due to inhibition of oxidation of the substrates of the
tricarboxylic acid cycle like pyruvate, α-ketoglutarate and citrate, and β- hydroxybutyrate.13-17
Structures of some anticonvulsant agents bearing benzamide and thiazolidinone nucleus were
reported in literature and are represented in Fig. 1. Based on these facts of available literature
and as a part of our continuous investigation in the area of anticonvulsant synthesis and its
biological evaluation 18-20 herein, we designed and synthesized a series of compounds having
benzamide group coupled with thiazolidinone ring via amide linkage which serves as a
hydrogen binding domain with the possibility to get optimal pharmacological profile. A four
point pharmacophoric model was proposed for studying structurally different compounds
with anticonvulsant activity with different mechanism of action.21 Based on this proposition,
our synthesized compounds also comprises of this four point pharmacophoric model (Fig. 2)
as follows:
1. Hydrogen Binding Domain (HBD): amide group which is attached to phenyl ring i.e.
benzamide ring system.
2. Electron donor moiety (D): keto group near thiazolidinone ring system acts as electron
donor.
3. Distal aryl domain (A): phenyl ring of benzamide ring system can perform function of
distal aryl domain.
4. Distal hydrophilic-hydrophobic aryl ring (C): thiazolidinone nucleus with phenyl ring
attached can serve as distal hydrophilic-hydrophobic aryl ring.
2

The computational parameter like molecular docking study, pharmacokinetic properties
(ADME) and log P were determined. Along with the synthesis and anticonvulsant evaluation
of titled compounds, toxicity study was also evaluated.
Target compounds 7(a-j) were obtained according to Scheme 1. In first step, 2-
benzamidoacetic acid 3 was synthesized by stirring benzoyl chloride 1 with glycine 2 in aq.
NaOH in ice-bath. Then compound 3 was esterified by refluxing in ethanol and conc. H2SO4
for 6-8 h to get ethyl 2-benzamido acetate 4. Compound 4 was further refluxed with
hydrazine hydrate in ethanol for 3 h to obtain (2-hydrazinyl-2-oxoethyl)benzamide 5.22 The
Schiff’s bases 6(a-j) were prepared by refluxing compound 5 with various aromatic and
heterocyclic aldehydes in the presence of glacial acetic acid using ethanol as solvent.23 In
final step, respective Schiff’s bases 6(a-j) were cyclized with thioglycolic acid in presence of
anhydrous zinc chloride as a catalyst in DMF as solvent under microwave irradition for 12-17
min to obtain titled compounds 7(a-j). The structures of the synthesized compounds were
confirmed by their physical characterization and spectral data, given in Supplementary
material.
The anticovulsant activity of titled compounds 7(a-j) were assessed by anticonvulsant drug
development (ADD) program protocol.24,25 The anticonvulsant potential of test compounds
were performed by two models namely, maximal electroshock seizure (MES) and
subcutaneous pentylenetetrazole (sc-PTZ), at the dose of 30, 100 and 300 mg/kg.
Neurotoxicity screening was performed by measuring minimal motor impairment using
rotorod test26 and behavioral study was evaluated by actophotometer.27 The toxicity study on
mice liver with i.p. administration of test compounds was also performed.28
The MES and sc-PTZ results of titled compounds were shown in Table 1. In MES,
compounds 7f and 7h showed protection at 30 mg/kg while compounds 7b, 7d and 7i showed
protection against at the dose of 100 mg/kg. The compound 7h showed protection at the dose
of 30 mg/kg at 0.5 h and 4 h time interval indicating the compound to be highly potent and
long acting. Similarly compound 7f was showed protection against 30 mg/kg at 0.5 h
indicating that it was highly potent and short acting as requires 4 h protection at the dose of
100 mg/kg. The compound 7d showed protection at the dose of 100 mg/kg at both time
intervals indicating that the compound is potent and long acting. In sc-PTZ screening,
compounds 7a, 7g, and 7h showed protection against 100 mg/kg at 0.5 h time interval, while
compounds 7a, 7h and 7i showed protection the dose of 300 mg/kg at 4 h time interval. None
of the compounds was found potent in sc-PTZ test at the minimum dose 30 mg/kg. The data
3

