Solvent effects on the structure-property relationship of some potentially pharmacologically active 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted benzyl)-5,5-diphenylhydantoins

Article abstract of DOI:10.1007/s10953-010-9641-7

Two series of 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted benzyl)-5,5-diphenylhydantoins were 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 on the spectral shifts were analyzed by means of the linear solvation energy relationship (LSER) methodology of Kamlet and Taft. The quantitative relationships between hydrogen bonding interactions and the lipophilicity and blood-brain permeation of the studied compounds were discussed. Satisfactory linear dependences were obtained for moderate electron-donating and electron-withdrawing substituents at the benzyl moiety, while the strong electron-withdrawing substituent (NO₂) significantly modifies the solvation characteristics of the molecule. The paper clearly demonstrates how the solvatochromic comparison method may be applied to estimate the contributions of various modes of solvation to the pharmaceutically relevant properties of these newly synthetized hydantoin derivatives.

Full text of DOI:10.1007/s10953-010-9641-7

J Solution Chem (2011) 40: 307–319
DOI 10.1007/s10953-010-9641-7
Solvent Effects on the Structure-Property Relationship
of Some Potentially Pharmacologically Active
3-(4-Substituted Benzyl)-5-Ethyl-5-Phenyl-
and 3-(4-Substituted Benzyl)-5,5-Diphenylhydantoins
Sleem F. Hmuda · Nemanja P. Trišovic´ ·
Nataša V. Valentic´ · Gordana S. Ušc´umlic´
Received: 16 March 2010 / Accepted: 22 July 2010 / Published online: 5 January 2011
© Springer Science+Business Media, LLC 2011
Abstract Two series of 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted
benzyl)-5,5-diphenylhydantoins were 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 on the
spectral shifts were analyzed by means of the linear solvation energy relationship (LSER)
methodology of Kamlet and Taft. The quantitative relationships between hydrogen bonding
interactions and the lipophilicity and blood-brain permeation of the studied compounds were
discussed. Satisfactory linear dependences were obtained for moderate electron-donating
and electron-withdrawing substituents at the benzyl moiety, while the strong electron-
withdrawing substituent (NO2) significantly modifies the solvation characteristics of the
molecule. The paper clearly demonstrates how the solvatochromic comparison method may
be applied to estimate the contributions of various modes of solvation to the pharmaceuti-
cally relevant properties of these newly synthetized hydantoin derivatives.
Keywords Hydantoin derivatives · Absorption frequencies · Kamlet-Taft equation ·
Hydrogen bonding · Lipophilicity · Blood-brain barrier permeability
1 Introduction
Hydantoins (imidazolidine-2,4-diones) have been widely used in biological screenings re-
sulting in numerous pharmaceutical applications. Many of them have been identified as an-
tiarrhytmics [1], antimuscarinics [2], antidiabetics [3] and drugs in cancer therapy [4]. How-
ever, the hydantoin derivatives are most commonly used in epilepsy treatment. Phenytoin
(5,5-diphenylhydantoin) is a major anticonvulsant drug being very effective in controlling a
variety of seizure disorders while impairing neurological function little, if at all [5]. More-
over, several 5-phenylhydantoins are known to be active anticonvulsants (nirvanol, etothoin,
S.F. Hmuda · N.P. Trišovic´ · N.V. Valentic´ ( ) · G.S. Ušc´umlic´
ꢀ
Department of Organic Chemistry, Faculty of Technology and Metallurgy, University of Belgrade,
Karnegijeva 4, PO Box 3503, 11120 Belgrade, Serbia
e-mail: naca@tmf.bg.ac.rs

