Synthesis, structure, and solvatochromic properties of pharmacologically active 5-substituted 5-phenylhydantoins

Article abstract of DOI:10.1007/s00706-011-0639-7

A series of 5-substituted 5-phenylhydantoins was synthesized and their UV absorption spectra were recorded in the region 200-400 nm in selected solvents of different polarity. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen-bonding interactions were analyzed by means of the linear solvation energy relationship concept proposed by Kamlet and Taft. The lipophilicities of the investigated hydantoins were estimated by calculation of their log P values. The quantitative relationship between the ratio of the contributions of specific solvent interactions and the corresponding lipophilicity parameter is discussed. The correlation equations were combined with the corresponding ED₅₀ values and different physicochemical parameters to generate new equations that demonstrate the reasonable relationships between solute-solvent interactions and the structure-activity parameters. In order to determine a spectroscopic assignment of the absorption bands in different solvents, quantum chemical calculations were done. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0639-7

Monatsh Chem (2011) 142:1227–1234
DOI 10.1007/s00706-011-0639-7
ORIGINAL PAPER
Synthesis, structure, and solvatochromic properties
of pharmacologically active 5-substituted 5-phenylhydantoins
•
Nemanja Trisovic Natasa Valentic Marko Erovic
•
•
ˇ
Tatjana Ðakovic-Sekulic Gordana Uscumlic
´
ˇ
´
´
•
•
´
´
ˇ´
´
´
Ivan Juranic
Received: 1 July 2010 / Accepted: 24 August 2011 / Published online: 24 September 2011
Ó Springer-Verlag 2011
Abstract A series of 5-substituted 5-phenylhydantoins
was synthesized and their UV absorption spectra were
recorded in the region 200–400 nm in selected solvents of
different polarity. The effects of solvent dipolarity/polar-
izability and solvent–solute hydrogen-bonding interactions
were analyzed by means of the linear solvation energy
relationship concept proposed by Kamlet and Taft. The
lipophilicities of the investigated hydantoins were esti-
mated by calculation of their log P values. The quantitative
relationship between the ratio of the contributions of
specific solvent interactions and the corresponding lipo-
philicity parameter is discussed. The correlation equations
were combined with the corresponding ED50 values and
different physicochemical parameters to generate new
equations that demonstrate the reasonable relationships
between solute–solvent interactions and the structure–
activity parameters. In order to determine a spectroscopic
assignment of the absorption bands in different solvents,
quantum chemical calculations were done.
Keywords Hydantoins ꢀ Absorption spectra ꢀ
Solvent effect ꢀ Hydrogen bonds ꢀ Lipophilicity ꢀ
Anticonvulsant activity
Introduction
Hydantoins (imidazolidine-2,4-diones) have been demon-
strated to possess good anticonvulsant activity [1].
Depending on the nature of the substitution on the
hydantoin ring, a wide range of other pharmacological
properties, e.g., antiarrhythmic [2], anti-inflammatory [3],
anti-HIV [4], hypolipidemic [5], and antihypertensive
activities [6], have also been identified.
Understanding the anticonvulsant activity of hydantoin
derivatives has been a focus of research since 1938 when
Merritt and Putnam found that 5,5-diphenylhydantoin
(phenytoin) has anticonvulsant properties. In principle,
three crucial points should be taken into account. The first
and the second are related to the transport phenomena in
vivo, depending on the general lipophilic properties of the
hydantoin derivative, and the penetration of the latter
through the blood–brain barrier (BBB) into the cell mem-
branes, determined by the amount and position of the
lipophilic parts of the molecule [7]. The n-octanol–water
partition coefficient (log P) has been traditionally used to
measure the lipophilicity of drugs as a predictor of solute–
membrane partitioning [8]. The third point concerns the
receptor interactions. Hydantoins target the neuronal volt-
age-gated sodium channels (NVSC) to reproduce the
normal ion potential [9]. Regarding the molecular mode of
action of phenytoin, Smythies [10] suggested that it forms
an array of molecules stacked on a b-turn segment of the
proteic part of a putative receptor site through the forma-
tion of hydrogen bonds with the carbonyl in position 2 and
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0639-7) contains supplementary
material, which is available to authorized users.