is shown in Table 1. The anticonvulsant screening data shows that 65% of the compounds
were found active against MES model when compared to 35% sc-PTZ model.
As observed through data analysis, the compounds with smaller electron donating polar
groups like dimethoxy and hydroxy attached to phenyl ring show good anticonvulsant
activity. Substitution of 3, 4-dimethoxy group on aromatic ring 7h was found to be the most
effective in MES model and sc-PTZ model. In MES model, 7h was found to be highly potent
and of long duration of action. Hydroxy substitution at para position 7f of phenyl ring was
found to be potent and short acting. When aromatic ring was replaced by heterocyclic ring (-
indolyl), there is loss in anticonvulsant activity. During the study most of the synthesized
derivatives were more effective in the MES test and the MES test is known to be sensitive to
sodium channel inhibitors (e.g. Phenytoin), which suggested that tested compounds may
inhibit voltage-gated ion channels (particularly sodium channels).18, 29
In neurotoxicity screening (Table 1), compounds 7b and 7i showed neurotoxicity at 100
mg/kg in both intervals while the compound 7c showed neurotoxicity at the dose 30 mg/kg in
both time intervals. Some compounds were found to be less neurotoxic as compared to
phenytoin. In behavioral activity (Table 2) using actophotometer (locomotor activity), all the
titled compounds showed no behavioral despair effect when compared to diazepam at 0.5 h.
The compound 7d showed decreased locomotor activity in the 4 h interval but no significant
effect on behavioral despair at 0.5 h interval when compared to standard diazepam. All other
compounds 7a, 7b, 7c, 7e, 7f, 7g, 7h, 7i and 7j were found to decrease locomotor activity of
the animals as compared to diazepam at 4 h time interval.
In toxicity study we evaluated the histopathology of mice liver (T.S. of liver) given in Fig. 3.
The Fig. 3(a) indicates the effect of control group (0.5 % Tween 80) on albino mice liver
which shows no inflammation and no toxicity and only fatty changes were observed. Fig.
3(b) indicates the effect of standard drug (phenytoin), which shows hepatotoxicity on mice
liver at dose 300 mg/kg. Section from liver shows lobules of the liver with extensive necrosis
and fatty changes. The Fig. 3(c) indicates that the effect of compound 7h shows fatty changes
and lesser inflammation seen at some places at dose 300 mg/kg. Finally in Fig. 3(d) the effect
of compound 7a shows inflammation and extensive necrosis on albino mice at dose 300
mg/kg.
Titled compounds were docked against the crystal structure of sodium channel receptor (PDB
ID: 1BYY)30 using VLife MDS 4.3 package.31 The docking study results revealed that the
compound binds to the active site of sodium channel receptor by forming various
hydrophobic and Van der Waal’s interactions. The compound 7h has shown good binding
4

energy i.e. -36.45 Kcal/mol. Benzamide coupled with thiazolidinone core is located in the
hydrophobic binding cleft lined with PHE1489, MET1490, THR1491, and LYS1495. Also,
the 3,4-dimethoxy phenyl group of compound 7h has formed hydrophobic interactions with
amino acid residues PHE1489, MET1490, THR1491 and LYS1495. The docking pose for
compound 7h was shown in Fig. 4. The oxygen of -OCH3 group at para position has formed
hydrogen bond with amino acid MET1490 (2.578 Å). The compound has formed various Van
der Waal’s interactions with surrounding amino acid residues like PHE1489, MET1490,
THR1491 and LYS1495. Thus compound 7h has potential to inhibit sodium channel receptor
and can be processed further to develop as a lead compound. Log P values of titled
compounds were determined by measuring the partition coefficient between octanol and
phosphate buffer at room temperature using UV spectroscopy.32 We found that the
experimental values of titled compound are in good agreement with theoretical values and are
given in Table 3. The prediction of ADME properties were determined by Molinspiration
online property toolkit33 and are given in Table 4. The properties such as total polar surface
area (TPSA), number of rotatable bonds (n-ROTB), number of hydrogen bond donor (n-
OHNH) and acceptors (n-ON) and log P was determined. The compounds exhibited highest
% absorption (ABS) ranging from 72.37 to 81.92 %. None of the compounds synthesized
violated Lipinski’s parameters. From the above results, it can be concluded that titled
compounds 7(a-j) possess property of drug-likeness. The details of experimental procedures,
pharmacology, toxicity study and computational parameters studied such as docking, Log P
calculations and ADME properties are given in supplementary material.
In conclusion, a series of titled compounds 7(a-j) were designed and synthesized by efficient
microwave irradiation in good to excellent yields. In this study, we validated the four
component pharmacophoric model which is important for anticonvulsant activity.
Preliminary anticonvulsant evaluation was analyzed by electrical test (MES model) and
chemical test (sc-PTZ test) in animal mice model. The compound 7h showed potent
anticonvulsant activity in MES model while compounds 7a and 7h showed significant
anticonvulsant activity in sc-PTZ model. The structure activity relationship revealed that the
compounds having 3, 4-dimethoxy phenyl and 4-hydroxy phenyl group attached to 2nd
position of thiazolidinone ring were responsible for enhancing anticonvulsant activity in MES
model and can be developed as lead candidates. The docking study exhibited good binding
properties, thus indicating that the most active compound 7h acts by inhibiting sodium
channel receptor. Also, none of the synthesized compounds have violated Lipinski’s rule of
five, thus showing good drug like properties.
5