308
J Solution Chem (2011) 40: 307–319
mephenytoin). The observed activities usually do not arise only from the heterocycle itself,
but from the different substituents attached to it [6]. In this context, much attention has been
paid to the determination of the structural elements of pharmacologically active drugs that
are responsible for both their beneficial biological activity and unwanted side effects.
The lipophilicity of compounds is very important from physicochemical and biological
viewpoints. Transport phenomena in vivo and through membranes proved to be dependent
on lipophilic contributions [7]. In the case of hydantoins, lipophilic interactions have been
used to explain the binding to receptor or receptor sites [8]. The n-octanol/water partition-
ing coefficient (log10 P ) has been traditionally used to measure the lipophilicity of drugs
as a predictor of solute/membrane partitioning [9]. Because of the complexity of solvent
effects, this property reflects well intermolecular interactions in condensed media. For the
anticonvulsant assays, the optimal lipophilicity for penetration through the blood-brain bar-
rier appears to exist at about log10 P = 2.
Knowledge of the equilibrium distribution between blood and brain is a fundamental
aspect of drug design. The blood-brain barrier (BBB) is a complicated system formed of
tight junctions between brain parenchymal capillary cells in the choroid plexus and external
tissue capillary cells [10]. Its role is to maintain the homeostasis of the CNS and effective
penetration is desirable for drugs targeting CNS diseases. Relatively lipophilic drugs can
cross the BBB by passive diffusion, influenced by their hydrogen-bonding capacity. The
more capable of hydrogen bonding a molecule is, the more hydrophilic it will be and the
more it will distribute toward blood rather than the brain, since blood is more water-like and
less lipid like than brain [11]. The general solvation equation for the interpretation of the
BBB permeation of Abraham [12] shows that the solute dipolarity/polarizability, hydrogen-
bond acidity, and hydrogen-bond basicity favor blood and the solute size favors the brain.
In the course of structure-property studies of various hydantoin derivatives, we have fo-
cused much attention on the estimation of their ability to form hydrogen bonds. Two sets of
newly synthesized derivatives of nirvanol (5-ethyl-5-phenylhydantoin) and phenytoin (5,5-
diphenylhydantoin) with potential for pharmaceutical applications are assembled in this
work (Fig. 1). It has been of interest to prepare such sets of compounds so that their phar-
macologically relevant properties might be compared with that of the parent compounds, so
that lead candidates for future characterization in the maximal electroshock seizure (MES)
test could be identified. The focus of our research has been to the determination of their
chemical behavior in different solvents using UV/Vis spectroscopic methods. The UV ab-
sorption spectra have been recorded in the region 200–400 nm in twelve solvents of different
polarity.
The effects of solvent dipolarity/polarizability and hydrogen bonding on the spectral
shifts were interpreted by means of a linear solvation energy relationship using the Kamlet-
Taft equation [13] of the form:
ν = ν0 + sπ∗ + bβ + aα
(1)
where π∗ is an index of the solvent dipolarity/polarizability; β is a measure of the solvent
hydrogen bonding acceptor (HBA) basicity; α is a measure of the solvent hydrogen bonding
donor (HBD) acidity; and ν0 is the regression value of this solvent property with cyclohexane
as reference solvent. The regression coefficients s, b and a in Eq. 1 measure the relative
susceptibilities of the absorption frequencies to the solvent parameters.This treatment of
solvation effects assumes attractive interactions between a solute and its environment and
allows estimation of the ability of the investigated compounds to form hydrogen bonds.

