Synthesis, in silico metabolic and toxicity prediction of some novel imidazolinones derivatives as potent anticonvulsant agents

Article abstract of DOI:10.3109/14756366.2011.584191

A series of 1,2,4-trisubstituted 5-imidazolinone derivatives were synthesized by Erlenmeyer condensation of benzoylglycine (hippuric acid) with different aldehydes in the presence of sodium acetate and acetic anhydride. The derivatives of the compounds we

Full text of DOI:10.3109/14756366.2011.584191

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(2): 201–207
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.584191
RESEARCH ARTICLE
Synthesis, in silico metabolic and toxicity prediction of
some novel imidazolinones derivatives as potent
anticonvulsant agents
N. S. Hari Narayana Moorthy, Vipin Saxena, C. Karthikeyan, and Piyush Trivedi
School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Gandhi Nagar, Bhopal, India
Abstract
A series of 1,2,4-trisubstituted 5-imidazolinone derivatives were synthesized by Erlenmeyer condensation of
benzoylglycine (hippuric acid) with different aldehydes in the presence of sodium acetate and acetic anhydride.
The derivatives of the compounds were prepared by condensation of some known sulpha drugs with 5-oxazolone
derivatives. The anticonvulsant activity of the compounds was determined by the protection of pentylenetetrazole-
induced convulsions that was ranged from 10 to 60%. The compounds with p-OCH3, p-OH and o-Cl substitutions in
the phenyl ring on 4th position of the imidazolinone ring exhibited good anticonvulsant activity. In silico metabolic and
toxicity studies showed that all the compounds in the series are not likely to exhibit toxicity except the compounds
IIIa, IIIb, VIa and VIb, that is predicted to show 29% mutagenicity and 53% irritation in comparison to the other
compounds. The predicted lethal effect and hERG toxicity of the compounds showed that IIa, IVa, Va and Vb might be
toxic at higher concentrations. The results successfully establish the synthesized imidazolinone derivatives as novel
compounds with anticonvulsant properties, low predicted cardiotoxicity and lethal effects thus can be promising
leads for further development as novel anticonvulsants.
Keywords: Imidazolinone, in silico, anticonvulsant, toxicity, hERG
Introduction
Imidazolinone is an important scaffold possessing a
e development of a new bioactive molecule is com-
plex, time consuming and very expensive and also the
developed drugs may suffer from unwanted side effects,
toxicity, resistance, etc. It is the primary thought of the
scientist in the medicinal chemistry field to develop safe
and potent molecules. e last two decades is called in
neuroscience as “decade of the brain” and it has brought
advances to the treatment of neurological disabilities,
including epilepsy1. Epilepsy, a group of disorders of the
CNS characterized by paroxysmal cerebral dysrhythmia
manifesting as brief episodes (seizures) of loss of or dis-
turbances of consciousness2,3. Although several classes
of anti-epileptic agents with different nucleus are avail-
able for treating epilepsy, these agents have a number of
spectrum of pharmacological actions, which includes
anticonvulsant, antiparkinsonism and monoamino-oxi-
dase inhibitory activities7–12. A careful scrutiny of struc-
ture activity relationship studies of anticonvulsant agents
reported in literature indicates that ureido moiety is
responsible for the anticonvulsant action13–15. Precedence
exist in literature on anticonvulsant properties of 1,2,4-
trisubstituted 5-imidazolinones12, the N arylation of
imide NH of the imidazolinone could serve two func-
tions; increases the partition coefficient and prevents the
dissociation of imido hydrogen, three both cases favored
more effective distribution of the central nervous sys-
tem16. e multiple biological properties of sulfonamides
are well documented in literature17,18. e present study
aims to introduce two sulfa drugs sulfamethoxazole and
shortcomings which limit their utility4–6
.
e first two authors contributed equally to this work.
Address for Correspondence: N.S. Hari Narayana Moorthy, School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya,
Airport Bypass Road, Gandhi Nagar, Bhopal-462036, (M.P), India. Tel.: +91–755-2678883, Fax: +91–755-2742006.