Acknowledgments
Authors are grateful to Mrs. Fatma Rafiq Zakaria Chairman, Maulana Azad Education Trust
and the Principal, Y.B Chavan College of Pharmacy, Aurangabad for encouragement and
support.
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R. K.; Stables, J. P. J. Med. Chem. 2005, 48, 6202.
22. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of
Practical Organic Chemistry; Pearson; New York, 1991, 5. pp 1156.
6

23. Pandeya, S. N.; Raja, A. S. J. Pharm. Pharmaceut. Sci. 2002, 5, 266.
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7

Captions:
Figure captions
Fig. 1 Structures of some anticonvulsants reported in literature 1-8.
Fig. 2 Structural requirement for anticonvulsant model bearing four component
pharmacophoric model.
Fig. 3 Histopathology of mice liver (T.S. of liver) showing effect of control (a), standard
drug (b), compound 7h (c) and compound 7a (d).
Fig. 4 Docking image of compound 7h.
8

Table 1 Anticonvulsant and neurotoxicity screening of compounds
MES screen scPTZ Screen Neurotoxicity
Entry
0.5 h
4 h
300
300
-
100
-
100
-
30
300
-
0.5 h
100
-
4 h
300
-
-
-
-
-
-
0.5 h
4 h
300
100
30
7a
7b
7c
7d
7e
7f
7g
7h
300
100
300
100
-
30
300
30
100
100
30
-
-
-
300
-
100
300
-
-
300
-
-
100
100
300
-
-
300
-
300
-
100
100
100
-
300
300
-
7i
7j
100
300
30
Phenytoin
Sodium Valproate
30
x
x
300
x
-
x
-
Doses of 30, 100, 300 mg/kg of the compound were administered intraperitoneally the
protection and neurotoxicity measured after 0.5 h and 4 h. The above figure clearly indicates
that the minimal dose required causing protection or neurotoxicity in 50% or more of the
animals. The dash (-) indicates the absence of anticonvulsant activity or neurotoxicity (×)
denotes not tested.
9

Table 2 Behavioral study of compounds by using Actophotometer
Entry Activity score by using Actophotometer
Control (24 h before)
Post treatmenta
0.5 h
74.00±3.715**
4 h
7a
119.62±16.53
133.25±2.30
170.41±8.34
115.39±3.80
182.36±3.58
177.68±7.98
157.22±2.76
118.33±15.33
140.28±2.85
210.71±9.62
118.20±9.22**
94.80±4.893**
7b
108.80±7.324** 110.80±7.324**
102.60±9.770** 108.20±1.463**
7c
7d
103.60±2.713**
64.60±7.501**
38.20±3.184ns
77.80±3.277**
42.00±11.375**
92.60±3.776**
71.60±8.875**
94.00±9.659**
99.60±2.159**
80.20±5.987**
88.60±9.532**
101.00±2.345**
7e
7f
7g
7h
7i
7j
102.60±3.265** 120.00±4.506**
33.30±2.557** 75.40±13.309**
Diazepamb
a
denotes each value represents the mean ± SEM significantly different from the control at p
<0.05, ns denotes not significant at p < 0.05 (Student’s t test), ** indicates p value is between
b
0.001-0.01 and very significant and denotes the compound was tested at dose level of 4
mg/kg (i. p.).
10