J Solution Chem (2011) 40: 307–319
309
Fig. 1 Structures of the investigated 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted ben-
zyl)-5,5-diphenylhydantoins
To analyze the role of hydrogen bonding in their pharmacologically relevant properties,
we correlated the n-octanol/water partitioning coefficient (log10 P ) and blood-brain penetra-
tion property data (log10 BB) against regression coefficients from Eq. 1. The corresponding
values are in silico calculated, because their experimental determination is time-consuming,
expensive and difficult. The lipophilicities of the investigated hydantoin derivatives were
estimated by the calculation of log10 P values with the Advanced Chemistry Develop-
ment (ACD) Software Solaris v. 4.67. The blood-brain barrier penetration property data
(log10 BB) were obtained by the ChemSilico program. The correlation equations demon-
strate reasonable relationships between solute–solvent interactions and structure–property
parameters.
2 Experimental
2.1 Chemicals and Materials
All the investigated compounds were synthesized following the procedure presented in the
synthesis scheme (Scheme 1) [14]. The appropriate hydantoin was dissolved in DMF and
potassium carbonate (4.4 equivalents) was added. 4-Substituted benzyl halide (1.1 equiva-
lents) was then added and the reaction mixture was stirred for 24 h. The reaction mixture
was poured into three volumes of water and extracted with ethyl acetate. The ethyl acetate
extracts were washed with 5% NaOH and water, and brine, and then dried over MgSO4. The
solvent was removed and the resulting solid was recrystallized from ethanol until a constant
melting point was achieved.

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J Solution Chem (2011) 40: 307–319
Scheme 1 Synthesis of the investigated compounds
2.2 Spectral Analysis
The chemical structures and purities of the synthesized compounds were confirmed by their
melting points, 1H NMR, FT-IR and UV spectra. Their full characterization is presented in
Table 1.
The 1H NMR spectra of DMSO-d6 solutions (TMS as internal standard) were measured
with a Varian-Gemini 200 MHz spectrometer.
The FT-IR spectra were recorded with a Bomem MB 100 spectrophotometer.
The UV absorption spectra were measured with a Shimadzu 1700 spectrophotometer.
The UV spectra were taken in spectroquality solvents (Fluka) at 10−5 mol·dm−3 concentra-
tion.
2.3 Methods of Calculation
The lipophilic activity of the investigated hydantoin derivatives was estimated by the calcu-
lation of log10 P values with the Advanced Chemistry Development (ACD) Software Solaris
v. 4.67. The blood-brain barrier penetration property data (log10 BB) were obtained by the
ChemSilico program (http://chemsilico.com).
The corresponding physicochemical characteristics and pharmacologically relevant data
of the studied compounds are collected in Table 2.
2.4 Regression Analysis
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 correlation coefficient
(R), standard error of the estimate (S) and Fisher criterion (F).
3 Results and Discussion
The UV absorption frequencies of the investigated hydantoin derivatives in twelve solvents
are given in Table 3. Hydrogen bonding and solvent polarity are the key factors in con-
trolling pathways of energy dissipation following electronic excitation. The red shift of the
absorption band when the solvent polarity is decreased supports its n-π∗ nature, since in
protic solvents, the n-electrons are expected to be blocked by the solvent proton through
intermolecular hydrogen bonds and consequently the excitation of n-electrons is difficult.
These results are in accordance with our previously published data [18, 19].
The effects of solvent dipolarity/polarizability and hydrogen bonding are interpreted by
means of the LSER concept using Eq. 1. The solvent parameters are collected in the Table 4.