E-mail: nshnm06@yahoo.co.in
(Received 01 June 2010; revised 20 March 2011; accepted 23 April 2011)
201

202 N.S.H.N. Moorthy
sulfadoxin into 4-arylidene-2-phenyl-5-(4H)-oxazolones
to formulate 1,2,4-trisubstituted 5-imidazolinones bear-
ing sulfonamide moiety with the hope that combina-
tion of these active groups in the new molecular design
would lead to better anticonvulsant agents. Based on
the aforementioned, we have designed and synthesized
trisubsituted imidazolinone compounds incorporating
sulfa drugs (sulfamethoxazole and sulfadoxin) and eval-
uated them in vivo for ascertaining their anticonvulsant
efficacy.
soon as the mixture had liquefied completely, the flask
was transferred on to a water bath and heated at 60°C for
2 h. en 100 ml of ethanol was added slowly to the con-
tent of the flask and allowed the mixture to stand over-
night. e crystalline product was filtered with suction
and washed with two 25 ml portion of ice cold alcohol
and then washed with two 25 ml portion of boiling water
and dried at 100°C. e yield of almost pure oxazolone,
m.p. 165–166°C was 4 g (64%). Recrystallization from
benzene raises the m.p. to 167–168°C.
ADME-Tox property of molecules is an important
parameter for the success of some compounds in clinic.
In silico methods to predict toxicity and ADME properties
even before a drug candidate was synthesized is widely
used in drug discovery to understand the properties
that are necessary to convert leads into good medicines,
which increase the success rate19,20. Drug metabolism
and clearance determine the success of a drug, as these
properties have a significant impact on bioavailabil-
ity (oral or intravenous) and give an idea about how a
drug behave in the human body. e recognition of the
metabolic site could be of great help in designing new
compounds with better pharmacokinetic profile as well
as to avoid the presence of toxic metabolites by chemi-
cally protecting the metabolic labile moieties in the drug
candidate21–24. Related to the foregoing, the synthesized
compounds were subjected to in silico toxicity and
metabolism studies in order to predict their metabolic
and toxicity profile. A preliminary idea of the metabolic
and toxicity profile of a compound could be of great help
in assessing the suitability of the proposed molecule as a
probable anticonvulsant drug candidate and as well as to
avoid the presence functionalities that might lead to toxic
metabolites.
Synthesis of 1-N-substituted 4-(4-benzylidene-
5-oxo-2-phenyl-4,5dihydro-1H-imidazol-1-yl)
benzenesulfonamide
4-Arylidene-2-phenyloxazol-5(4H)-one
derivatives
(0.004 mol) was heated with an equimolar quantity of
sulfonamide (sulfamethoxazole and sulfadoxin) in an
oil bath at 140°C for 1 h. e resulting jelly like mass was
taken in an organic solvent (acetone) and refluxed for 8 h
with continuous removal of water and cooled, the excess
solvent removed under vacuum and the resultant solid
was collected. Crude solid product was recrystallized
from ethyl acetate to get flakes of 5-imidazolinones and
found chromatographically homogenous when detected
with iodine.
Determination of anticonvulsant activity
Anticonvulsant activity was determined against pen-
tylenetetrazole-induced seizures in mice, 25–30 g of
either sex11,12,14. e mice were divided into groups of
five mice and keeping the group weight as near as pos-
sible. All compounds were suspended in 5% aqueous
gum acacia (have devoid of anticonvulsant activity) to
give a concentration of (0.025% w/v). An arbitary dose
of 100 mg/kg i.p. of imidazolinone was administered
to five mice. e mice were then injected with penty-
lenetetrazole (90 mg/kg i.p.) 30 min after the adminis-
tration of the test compounds. e pentylenetetrazole
has been shown to produce convulsions in almost all
untreated mice and to exhibit 100% mortality during
24 h. No mortality of animals was observed during 24 h
treatment with 100 mg/kg of the imidazolinones alone.
e mice were observed 60 min for the occurrence of
seizures and an episode of clonic spasm persisting for
a minimum of 5 s was considered a threshold convul-
sion. Transient intermittent jerks and tremulousness
were not counted. Mice devoid of threshold convul-
sions during 60 min were considered protected. e
number of mice protected in each group was recorded
and the anticonvulsant activity of these imidazolinone
was represented as percent protection.