ˇ
´
´
´
ˇ´
´
N. Trisovic ꢀ N. Valentic (&) ꢀ M. Erovic ꢀ G. Uscumlic
Faculty of Technology and Metallurgy, University of Belgrade,
Karnegijeva 4, P.O. Box 3503, 11120 Belgrade, Serbia
e-mail: naca@tmf.bg.ac.rs
´
T. Ðakovic-Sekulic
Faculty of Science, University of Novi Sad,
´
´
Trg Dositeja Obradovica 3, 21000 Novi Sad, Serbia
´
I. Juranic
Faculty of Chemistry, University of Belgrade and Center
of Chemistry, IChTM, Studentski trg 12-14,
11000 Belgrade, Serbia
123

ˇ ´
N. Trisovic et al.
1228
m ¼ m0 þ spꢁ þ bb þ aa
ð1Þ
the NH in position 3. However, phenytoin has two alter-
native C(=O)NH edges and two prochiral phenyl groups
connected to the quaternary carbon in position 5. This
arrangement suggests that other modes of hydrogen bond
formation may also take place.
where pꢁ is an index of the solvent dipolarity/polarizability,
b is a measure of the solvent hydrogen-bonding acceptor
(HBA) basicity, a is a measure of the solvent hydrogen-
bonding donor (HBD) acidity, and m0 is the regression value
of this solvent property in cyclohexane as the reference
solvent. The regression coefficients s, b, and a in Eq. 1
measure the relative susceptibilities of the absorption fre-
quencies to the indicated solvent parameters. This treatment
of solvation effects assumes attractive solute–solvent
interactions and allows one to estimate the ability of the
investigated compounds to form hydrogen bonds. In order
to determine a spectroscopic assignment of the absorption
bands and analyze the solvent effects on the electronic
charge distribution in the ground and excited state, we
performed quantum chemical calculations using Gaussian
03 [18] for density functional theory (DFT) calculations and
MOPAC 2009 [19] for semiempirical calculations.
The capacity of organic molecules to form hydrogen
bonds very significantly affects a wide range of their
properties, including aqueous solubility, cell permeability,
human intestinal absorption (HIA), BBB permeation,
nonspecific plasma protein binding, and many others [11,
12]. Poupaert et al. [13] observed that the anticonvulsant
activity of phenytoin-like compounds was reduced when
the hydrogen-bonding groups (CO and NH) were removed
from the phenytoin structure. This study was supported by
Cortes et al. [14] as they observed the loss of the activity
with changing the hydantoin skeleton to imidazolone or
imidazolidinone by removing or modifying the hydrogen-
bonding groups. In the present work, eleven compounds
structurally related to phenytoin (10) with reported maxi-
mal electroshock seizure (MES) activities in rats were
prepared [15, 16] (Fig. 1).
The lipophilicities of the investigated hydantoins were
estimated by the calculation of the log P values with the
Advanced Chemistry Development (ACD) software Solaris
v. 4.67. The calculated values of log P were correlated
with the ratio of the contributions of specific solvent–solute
interactions a/b calculated from Eq. 1. By employing the
linear dependence thus obtained, we analyzed the phar-
macological activity of the studied hydantoin derivatives.
The correlation equations were combined with the corre-
sponding ED50 values (the effective dose required to
protect a rat against spasms induced by the maximum
The focus of our research was the determination of the
chemical behavior of the prepared phenytoin analogues in
different solvents using UV/Vis spectroscopic methods.