J Solution Chem (2011) 40: 307–319
311
Table 1 Characterization of investigated 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted
benzyl)-5,5-diphenylhydantoins
1
No.
1
R
Y
H
mp
lit. mp
(°C)
IR (KBr)
H NMR
−1
(°C)
ν
(cm
)
δ (ppm) (DMS-d6)
max
C H
2
138–140
164–167
139–140 [15]
3212 (N–H)
9.12 [s, 1H, (N − 1)H],
5
1768 (C=O)
1707 (C=O)
7.30–7.44 [m, 5H, Ph], 7.21–
7.27 [m, 5H, CH –Ph],
2
4.56 [s, 2H, N–CH –],
2
1.88–2.22 [m, 2H, –CH –],
2
0.75 [t, 3H, –CH ]
3
2
C H
2
CH
3269 (N–H)
1762 (C=O)
1710 (C=O)
9.10 [s, 1H, (N − 1)H], 7.32–
7.43 [m, 5H, Ph], 7.23–
5
3
7.31 [m, 4H, –C H –CH ],
6
4
3
4.49 [s, 2H, N–CH –], 2.24
2
[s, 3H, –C H –CH ], 1.89–
6
4
3
2.16 [m, 2H, –CH –], 0.74
2
[t, 3H, –CH ]
3
3
4
5
C H
2
Cl
Br
165–168
170–173
174–176
3259 (N–H)
1763 (C=O)
1710 (C=O)
9.13 [s, 1H, (N − 1)H], 7.40–
7.55 [m, 5H, Ph], 7.23–
5
5
5
7.36 [m, 4H, –C H –Cl],
6
4
4.54 [s, 2H, N–CH –],
2
1.86–2.21 [m, 2H, –CH –],
2
0.74 [t, 3H, –CH ]
3
C H
2
3245 (N–H)
1763 (C=O)
1710 (C=O)
9.13 [s, 1H, (N − 1)H], 7.30–
7.53 [m, 5H, Ph], 7.21–
7.29 [m, 4H, –C H –Br],
6
4
4.53 [s, 2H, N–CH –],
2
1.87–2.21 [m, 2H, –CH –],
2
0.74 [t, 3H, –CH ]
3
C H
2
NO
3269 (N–H)
1764 (C=O)
1711 (C=O)
9.23 [s, 1H, (N − 1)H], 7.46–
7.57 [m, 5H, Ph], 7.36–
2
7.43[m, 4H, –C H –NO ],
6
4
2
4.71 [s, 2H, N–CH –],
2
1.91–2.25 [m, 2H, –CH –],
2
0.78 [t, 3H, –CH ]
3
6
7
C H
6
H
145–146
110–112
145-146 [16]
3275 (N–H)
1760 (C=O)
1715 (C=O)
9.81 [s, 1H, (N − 1)H], 7.32–
5
5
7.44 [m, 10H, 2Ph], 7.23–
7.31 [m, 5H, CH –Ph],
2
4.66 [s, 2H, N–CH –]
2
C H
6
CH
3262 (N–H)
1760 (C=O)
1711 (C=O)
9.77 [s, 1H, (N − 1)H], 7.30–
7.44 [m, 10H, 2Ph], 7.07–
7.16 [m, 4H, –C H –CH ],
3
6
4
3
4.60 [s, 2H, N–CH –], 2.24
2
[s, 3H, –C H –CH ]
6
4
3