Materials and methods
Materials used
Melting points were determined on electrothermal capil-
lary melting point apparatus and were uncorrected. e
progress of the reactions was monitored by thin layer
chromatography (TLC) using silica gel G on glass plate
as stationary phase and benzene: ethylacetate (80:20) as
mobile phase. IR (KBr) (cm−1) spectra were recorded on
1
FT/IR-470 Plus Jasco spectrophotometer. H NMR spec-
tra were recorded on Brucker DRx (300 MHz) spectrom-
eters and the chemical shift values are reported in parts
per million using tetramethylsilane as internal standard.
e samples were dissolved in CDCl3.
Synthesis of 4-arylidene-2-phenyloxazol-5(4H)-one
derivatives
A mixture of 0.025 mol of redistilled benzaldehyde deriv-
atives, 4.48 g (0.025 mol) of benzoyl glycine (hippuric
acid), 7.66 g (0.075 mol) of acetic anhydride and 2.05 g
(0.025 mol) of anhydrous sodium acetates were placed
in a 100 ml were placed in a conical flask and heated on
an electric hotplate with constant stirring till liquified. As
In silico metabolites and toxicity prediction
e metabolites and the toxicity profile of the compounds
were predicted by computational method using Pallas
3.1.1.2. ADME-Tox prediction software25. e LD50 and
the hERG (pIC50) were predicted using q-Tox and q-hERG
softwares, respectively26.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis, In silico metabolic and toxicity prediction 203
condensation of some known sulpha drugs (sulfamethox-
azole and sulfadoxin) with 5-oxazolone derivatives. e
imidazolinone derivatives were synthesized employing a
two step procedure as outlined in scheme 1. e physico-
chemical characterization was performed in order to con-
firm the progress of reaction and the purity of compounds.
TLC was carried out on silica gel G using benzene: ethyl
Results and discussion
Chemistry
eoxazolonederivativesweresynthesizedbytheconden-
sation of benzaldehyde and hippuric acid in acetic anhy-
dride and anhydrous sodium acetate. 1,2,4-trisubstituted
5-imidazolinones derivatives were synthesized by the
CH2COOH
+
CHO
HN
O
R
Substituted aldehydes
Acetic anhydride
anhydrous sod. Acetate
60°C, 2 hr
Hippuric acid
O
O
C
C
N
H
R
I-VI
Sulfonamides,
140°C,reflux 8 hr
O
N
N
O
C
H
C
N
SO2NH
R
CH3
I-VIa
O
N
N
N
C
H
C
N
SO2NH
H3CO
R
OCH3
I-VIb
Structures: I = H, II = p-dimethylamino, III = p-OH, IV = p-OCH3, V = o-Cl,
VI = o-OH
Scheme 1. Synthesis of proposed imidazolinone derivatives.
© 2012 Informa UK, Ltd.

204 N.S.H.N. Moorthy
acetate (80:20) as eluent (Table 1). e constitutions of the
synthesized compounds were confirmed by IR and NMR.