The UV absorption spectra were recorded in the region
200–400 nm in selected solvents of different polarity. In
order to obtain an insight into the various modes of sol-
vation determining the absorption energies, we interpreted
the effects of solvent dipolarity/polarizability and hydrogen
bonding on the absorption spectra by means of a linear
solvation energy relationship (LSER) using the Kamlet–
Taft equation [17] of the form:
Fig. 2 UV spectra of compounds 1 (continuous line), 3 (space-
dashed line), 5 (dashed line), 9 (dash-single dotted line), and 11
(dash-double dotted line) in ethanol
Fig. 1 Structures of the investigated 5-substituted 5-phenylhydantoins
123

Synthesis, structure, and solvatochromic properties of 5-substituted 5-phenylhydantoins
1229
electric shock) and different physicochemical parameters
to generate new equations demonstrating the reasonable
relationships between solute–solvent interactions and the
structure–activity parameters.
were done. Two program packages were used to obtain
information about excited states and electronic transition
probabilities. The DFT calculations were done with
Gaussian 03 [18] and the semiempirical calculations with
MOPAC 2009 [19]. This detailed analysis of the compo-
nents of electronic transitions revealed that the most
intense transitions are essentially charge transfer transitions
(Fig. 3). Several most intense excitations involve electron
density shift from the imidazole moiety to the phenyl ring
in compound 1. As is shown in Figs. 2 and 3, there is good
agreement between the computed and experimentally
determined spectra. The relevant part of the computational
output is given in the ‘‘Supplementary material’’.
Results and discussion
All of the investigated molecules give similar UV
absorption spectra with one band in the region 200–400 nm
(Fig. 2). Their absorbance maxima in 15 solvents are col-
lected in Table 1. In order to understand the photophysical
facets of UV absorption, quantum chemical calculations
Table 1 UV spectral data of the investigated compounds
Solvent/R
m
max/103 cm–1
CH3 C2H5
n-C3H7 i-C3H7 n-C4H9 i-C4H9 t-C4H9 cyc-C5H9 cyc-C6H11 C6H5
C6H5CH2
Methanol
47.80 47.44 47.57
47.76 47.26 47.26
46.86 46.38 46.43
47.30 47.02 46.98
47.04 46.99 46.77
46.69 46.51 46.51
39.28 39.15 39.75
41.19 41.60 41.32
39.57 38.88 39.82
39.03 39.12 39.49
40.72 40.52 40.49
47.71
47.57
46.30
46.90
46.25
46.51
39.62
41.36
39.76
38.97
40.62
38.97
38.11
38.26
41.12
47.89
47.89
46.00
46.81
45.75
46.51
39.71
41.67
40.16
38.97
40.49
39.18
38.11
37.79
41.08
47.48
47.71
47.53
47.46
46.82
46.78
41.46
41.68
39.62
40.34
40.78
37.68
39.75
38.70
41.16
48.08
48.03
47.80
47.91
47.26
47.38
41.36
41.74
39.74
40.97
41.12
37.68
39.60
39.49
41.22
47.89
47.66
46.55
47.48
47.30
47.30
39.59
41.43
39.7
47.85
47.71
46.34
47.14
46.99
46.64
39.56
41.74
40.92
38.74
40.49
39.12
38.46
39.71
41.46
45.33 47.35
Ethanol
47.71 47.80
46.30 46.30
46.72 47.20
46.77 47.04
46.21 46.82
39.81 39.56
41.84 41.63
40.11 39.94
38.73 38.88
40.29 40.55
37.34 39.28
38.37 38.43
38.46 37.91
40.95 41.12
1-Propanol
2-Propanol
1-Butanol
2-Methylpropan-2-ol
Tetrahydrofuran
Diisopropyl ether
Methyl acetate
Ethyl acetate
Dioxane
38.85
40.55
39.53
37.4
N,N-Dimethylformamide 37.54 37.54 37.37
N,N-Dimethylacetamide
Dimethyl sulfoxide
Chloroform
38.76 38.40 38.49
39.78 39.59 37.85
41.15 41.15 40.95
39.59
40.98
Fig. 3 Gaussview interpretation of UV–Vis spectrum of compound 1 derived from Gaussian 03 calculation
123