Table 3 Log P for synthesized compounds.
Entry
Experimental log P
Theoretical log P
7a
7b
7c
7d
7e
7f
1.95
2.30
2.80
2.87
2.10
1.75
1.85
1.85
1.65
1.70
1.81
2.36
2.36
2.36
1.96
1.45
1.68
1.55
1.48
1.45
7g
7h
7i
7j
Theoretical Log P was calculated by Molinspiration online property toolkit.
11

Table 4 Pharmacokinetic parameter important for good oral bioavailability of compounds
Entry %ABS TPSA n-ROTB
(A2)
MW
MV
-
n-OHNH
donors
<5
n-ON
Lipinski’s
acceptors violations
Rule
7a
-
-
-
5
<500
<10
6
≤1
0
81.92
78.50
355.41 307.70
389.86 321.24
389.86 321.24
389.86 321.24
373.48 312.64
371.41 315.72
385.44 333.25
415.47 358.80
445.49 384.34
394.45 336.68
2
7b
7c
7d
7e
7f
81.92
81.92
81.92
81.92
74.93
75.55
75.55
78.50
78.50
78.50
78.50
98.73
96.97
96.97
5
5
5
5
5
6
7
8
5
2
2
2
2
3
2
2
2
3
6
6
6
5
7
7
8
9
7
0
0
0
0
0
0
0
0
0
7g
7h
7i
72.37 106.20
76.47 94.29
7j
%ABS, percentage of absorption; TPSA, topological polar surface area; n-ROTB, number of
rotatable bonds; MW, molecular weight; MV, molecular volume; n-OHNH, number of
hydrogen bond donors; n-ON, number of hydrogen bond acceptors.
12

Fig. 1 Structures of some anticonvulsants reported in literature 1-8
13

Fig. 2 Structural requirement for anticonvulsant model bearing four component
pharmacophoric model
14

Fig. 3 Histopathology of mice liver (T.S. of liver) showing effect of control (a), standard
drug (b), compound 7h (c) and compound 7a (d)
15

Fig. 4 Docking image of compound 7h
16

O
O
(i)
N
COOH
Cl
+ H2N
COOH
H
3
1
2
(ii)
O
O
O
H
(iii)
N
CH2CH3
N
H
N
NH2
O
H
O
4
5
(iv)
O
Ar
H
O
Ar
N
H
N
H
N
S
(v)
N
N
N
O
H
O
O
7(a-j)
6(a-j)
Where Ar (a-j)
OCH3
Cl
d=
e=
a=
b=
i=
OCH3
OCH3
g=
OCH3
F
OCH3
OCH3
h=
Cl
j=
OH
f=
c=
N
H
Cl
Reagents and conditions: (i) aq. NaOH, HCl, Stirring 1-2 h (ii) Conc. H2SO4, Ethanol,
Reflux 6-8 h (iii) NH2NH2 H2O, Ethanol, Reflux 3 h (iv) Ar-CHO, Gla. acetic acid, Ethanol,
Reflux 6-8 h (v) SHCH2COOH, anhydrous ZnCl2, DMF, Microwave irradiation 12-17 min.
Scheme 1. Synthesis of titled compounds 7(a-j)
17

Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted
thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant agents
Anna Pratima G. Nikaljea,*, Arfat N. Shaikha, Sameer I. Shaikha, Firoz A. Kalam Khana,
Jaiprakash N. Sangshettia, Devanand B. Shindeb
aDepartment of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr. Rafiq
Zakaria Campus, Rauza Bagh, P.B. No. 33, Aurangabad 431001 (M.S.), India
bDepartment of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431004 (M.S.), India
* Corresponding author. Tel.: +91 9823619992; fax: +91 0240 2381129.
E-mail address: annapratimanikalje@gmail.com (A.P.G. Nikalje).
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