e functional groups on the compounds were confirmed
by IR spectroscopy and the number and the environment
of hydrogen atoms in the compounds were confirmed
by NMR spectrum (Table 2). e anticonvulsant activity
of the compounds (as per ethical guidelines) was deter-
mined by ascertaining the percentage protection against
pentylenetetrazole-induced convulsions in mice and the
activity of the synthesized compounds ranged from 10 to
60%. Amongst the compounds tested, maximal protection
was observed for compounds with p-OCH3 (IVa), p-OH
(IIIa) substitution in phenyl ring on the 4th positions of the
imidazolinone ring of series bearing sulfamethoxazole
moiety, and p-OCH3 (IVb), o-Cl (Vb), substitutions in
the phenyl ring on the 4th positions of the imidazolinone
ring of series bearing sulfadoxin moiety. In case of the
unsubstituted compounds, the compound Ib with sulfa-
doxin moiety showed better protection (20%) compared
to the compound Ia with sulfamethoxazole moiety sug-
gesting that incorporation of sulfadoxin in the nucleus is
most favoured for anticonvulsant activity exhibited by the
title compounds. In sulfamethoxazole series, p-dimethyl
aminosubstitution(IIa)ando-OHsubstitution(VIa)inthe
phenyl ring resulted in two fold increase in the protection
whereas o-Cl substitution (Va) caused a fourfold increase
in protection against pentylenetetrazole-induced convul-
sions in comparison to the unsubstituted compound Ia.
Table 1. Anticonvulsant activity of the synthesized compound.
Compound No
Mol. Formula
C26H20N4O4S
C28H23N5O5S
C28H25N5O4S
C30H28N6O5S
C26H20N4O5S
C28H23N5O6S
C27H22N4O5S
C29H25N5O6S
C26H19ClN4O4S
C28H22ClN5O5S
C26H20N4O5S
C28H23N5O6S
Phenobarbital
Mol. Wt
484.55
541.60
527.16
584.67
500.12
557.58
514.57
571.62
518.97
576.02
500.55
557.56
M.P. (°C)
126
160
170
166
134
130
80
% Yield
61
Anticonvulsant activity % protection
Ia
10
20
20
20
60
40
60
60
40
60
20
40
100
Ib
47
IIa
60
IIb
74
IIIa
IIIb
IVa
IVb
Va
93
95
89
84
87
80
65
Vb
85
53
Via
VIb
Reference
108
164
84
83
Table 2. Analytical spectra data of the synthesized compounds.
Compound No
Ia
Spectra details
IR (KBr) (cm−1) 3194 (Ar-CH), 1723 (C=O), 1641 (C=N), 1169 (S=O); 1H NMR (CDCl3) 2.29 (s, 3H, CH3), 4.00 (s, 1H,
SO2NH), 6.20 (s, 1H, -CH oxazole), 7.36 (s, 1H, C=CH), 7.10–8.90 (m, 14H, Ar-H).
Ib
IR (KBr) (cm−1) 3102 (Ar-CH), 1731 (C=O), 1651 (C=N), 1162 (S=O); 1H NMR (CDCl3) 3.81–3.90 (bs, 6H, OCH3), 4.70 (s,
1H, SO2NH), 7.56 (s, 1H, C=CH), 7.10–8.80 (m, 14H, Ar-H), 9.20 (s, 1H, -CH pyrimidine).
IIa
IR (KBr) (cm−1) 3161 (Ar-CH), 1716 (C=O), 1646 (C=N), 1161 (S=O), 1374 (C-N); 1H NMR (CDCl3) 2.42 (s, 3H, CH3), 2.90
(s, 6H, N(CH3)2), 4.10 (s, 1H, SO2NH), 6.23 (s, 1H, -CH oxazole), 6.55 (s, 1H, C=CH), 6.50–7.80 (m, 13H, Ar-H).
IIb
IIIa
IIIb
Iva
IVb
Va
IR (KBr) (cm−1) 3239 (Ar-CH), 1716 (C=O), 1647 (C=N), 1321 (S=O); 1H NMR (CDCl3) 3.28–3.40 (bs, 6H, OCH3), 2.87 (s,
6H, N(CH3)2), 4.10 (s, 1H, SO2NH), 6.60 (s, 1H, C=CH), 7.20–8.20 (m, 13H, Ar-H), 9.11 (s, 1H, -CH pyrimidine).
IR (KBr) (cm−1) 3379 (OH), 3098 (Ar-CH, 1758 (C=O), 1653 (C=N), 1324 (S=O); 1H NMR (CDCl3) 2.25 (s, 3H, CH3), 4.00
(s, 1H, SO2NH), 6.00 (s, 1H, OH), 6.30 (s, 1H, -CH oxazole), 7.60 (s, 1H, C=CH), 6.68–7.90 (m, 13H, Ar-H).