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J Solution Chem (2011) 40: 307–319
Table 1 (Continued)
1
No.
R
Y
mp
lit. mp
(°C)
IR (KBr)
H NMR
−1
(°C)
ν
(cm
)
δ (ppm) (DMS-d6)
max
8
C H
6
Cl
140–142
130–133
174–177
3325 (N–H)
9.84 [s, 1H, (N − 1)H], 7.28–
7.43 [m, 10H, 2Ph], 7.24–
7.28 [m, 4H, –C H –Cl],
5
5
5
1773 (C=O)
1704 (C=O)
6
4
4.64 [s, 2H, N–CH –]
2
9
C H
6
Br
3318 (N–H)
1773 (C=O)
1705 (C=O)
9.82[s, 1H, (N − 1)H], 7.22–
7.50 [m, 10H, 2Ph], 7.15–
7.20 [m, 4H, –C H –Br],
6
4
4.61 [s, 2H, N–CH –]
2
10
C H
6
NO
3219 (N–H)
1770 (C=O)
1712 (C=O)
9.89 [s, 1H, (N − 1)H], 7.34–
7.51 [m, 10H, 2Ph], 7.24–
7.31 [m, 4H, –C H –NO ],
2
6
4
2
4.78 [s, 2H, N–CH –]
2
Table 2 Physicochemical
parameters and
a
b
c
d
No.
R
Y
σ
I
σ
R
log
P
log BB
10
10
pharmacologically relevant data
of the investigated compounds
1
2
C H
2
H
0
0
3.25
3.71
3.84
4.02
2.98
3.89
4.35
4.49
4.67
3.62
−0.01
−0.03
−0.05
−0.07
−0.49
−0.14
−0.11
−0.13
−0.16
−0.42
5
5
5
5
5
5
5
5
5
5
C H
2
CH
Cl
Br
−0.01
0.47
0.47
0.67
0
−0.16
−0.25
−0.25
0.10
3
3
C H
2
a
Inductive substituent constant
4
C H
2
[17]
5
C H
2
NO
H
2
b
Resonance substituent constant
6
C H
6
0
[17]
7
C H
6
CH
−0.01
0.47
0.47
0.67
−0.16
−0.25
−0.25
0.10
c
3
Calculated by ACD Solaris v.
8
C H
6
Cl
Br
4.67
d
9
C H
6
Blood-brain penetration
property data (log BB) were
10
10
C H
6
NO
2
calculated by ChemSilico
The correlation of the spectroscopic data was carried out in terms of multiple linear regres-
sion. Stepwise regression analysis was used to determine the most significant parameters. It
has been found that absorption frequencies of studied compounds in selected solvents show
a satisfactory correlation with the π∗ and α parameters (Eq. 2). The β parameter isn’t statis-
tically significant. Hydantoins are weak acids which dissociate at the N − 3 atom, because
this allows more efficient delocalization of the negative charge than ionization at N − 1. It
has been demonstrated that 3-substituted hydantoins show no appreciable ionization [20].
The regression values ν0, s and a fit at the 95% confidence level are presented in Table 5.
The success of Eq. 2 is shown in Fig. 2 by means of a plot of calculated values of νmax versus
observed values νmax in different solvents (R = 0.984, S = 0.76, F = 3539).
ν = ν0 + sπ∗ + aα
(2)
The negative sign of the s coefficient in the solvatochromic equation (Table 5) indicates a
bathochromic shift with increasing solvent dipolarity/polarizability. This suggests stabiliza-
tion of the electronic excited state relative to the ground state occurs. The positive sign of the

J Solution Chem (2011) 40: 307–319
313

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J Solution Chem (2011) 40: 307–319
Table 4 Solvent parameters [13]
∗
Solvent
π
β
α
Methanol
0.60
0.54
0.52
0.48
0.47
0.41
0.27
1.00
0.60
0.55
0.88
0.88
0.62
0.77
0.83
0.95
0.88
1.01
0.49
0.76
0.42
0.45
0.69
0.76
0.93
0.83
0.78
0.76
0.79
0.68
0.00
0.00
0.00
0.00
0.00
0.00
Ethanol
1-propanol
2-propanol
1-butanol
2-methyl-2-propanol
Diisopropyl ether
Dimethyl sulfoxide
Methyl acetate
Ethyl acetate
N,N-dimethylformamide
N,N-dimethylacetamide
Fig. 2 Experimental versus calculated values of ν from Eq. 2
a coefficient for all compounds indicates a hypsochromic shift with increasing solvent hy-
drogen bond acidity. This implies stabilization of the ground state relative to the electronic
excited state.
The percentage contributions of the solvatochromic parameters (Table 6) for the studied
compounds show that the most of the solvatochromism is due to the solvent acidity (specific