ˇ ´
N. Trisovic et al.
1230
The effects of the solvent dipolarity/polarizability
positive signs of the a and b coefficients indicate a hyp-
sochromic shift with increasing both solvent HBA basicity
and HBD acidity and imply stabilization of the ground state
relative to the electronic excited state. This is due to the
interactions of HBD solvents with the hydantoin carbonyl
moieties and the hydrogen bonding of the NH groups. The
acidity of hydantoins is mostly the result of the NH group
in position 3 which is flanked by two electron-withdrawing
carbonyl groups.
(nonspecific solvent interactions) and hydrogen bonding
(specific solvent interactions) on the spectral shifts are
interpreted by using the general Kamlet–Taft solvatochro-
mic equation, Eq. 1. The correlation of the spectroscopic
data with solvent parameters was performed by means of a
multiple linear regression analysis. The parameters for the
solvents used in correlations are listed in Table 2 and the
coefficient values m0, s, b, and a fit at the 95% confidence
level are given in Table 3.
The percentage contributions of the solvatochromic
parameters (Table 4) for the investigated hydantoins show
that most of the solvatochromism is due to the hydrogen
bonding rather than to the nonspecific solute–solvent
interactions. These results are in accordance with the pre-
ferred existence of the hydantoins as their lactam tautomer
[20].
The negative sign of the s coefficient (Table 3) indicates
a bathochromic shift with increasing solvent dipolarity/
polarizability. This suggests that stabilization of the elec-
tron excited state relative to the ground state occurs. The
Table 2 Kamlet–Taft solvent parameters [17]
In our recent paper [21], we reported experimentally
estimated lipophilicities of a representative number of
hydantoin derivatives by reversed-phase high-performance
thin-layer chromatography (HPTLC). Experimentally esti-
mated lipophilicities, expressed as the chromatographic
retention R0M (silica gel stationary phase with acetonitrile–
toluene mobile phase) for some of the 5-substituted 5-
phenylhydantoins studied in this work are listed in Table 5.
The R0M values were correlated against the calculated log P
data and the results are shown in Fig. 4. The satisfactory
correlation attests that both R0M and log P values can be
used as a measure of the lipophilicity of the investigated
compounds (r = 0.945, s = 0.05, F = 42).
Solvent
pꢁ
b
a
Methanol
0.6
0.62
0.77
0.83
0.95
0.88
1.01
0.55
0.49
0.42
0.45
0.37
0.69
0.76
0.76
0
0.93
0.83
0.78
0.76
0.79
0.68
0
Ethanol
0.54
0.52
0.48
0.47
0.41
0.58
0.27
0.60
0.55
0.55
0.88
0.88
1
1-Propanol
2-Propanol
1-Butanol
2-Methylpropan-2-ol
Tetrahydrofuran
Diisopropyl ether
Methyl acetate
Ethyl acetate
0
0
0
Dioxane
0
Because the solvent parameters used in Eq. 1 reflect
solute–solvent interactions, we interpreted the regression
parameters in terms of the ability of the studied compounds
to interact with their environment. Evidence for sol-
vent effects on the structure–activity relationship of
N,N-Dimethylformamide
N,N-Dimethylacetamide
Dimethyl sulfoxide
Chloroform
0
0
0
0.58
0.44
Table 3 Regression fits for solvatochromic parameters (Eq. 1)
No.