IR (KBr) (cm−1) 3473 (OH), 3248 (Ar-CH), 1733 (C=O), 1654 (C=N), 1351 (S=O); 1H NMR (CDCl3) 3.8–4.0 (bs, 6H, OCH3),
4.21 (s, 1H, SO2NH), 6.10 (s, 1H, OH), 7.60 (s, 1H, C=CH), 6.78–7.90 (m, 13H, Ar-H), 9.20 (s, 1H, -CH pyrimidine).
IR (KBr) (cm−1) 3063 (Ar-CH), 1732 (C=O), 1636 (C=N), 1325 (S=O); 1H NMR (CDCl3) 2.39 (s, 3H, CH3), 3.60 (s, 3H,
OCH3), 4.00 (s, 1H, SO2NH), 6.52 (s, 1H, -CH oxazole), 7.51 (s, 1H, C=CH), 6.21–7.90 (m, 13H, Ar-H).
IR (KBr) (cm−1) 3102 (Ar-CH), 1716 (C=O), 1653 (C=N), 1311 (S=O) 1210 (C-O-C); 1H NMR (CDCl3) 3.71–3.90 (ts, 9H,
OCH3), 4.00 (s, 1H, SO2NH), 7.59 (s, 1H, C=CH), 6.71–7.90 (m, 13H, Ar-H), 9.40 (s, 1H, -CH pyrimidine).
IR (KBr) (cm−1) 3289 (Ar-CH), 1731 (C=O), 1616 (C=N), 1338 (S=O) 1165 (C-O); 1H NMR (CDCl3) 2.32 (s, 3H, CH3), 4.00
(s, 1H, SO2NH), 6.72 (s, 1H, -CH oxazole), 7.79 (s, 1H, C=CH), 7.00–7.90 (m, 13H, Ar-H).
Vb
Via
Vib
IR (KBr) (cm−1) 3239 (Ar-CH), 1734 (C=O), 1651 (C=N), 1318 (S=O); 1H NMR (CDCl3) 3.81 (s, 6H, OCH3), 4.22 (s, 1H,
SO2NH), 7.76 (s, 1H, C=CH), 7.00–7.90 (m, 13H, Ar-H), 9.40 (s, 1H, -CH pyrimidine).
IR (KBr) (cm−1) 3235 (Ar-CH), 1764 (C=O), 1666 (C=N), 1326 (S=O); 1H NMR (CDCl3) 2.34 (s, 3H, CH3), 4.10 (s, 1H,
SO2NH), 5.20 (s, 1H, OH), 6.40 (s, 1H, -CH oxazole), 7.80 (s, 1H, C=CH), 6.68–7.90 (m, 13H, Ar-H).
IR (KBr) (cm−1) 3376 (OH), 3241 (Ar-CH), 1765 (C=O), 1650 (C=N), 1320 (S=O); 1H NMR (CDCl3) 3.80 (s, 6H, OCH3),
4.00 (s, 1H, SO2NH), 4.80 (s, 1H, OH), 7.80 (s, 1H, C=CH), 6.68–7.90 (m, 13H, Ar-H), 9.20 (s, 1H, -CH pyrimidine).
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis, In silico metabolic and toxicity prediction 205
In sulfadoxin series, p-dimethyl amino substitution (IIb)
in phenyl ring did not improve the anticonvulsant activ-
ity whereas, p-OH (IIIb) and o-OH (VIb) substitution in
phenyl ring improved anticonvulsant activity two-fold
in comparison to the unsubstituted compound Ib. It is
worth mentioning that the majority of the compounds
have shown significant activity.