J Solution Chem (2011) 40: 307–319
315
Table 5 Regression fits to the solvatochromic parameters
−3
−3
−3
a
b
c
No.
R
Y
ν × 10
s × 10
a × 10
R
S
F
0
−1
−1
−1
(cm
)
(cm
)
(cm
)
1
2
C H
2
H
42.61
−5.21
9.36
0.985
0.984
0.979
0.977
0.987
0.987
0.988
0.974
0.981
0.989
0.87
0.85
0.93
0.99
0.94
0.74
0.67
0.98
0.78
0.85
148
141
104
94
5
5
5
5
5
5
5
5
5
5
(
1.00)
(
1.36)
(
0.70)
C H
2
CH
Cl
Br
43.14
−6.25
8.44
3
(
0.98)
(
1.33)
(
0.68)
3
C H
2
42.56
−5.23
8.14
(
1.07)
(
1.45)
(
0.74)
4
C H
2
42.67
−5.30
8.29
(
1.14)
(
1.55)
(
0.79)
5
C H
2
NO
H
39.45
−3.23
11.60
168
166
179
83
2
(
1.09)
(
1.48)
(
0.76)
6
C H
6
42.64
−5.16
8.27
(
0.86)
(
1.16)
(
0.70)
7
C H
6
CH
42.70
−5.34
7.51
3
(
0.77)
(
1.04)
(
0.53)
8
C H
6
Cl
Br
43.16
−5.83
7.42
(
1.13)
(
1.54)
(
0.79)
9
C H
6
42.62
−5.11
6.97
114
201
(
0.90)
(
1.22)
(
0.62)
10
C H
6
NO
39.24
−2.85
11.51
2
(
0.98)
(
1.33)
( 1.12)
a
Correlation coefficient
b
c
Standard error
Fisher test
Table 6 Percentage contribution
of the solvatochromic effects
No.
R
Y
P
π
∗ (%)
P (%)
α
1
2
C H
H
35.76
42.52
39.12
39.03
21.72
38.42
41.56
44.00
42.30
19.86
64.24
57.48
60.88
60.97
78.28
61.58
58.44
56.00
57.70
80.14
2
5
5
5
5
5
5
5
5
5
5
C H
2
CH
Cl
Br
3
3
C H
2
4
C H
2
5
C H
2
NO
H
2
6
C H
6
7
C H
6
CH
Cl
3
8
C H
6
9
C H
6
Br
10
C H
6
NO
2
solute/solvent interactions) rather than to the solvent dipolarity/polarizability (nonspecific
solute/solvent interactions). These results are in accordance with the preferred existence of
all studied molecules in their imido tautomeric forms. In order to obtain an insight into sub-

316
J Solution Chem (2011) 40: 307–319
Fig. 3 Correlation between the log P values and the regression coefficient a from Eq. 2, for the studied
10
compounds
stituent effects favoring particular modes of solvation in the ground and excited states of the
compounds, we analyzed the ratio a/s, as a convenient measure of the relative contributions
of indicated solvent properties, by using Taft’s dual substituent parameter (DSP) method
[21] in the form:
a/|s| = (a/|s|)0 + ρI σI + ρRσR
(3)
The obtained correlation (Eq. 4) indicates that the main effect through which these sub-
stituents influence the solvation characteristics of the derivatives is the resonance effect
while the inductive effect is less significant (the blending constant, defined as ρR/ρI, is
2.83).
a/|s| = 1.95( 0.15) + 1.85( 0.31)σI + 5.24( 0.61)σR
(R = 0.971, S = 0.27, F = 59, n = 10)
(4)
Because the solvent parameters used in Eq. 2 reflect solute/solvent interactions, the re-
gression coefficients obtained in Eq. 4 are interpreted in terms of the ability of the studied
compounds to interact with their environment.
We estimated lipophilicities of the investigated hydantoin derivatives by calculation of
log10 P values with Advanced Chemistry Development (ACD) Software Solaris v. 4.67 (Ta-
ble 2). The log10 P parameter is a solvation characteristic, since it is directly related to the
change in the Gibbs energy of solvation of a solute between two solvents [22]. The calculated
values of log10 P were correlated against the regression coefficient a from Eq. 2 as a mea-
sure of the solute hydrogen-bond accepting ability. The result of this correlation is shown
in Fig. 3. The plot of log10 P values versus a reveals a satisfactory linear relationship for
eight compounds, excluding the points for compounds with the strong electron-withdrawing
substituent NO2, which can be represented by Eq. 5:
log10 P = 8.96( 0.37) − 0.61( 0.05)a × 10−3
(R = 0.984, S = 0.09, F = 183, n = 8)
(5)