R
m0/103 cm-1
s/103 cm-1
b/103 cm-1
a/103 cm-1
ra
SDb
Fc
1
CH3
40.69 ( 0.91)
40.99 ( 0.86)
41.99 ( 0.68)
41.41 ( 0.78)
41.81 ( 0.97)
42.13 ( 0.86)
42.13 ( 0.92)
40.79 ( 0.96)
40.14 ( 0.92)
42.09 ( 0.87)
41.60 ( 0.72)
-4.09 ( 1.27)
-4.70 ( 1.21)
-6.03 ( 0.95)
-4.82 ( 1.08)
-5.21 ( 1.35)
-5.76 ( 1.20)
-5.63 ( 1.29)
-4.46 ( 1.34)
-3.93 ( 1.29)
-6.57 ( 1.24)
-5.43 ( 1.01)
2.58 ( 0.95)
2.55 ( 0.90)
2.24 ( 0.71)
2.09 ( 0.80)
1.89 ( 1.00)
2.90 ( 0.89)
3.11 ( 0.96)
3.02 ( 0.99)
2.23 ( 0.96)
2.88 ( 0.92)
2.62 ( 0.75)
8.05 ( 0.68)
7.72 ( 0.64)
7.58 ( 0.51)
7.65 ( 0.58)
7.51 ( 0.72)
7.03 ( 0.64)
7.27 ( 0.69)
7.84 ( 0.72)
7.59 ( 0.69)
6.63 ( 0.66)
7.52 ( 0.54)
0.983
0.985
0.990
0.987
0.980
0.984
0.982
0.982
0.981
0.982
0.989
0.81
0.77
0.60
0.70
0.86
0.76
0.82
0.85
0.82
0.79
0.64
108
115
191
138
87
2
C2H5
3
n-C3H7
i-C3H7
n-C4H9
i-C4H9
t-C4H9
cyc-C5H9
cyc-C6H11
C6H5
4
5
6
110
101
98
7
8
9
93
10
11
a
100
165
C6H5CH2
Correlation coefficient
Standard deviation
Fisher test
b
c
123

Synthesis, structure, and solvatochromic properties of 5-substituted 5-phenylhydantoins
1231
hydrogen bond acidities between these two solvents affects
the partitioning of a solute more significantly for the
investigated set of compounds. The plot of log P versus a/
b reveals a linear relationship for compounds 6, 7, 8, 9, 10,
and 11 (r = 0.935). However, the points for compounds 1,
2, 3, 4, and 5 form a separate line (r = 0.855) due to the
different structural characteristics of substituents in posi-
tion 5 (R is a lower homologue). In a previous study, a set
of eight 3-substituted 5,5-diphenylhydantoins [23] was
used to analyze the structural determinants governing the
partitioning of the solute between n-octanol and water. An
analogous linear relationship between log P and a/b was
obtained, but with the opposite slope, compared with the
dependencies in this work, and there was no separation of
homologues. This is reasonable, because the compounds of
such a set have reduced hydrogen-bonding ability due to
lack of the proton at N3. The existence of these correlations
(Fig. 5) supports the hypothesis of Poupaert et al. [13] that
the hydrogen bonding is an essential factor in the anti-
convulsant action of phenytoin-like compounds in terms of
their transport properties.
Table 4 Percentage contributions of the solvatochromic parameters
and values a/b
ꢁ
Pp /%
No.
Pb/%
Pa/%
a/ba
1
28
31
38
33
36
37
35
29
29
41
35
18
17
14
14
13
18
19
20
16
18
17
55
52
48
53
51
45
45
51
55
41
48
3.12
3.03
3.38
3.66
3.97
2.42
2.34
2.60
3.40
2.30
2.87
2
3
4
5
6
7
8
9
10
11
a
Relation of regression coefficients of specific solvent interactions
(Table 3)
5-substituted 5-phenylhydantoins was obtained by the
correlation of the calculated log P values against the ratio
of the contributions of the specific solvent interactions a/
b (Fig. 5). All parameters are dependent on the structural
features of the studied compounds. The log P parameter is
a solvational characteristic, because it is directly related to
the change in the Gibbs free energy of solvation of a solute
distributed between two solvents. Abraham et al. [22]
demonstrated that the hydrogen bond acidity of a solute
plays a minor role, compared with the basicity, in parti-
tioning between n-octanol and water. Although n-octanol is
a stronger hydrogen bond base than water, the difference in
In this work, we used a three-parameter quantitative
structure–activity relationship (QSAR) model for the
analysis of the anticonvulsant potencies for the set of eight
5-substituted 5-phenylhydantoins using the MES assay
(ED50 values are converted into millimoles per kilo) and
the obtained result is given by Eq. 2:
log ED50 ¼ 1:09ðꢂ0:23Þ log P ꢃ 0:69ðꢂ0:36Þrꢁ
þ 0:35ðꢂ0:12ÞEs ꢃ 2:66ðꢂ0:42Þ
(r = 0.942, s = 0.21, F = 11, n = 8).