In silico metabolites and toxicity of the synthesized
compounds were predicted by using Pallas 3.1.1.2., q-Tox
and q-hERG software and the result obtained are tabu-
lated in Table 3. e possible position of metabolism of
the synthesized compounds is given in Figures 1 and 2. All
the compounds appear to undergo hydroxylation at the
para and meta position of the phenyl ring. N-oxidation of
the aromatic heterocycles in the oxazole and pyrimidine
ring occurred alongwith oxidation of the tertiary nitro-
gen atom in the imidazolinone ring. e imidazolinone
ring has cleaved in all compounds. e methoxy com-
pounds especially pyrimidine substituents containing
compounds (Ib to VIb) and p-methoxy phenyl substitu-
ents (IVa) of the compounds undergo demethylation to
give a free phenolic group. e results show that all the
compounds in the series are expected to undergo phase
I metabolism such as oxidation, hydration, ring cleavage,
etc. (Figures 1 and 2). Only hydroxyl group containing
compound IIIa,b and VIa,b are expected to undergo
phase II metabolism of O-glucouronide conjugation and
phenol sulfate conjugation.
e compounds except IIIa,b and VIa,b shows toxicity.
All the compounds in this series show 0% toxicity in terms
of oncogenicity and sensitivity. e teratogenic properties
of the compounds are <50% which shows the probability
of this toxicity is less. e compounds IIIa,b and VIa,b have
>50% (53%) overall toxicity compared to other compounds
(34%) and these four compounds exhibit irritation 53%
and mutragenicity 29%. It shows that these compounds are
more toxic than all other compounds. ese compounds
only give phase II metabolites due to the presence of OH
group in the benzene ring as phenolic OH.
e predicted LD50 and the pIC50 (hERG toxicity) of the
compounds show that the compounds IIa, IVa, Va and
Vb might have lethal effect at high concentration and
may also possess the cardiotoxicity in high concentration
compared with other compounds. ese compounds
also exhibit significant anticonvulsant activities than
other compounds. In comparison with the other toxicity
studies as mentioned earlier, the compound with −OH
groups in phenyl rings of their structure are more toxic
Table 3. Predicted toxicities of the synthesized compounds.
Compound No
hERG (pIC50)
LD50 (pIC50)
0.8
Mutagenicity
Teratogenicity
Irritation
Ia
7.5
5.6
6.5
7.4
7.7
7.2
6.5
7.3
6.8
6.3
7.3
7
0
0
34
34
34
34
34
34
34
34
34
34
34
34
0
0
Ib
–0.2
0.7
IIa
IIb
IIIa
IIIb
Iva
IVb
Va
0
0
0.2
0
0
1.4
29
29
0
53
53
0
–0.5
0.4
1.0
0
0
0.8
0
0
Vb
VIa
VIb
1.1
0
0
1.5
29
29
53
53
0.7
B32_N-Oxidation of Aromatic Heterocycles
B13_C=C Double bond oxidation
B14_C=C Double bond Hydration
E19_Tertiary amine Oxidation
O
B47_ParahydroxylationIII
N
SO2NH
N
N
C
B11_Demethylation of Amines
E19_Tertiaryamine Oxidation
A13_Phenol Sulfate Conjugation
F26_O-Glucouronide conjugation-I
E32_ODemethylation of Phenol
N
CH
OCH3
H3CO
R
E32_O-Demethylation of Phenol
B47_ParahydroxylationIII
B48_Metahydroxylation
B48_Metahydroxylation
CL17_Imidazole ring cleavage
B55_metahydroxylation/O-methylation
Figure 1. Predicted metabolic position of imidazolinones (Ia–VIa) derivatives.
© 2012 Informa UK, Ltd.

206 N.S.H.N. Moorthy
E19_Tertiary amine Oxidation
SO2NH
B13_C=C Double bond oxidation
B14_C=C Double bond Hydration
O
B47_Parahydroxylation III
N
C
CH3
N
B11_Demethylation of Amines
E19_Tertiary amine Oxidation
A13_Phenol Sulfate Conjugation
F26_O-Glucouronide conjugation-I
E32_ODemethylation of Phenol
O
CH
N
R
B03_Hydroxylation of Methyl group
B32_N-Oxidation of aromatic Heterocycles
B47_Parahydroxylation III
B48_Metahydroxylation
CL17_Imidazole ring cleavage
B48_Metahydroxylation
B55_metahydroxylation/O-methylation
Figure 2. Predicted metabolic position of imidazolinones (Ib–VIb) derivatives.
than others. Unfortunately the −OH substitution at the
para position on the phenyl ring of the molecule has
considerably significant anticonvulsant activity.