J Solution Chem (2011) 40: 307–319
317
Fig. 4 Correlation between the blood-brain penetration property data (log BB) and the regression coeffi-
10
cient a, from Eq. 2, for the studied compounds
The solute hydrogen-bond basicity favors partitioning in water rather than in n-octanol,
since water is the more acidic medium. This correlation is in agreement with Abraham’s
characterization of the n-octanol/water system, suggesting that the hydrogen-bond accepting
ability, polarity and size of a solute are good descriptors with which to model its lipophilicity
[23, 24].
Limited performance of log10 P has been known for predicting the blood-brain equi-
librium ratio [25]. We used the a coefficient from Eq. 2 to model the BBB penetration
property data of the investigated hydantoin derivatives. The BBB penetration property data
(log10 BB), calculated by the ChemSilico program, is based on a measure of the partition-
ing of a compound across the blood–brain barrier (Table 2). The property is expressed as the
ratio of the concentration in the brain to that in the blood:
BB = [brain]/[blood]
(6)
Correlating the data indicating likely brain penetration against the a coefficient from
Eq. 2, we have derived a predictive model for seven compounds (Eq. 7), excluding the points
5, 6 and 10:
log10 BB = −0.61( 0.07) + 0.07( 0.01)a × 10−3
(R = 0.945, S = 0.02, F = 51, n = 7)
(7)
The plots of the investigated pharmacologically relevant properties versus a give satis-
factory linear dependences for moderate electron-donating and electron-withdrawing sub-
stituents on the benzyl moiety. The data for the hydantoin derivatives with a strong electron-
withdrawing substituent (NO2) do not follow this correlation. This substituent significantly
changes solvation characteristics of the molecule and thus its lipophilicity is decreased due
to increased relative contributions of the specific interactions to the overall solvation effects.
This is in accordance with well accepted rule saying if the number of nitrogens and oxygens,
N+O, is five or less in a molecule, then it has high chances of entering the brain [26].
It can be seen that the hydrogen bond basicity of the investigated hydantoin derivatives
has an effect on the blood-brain barrier permeation. Previous investigation showed that the

318
J Solution Chem (2011) 40: 307–319
BBB permeability can be increased by lowering the overall hydrogen-bonding ability of a
compound by shielding with nonpolar groups [27]. However, this might be expected up to
the point where the hydrophobic region of the receptor is filled, and thereafter the activ-
ity and thus the penetration through the BBB decreases due to steric hindrance during the
interaction of the ligand and receptor.
The results obtained in this work can be used to determine how to modify the structure
of lipophilic hydantoin derivatives to improve their activity.
4 Conclusion
In the summary, the satisfactory correlation of the UV absorption frequencies of the stud-
ied 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted benzyl)-5,5-diphenyl-
hydantoins with Eq. 2 indicates that the correct model was selected. This means that this
model gives a correct interpretation of the linear solvation energy relationship for the com-
plex system of hydantoin derivatives in the selected solvent set. In such a case, where both
solvents and substrates are hydrogen bond donors and acceptors, it is quite difficult to untan-
gle the solvent dipolarity/polarizability, hydrogen bond basicity and hydrogen bond acidity
properties. The investigated hydantoin derivatives show significant terms in π∗ and α, but
the solvent basicity term is negligible due to the lack of a suitable HBD moiety. It was
pointed out that substituents of the benzyl moiety affect their ability to interact with molec-
ular environments.
This investigation also demonstrates how the solvatochromic comparison method may
be used to correlate and rationalize multiple interacting solvent effects on the pharmacolog-
ically relevant properties of the selected set of compounds. The proposed approach can help
in assessing their potential pharmaceutical application.
Acknowledgements The authors acknowledge the financial support of the Ministry of Science and Tech-
nologic Development of the Republic of Serbia (Project 142 063).
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