ð2Þ
Table 5 Physicochemical properties and activity data of the studied compounds
b
No.
R
MWa
rꢁ
Esc
log Pd
R0Me
ED5f0/mg kg-1
1
CH3
190.2
204.2
218.3
218.3
232.3
232.3
232.3
244.3
258.3
252.3
266.3
0
0
1.00
1.53
2.06
1.88
2.59
2.41
2.23
2.49
3.06
2.52
2.74
-0.9006
-0.8719
-1.0133
–
–
23
66
56
620
75
57
–
2
C2H5
-0.1
-0.07
-0.36
-0.47
-0.39
-0.93
-1.54
-0.51
-0.79
-2.55
-0.38
3
n-C3H7
i-C3H7
n-C4H9
i-C4H9
t-C4H9
cyc-C5H9
cyc-C6H11
C6H5
-0.115
-0.19
-0.13
-0.125
-0.3
4
5
-1.1615
–
6
7
–
8
-0.2
-1.1736
-1.2137
-1.1476
–
9
-0.15
0.6
–
10
11
a
18
200
C6H5CH2
0.215
Molecular weight
b
c
d
e
f
Taft electronic parameter [33]
Taft steric parameter [33]
Calculated by ACD Solaris v. 4.67
Chromatographic retention R0M (silica gel stationary phase with acetonitrile–toluene mobile phase) [21]
Effective dose to protect rats against spasms induced by maximum electric shock, i.e., reported pharmacological activity [15, 16]
123

ˇ ´
N. Trisovic et al.
1232
Fig. 4 Correlation between
experimentally estimated and
calculated lipophilicities
Fig. 5 Correlation between the
calculated log P and the ratio of
the specific solvent interactions
The rꢁ term seems to imply a significant role for elec-
tron-withdrawing groups in position 5, whereas the positive
coefficient for Es suggests that bulky substituents produce a
strong hydrophobic shield protecting the hydrogen bonds
formed by the imidic part of the hydantoin ring and a
b-bend protein segment from the water extrusion. This
indicates that the receptors involved possess special ste-
reochemical and electronic features. The phenyl ring
appears to reach a hydrophobic surface. However, the
definite identification of which binding sites are involved in
the activity is difficult as most anticonvulsants interact with
more than one receptor [24]. This also implies a particular
importance of the C5 substitution for the pharmacokinetic
phase of the drug action. Thus, the crucial factors in
determining the anticonvulsant potency are the hydrogen
bond acceptor, hydrogen bond donor, and an electronega-
tive group being a large hydrophobic part of the molecule.
Conclusions
We investigated the solvational characteristics in ground
and excited states of some hydantoin derivatives by mon-
itoring UV absorbance maxima in different solvents.
123

Synthesis, structure, and solvatochromic properties of 5-substituted 5-phenylhydantoins
1233
Quantum chemical calculations were performed to deter-
mine a spectroscopic assignment of the absorption bands.