References
1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N
Engl J Med 2000;342:314–319.
Summarizing the above, it can be concluded that we
have successfully synthesized 12 newly designed deriva-
tives of 1,2,4-trisubstituted 5-imidazolinones incorporat-
ing two sulfa drugs. All the title compounds have been
investigated for their anticonvulsant activity in mice mod-
els. Interestingly, the majority of the compounds showed
moderate to very good anticonvulsant activity. e best
results in terms of the percentage protection against pen-
tylenetetrazole-induced convulsions in mice was achieved
for compounds with p-OCH3 and p-OH substitution in the
phenyl ring on the 4th positionsoftheimidazolinoneringfor
sulfamethoxazole series and p-OCH3 and o-Cl substitution
in the phenyl ring on the 4th positions of the imidazolinone
ring for sulfadoxin series. In silico metabolite and toxicity
studies were also performed for the synthesized molecules
to assess their suitability in terms of their susceptibility to
metabolism and toxicity profile. Overall, the studies estab-
lish 1,2,4-trisubstituted 5-imidazolinones as novel leads for
further exploration as anticonvulsant agents.
2. Carroll BJ, Curtis GC, Mendels J. Neuroendocrine regulation in
depression. II Discrimination of depressed from non-depressed
patients. Arch Gen Psychol 1973;33:1051–1057.
3. Ellison G, Eison MS, Huberman HS, Daniel F. Long-term changes
in dopaminergic innervation of caudate nucleus after continuous
amphetamine administration. Science 1978;201:276–278.
4. Worthen DR, Bence AK, Stables JP, Crooks PA. In vivo evaluation
of diaminodiphenyls: anticonvulsant agents with minimal acute
neurotoxicity. Bioorg Med Chem Lett 2009;19:5012–5015.
5. Johannessen Landmark C, Johannessen LC. Pharmacological
management of epilepsy: recent advances and future prospects.
Drugs 2008;68:1925–1939.
6. Snead OC, Donner EJ. A new generation of anticonvulsants for
the treatment of epilepsy in children. Paediatr Child Health
2007;12:741–744.
7. Verma M, Chaturvedi AK, Chaudhari A, Parmar SS. Monoamine
oxidase inhibitory and anticonvulsant properties of 1,2,4-
trisubstituted 5-imidazolones. J Pharm Sci 1974;63:1740–1744.
8. Naithani PK, Srivastava VK, Barthwal JP, Saxena AK, Gupta TK,
Shanker K, Synthesis and antiparkinsonian activity of newer
imidazolones. Indian J Chem 1989;28:990–992
9. Harfenist M, Soroko FE, McKenzie GM. 2-(Alkoxyaryl)-2-
imidazoline monoamine oxidase inhibitors with antidepressant
activity. J Med Chem 1978;21:405–409.
10. Magd-El-Din AA, Abd-El-All AS, Roaiah HMF, El-Baroudy
MMS. New synthesis of furochromenyl imidazo [2a-1b] thiazole
derivatives, studies on their antitumor activities. J Am Sci
2010;6:251–256.
11. Desai NC, Bhavsar AM, Baldaniya BB. Synthesis and antimicrobial
activity of 5-imidazolinone derivatives. Indian J Pharm Sci
2009;71:90–94.
12. Joshi H, Upadhyay P, Karia D, Baxi AJ. Synthesis of some novel
imidazolinones as potent anticonvulsant agents. Eur J Med Chem
2003;38:837–840.
Acknowledgments
e author is thankful to the Vice Chancellor, RGPV,
Bhopal for providing laboratory facility. Authors would
like to give sincere thanks to AICTE for providing
Scholarship and Career Award grant during this project.
One of the authors, C. Karthikeyan, wishes to thank CSIR,
New Delhi, for providing a Senior Research Fellowship.
13. Siddiqui SA, Bhusare SR, Jorikot DV, Pawa RP, Vibhute YB. New
novel synthesis and antibacterial activity of 1-(substituted
Declaration of interest
phenyl)-2-phenyl-4-(3′-halo,
4′-hydroxy,
5′-methoxy
benzylidene)-imidazole-5-ones. Bull Korean Chem Soc
2001;22:1033–1036.
14. Patel HJ, Sarra J, Caruso F, Rossi M, Doshi U, Stephani RA. Synthesis
and anticonvulsant activity of new N-1′,N-3′-disubstituted-
2′H,3H,5′H-spiro-(2-benzofuran-1,4′-imidazolidine)-2′,3,5′-
triones. Bioorg Med Chem Lett 2006;16:4644–4647.
e authors would like to give sincere thanks to AICTE
for providing scholarship and career award grant during
this project. One of the authors, C. Karthikeyan, wishes to
thank CSIR, New Delhi, for providing a Senior Research
Fellowship.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis, In silico metabolic and toxicity prediction 207
15. Librowski T, Kubacka M, Meusel M, Scolari S, Müller CE,
Gütschow M. Evaluation of anticonvulsant and analgesic
effects of benzyl- and benzhydryl ureides. Eur J Pharmacol
2007;559:138–149.
20. Dearden JC. In silico prediction of drug toxicity. J Comput Aided
Mol Des 2003;17:119–127.
21. Sean E, John R. In silico ADME/Tox: the state of the art. J Mol Graph
Model 2002;20:305–309.
16. Bhusare SR, Patil PS, Chavan VP, Pawar RP, Bhawal BM, Vibhute
YB. Synthesis of 1-(substituted phenyl)-2-phenyl-4- (2′-hydroxy
3′-iodo-5′-choro benzylidene) -imidazole-5-ones. Mendeleev
Commun 2002;12:94–95.
17. iry A, Dogné JM, Supuran CT, Masereel B. Anticonvulsant
sulfonamides/sulfamates/sulfamides with carbonic anhydrase
inhibitory activity: drug design and mechanism of action. Curr
Pharm Des 2008;14:661–671.
18. Masereel B, Rolin S, Abbate F, Scozzafava A, Supuran CT.
Carbonic anhydrase inhibitors: anticonvulsant sulfonamides
incorporating valproyl and other lipophilic moieties. J Med Chem
2002;45:312–320.
22. Moorthy HN, Singh RJ, Singh HP, Gupta SD. Synthesis, biological
evaluation and in silico metabolic and toxicity prediction of some
flavanone derivatives. Chem Pharm Bull 2006;54:1384–1390.
23. Moorthy HN, Karthikeyan C, Trivedi P. Design, synthesis, cytotoxic
evaluation, and QSAR study of some 6H-indolo[2,3-b]quinoxaline
derivatives. J Enzyme Inhib Med Chem 2010;25:394–405.
24. Hari Narayana Moorthy HN, Karthikeyan C, Trivedi P. Synthesis,
cytotoxic evaluation and in silico pharmacokinetic prediction of
some benzo[a]phenazine-5-sulfonic acid derivatives. Med Chem
2009;5:549–557.
25. Pallas 3.1.1.2., ADME-Tox software, CompDrug International Inc.,
USA; 2000.
19. Wilhelm H, Regina T, Michael W. e virtual laboratory approaches
to pharmacokinetics: design principles and concepts. Drug Dis
Today 2006;11:800–805.
26. q-ADME, q-Tox and q-hERG software 2008, developed by Quantum
Pharmaceuticals, Moscow, Russia; 2008. http://www.q-lead.
com/.
© 2012 Informa UK, Ltd.

Copyright of Journal of Enzyme Inhibition & Medicinal Chemistry is the property of Taylor & Francis Ltd and
its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for individual use.