The solvent-dependent spectral shifts were analyzed using
theLSER method of Kamletand Taft. The derived ratio of the
specific solvent interactions of the investigated compounds
was the cornerstone of the description of anticonvulsant
potencies of the studied compounds, providing an indication
of the interaction between the hydantoin moiety and its sur-
roundings. The present study also shows that size and
electronic properties of the substituent in position 5 are
important structural features of such a set of compounds. The
proposed approach can be applied to generate new models
offering possibilities to optimize transport properties and
activity simultaneously.
Table 6 Synthesis of the investigated hydantoin derivatives
No.
R
Yield/%
m.p./°C
Found
Reported
1
CH3
75
72
70
80
68
70
48
52
45
85
84
194–196
196–199
163–165
209–211
203–204
176–178
271–273
223–225
269–270
293–295
214–216
196–198 [26]
194–196 [26]
165–166 [27]
210–212 [28]
204–205 [27]
177–178 [27]
271–273 [15]
–
2
C2H5
3
n-C3H7
i-C3H7
n-C4H9
i-C4H9
t-C4H9
cyc-C5H9
cyc-C6H11
C6H5
4
5
6
7
8
9
270 [29]
10
11
290–293 [30]
214–215 [31]
C6H5CH2
Experimental
Spectroscopic measurements
commercially available (Fluka). The chemical structures
and the purities of the synthesized hydantoins were con-
1
The H and 13C NMR spectral measurements were per-
1
firmed by melting points, FT-IR, H and 13C NMR spectra
formed on a Varian-Gemini 200 spectrometer at 200 or
50 MHz, respectively. The spectra were recorded at room
temperature in DMSO-d6. The chemical shifts are expres-
and agree well with reported data (Table 6).
Method of calculation
1
sed in ppm values referenced to TMS (dH = 0 ppm) in H
NMR spectra, and the residual solvent signal
(dC = 39.5 ppm) in 13C NMR spectra. FT-IR spectra were
recorded with a Bomem MB 100 spectrophotometer. UV
absorption spectra were measured with a Simadzu 1700
spectrophotometer. The UV spectra were taken in spectro
quality solvents (Fluka) at a fixed concentration of
Geometries of molecules were optimized using the semi-
empirical PM6 method. Initial structures were prepared
with the Vega ZZ graphic [32] interface. Gaussian 03 [18]
calculations were done on a four-processor machine with
Linux platform, using the following keywords: B3LYP/6-
31G(d TD=NS,p) FCheck tates=15 cube=orbitals Pop=
Full. MOPAC 2009 [19] was used on a two-processor PC
using the following keywords: PM6 PRECISE C.I.=6
MECI vectors large 1SCF EPS=4.8 MMOK, for the
geometry optimization, and PM6 PRECISE C.I.=6 MECI
vectors large 1SCF EPS=4.8 MMOK graph, for the cal-
culation of excited states.
10-5 mol dm-3
.
General procedure for synthesis of 5-substituted
5-phenylhydantoins
All of the investigated compounds were synthesized by a
modification of the method of Bucherer and Lieb [25]. The
appropriate ketone was heated with ammonium carbonate
and potassium cyanide in 50% aqueous ethanol. The
obtained precipitate was filtered and crystallized from
ethanol until constant melting point was achieved
(Scheme 1). The ketones used in this preparation were
The correlation analysis was carried out using Microsoft
Office Excel 2003, which considers the 95% confidence
level. The goodness of fit was discussed using the corre-
lation coefficient (r), standard deviation (SD), and Fisher
criterion (F). The lipophilicities were estimated by the
calculation of log P values with the Advanced Chemistry
Development (ACD) software Solaris v. 4.67.
The corresponding physicochemical parameters of the
studied compounds and their antiepileptic potencies in the
MES test are collected in Table 5. For the details of the
biological tests, the original articles should be consulted
[15, 16].
Acknowledgments This work was supported by the Ministry of
Science and Technological Development of Serbia (Project Number
172013).
Scheme 1
123

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N. Trisovic et al.
1234
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