Solvent effects on the structure-activity relationship of pharmacological active 3-substituted-5,5-diphenylhydantoins

Article abstract of DOI:10.1007/s10953-007-9153-2

Absorption spectra of eight 3-substituted-5,5-diphenylhydantoins have been recorded in fourteen solvents in the range 200-400 nm. The effect of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions are analyzed by means of the

Full text of DOI:10.1007/s10953-007-9153-2

J Solution Chem (2007) 36: 869–878
DOI 10.1007/s10953-007-9153-2
ORIGINAL PAPER
Solvent Effects on the Structure-Activity Relationship of
Pharmacological Active
3-Substituted-5,5-Diphenylhydantoins
Nebojša Banjac · Gordana Ušc´umlic´ · Nataša Valentic´ ·
Dušan Mijin
Received: 13 October 2006 / Accepted: 17 January 2007 /
Published online: 17 May 2007
© Springer Science+Business Media, LLC 2007
Abstract Absorption spectra of eight 3-substituted-5,5-diphenylhydantoins have been
recorded in fourteen solvents in the range 200–400 nm. The effect of solvent dipolar-
ity/polarizability and solvent/solute hydrogen bonding interactions are analyzed by means
of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft.
The lipophilic activity of the investigated hydantoins was estimated by the calculation of
log10 P values with the Advanced Chemistry Development Software. The calculated values
of log10 P were correlated with the ratio of the contributions of specific solvent interactions,
and, by employing the linear dependence thus obtained, the pharmacological activity of the
studied hydantoin derivatives is discussed.
Keywords Hydantoins · Absorption frequencies · Solvent effect · Kamlet–Taft equation ·
Pharmacological activity · Lipophilicity parameter · Specific solvent interactions
1 Introduction
Hydantoins (2,4-imidazolidinediones) are important anticonvulsant drugs [1, 2]. Also, they
have a number of other biological activities as antiarrhythmic drugs [3, 4], bactericides [5],
fungicides [5] and drugs in cancer therapy [6]. Understanding the anticonvulsant activity
of hydantoins has been a focus of research since 1938 when Merrit and Putman found that
5,5-diphenylhydantoin (phenytoin) showed anticonvulsant properties [5]. Hydantoins tar-
get the trans–membrane sodium channel in neurons to reproduce the normal ion potential.
Membrane interactions have been discussed with regard to transport phenomena through
the blood–brain barrier to the receptor binding site [7]. Transport phenomena in vivo and
through membranes proved to be dependent on lipophilic contributions. The importance of
lipophilicity has been known for a long time [8]. For anticonvulsant assays, it is known that
an optimal lipophilicity for penetration through the blood–brain barrier appears to exist at
N. Banjac · G. Ušc´umlic´ · N. Valentic´ ( ) · D. Mijin
ꢀ
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.yu

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J Solution Chem (2007) 36: 869–878
Fig. 1 Anticonvulsant pharmacophore model for the 3-substituted-5,5-diphenylhydantoins studied
about log10 P = 2 [9]. Also, lipophilic interactions were used to explain the binding of hy-
dantoin derivatives to receptors or receptor parts [10–12]. The previously reported results
[13] clearly confirmed the hypothesis that hydrogen bonding was an essential factor in the
anticonvulsant action of these compounds. Following this idea, a pharmacophore model was
proposed that is based on a hydrogen bonding acceptor, a hydrogen bonding donor and an
electronegative group with a large hydrophobic part of the molecule in a defined spatial
arrangement [12]. The position of hydrogen donors or electron donors in combination with
an aromatic ring in a specific orientation was found to be crucial (Fig. 1) [12, 14].
Our research on the pharmacological activity of hydantoin derivatives has been focused
on determination of the structural and chemical behavior of compounds in different solvents
using UV/vis spectroscopic methods. To the best of our knowledge, the influence of the sol-
vent on the UV absorption frequencies of hydantoins has not been systematically presented
before. In this work, eight 3-substituted-5,5-diphenylhydantoins (Fig. 1) were synthesized
and their ultraviolet absorption spectra have been recorded in the region, 200–400 nm, in
fourteen solvents of different polarity. The effect of solvent dipolarity/polarizability and hy-
drogen bonding on the absorption spectra are interpreted by means of a linear solvation
energy relationship (LSER) using a Kamlet–Taft equation [15] of the form:
ν = νo + sπ∗ + bβ + aα
(1)
where π∗ is a measure of the solvent dipolarity/polarizability [16], β is the scale of the
solvent hydrogen bond acceptor (HBA) basicities [17], α is the scale of the solvent hydrogen
bond donor (HBD) acidities [18] and νo is the regression value of the solute property in the
reference solvent cyclohexane. The regression coefficients s, b and a in Eq. 1 measure the
relative sensitivities of the solvent-dependent solute property (absorption frequencies) to the
indicated solvent parameters.
Linear free-energy relationships (LFER) are widely used to characterize chemical and
biochemical processes. A particular type of LFER is the linear solvation energy relationship
(LSER) proposed by Kamlet et al. [19] for physico-chemical and biochemical processes
that depend on solute–solvent interactions. The LSER have been widely applied to differ-
ent partition processes, mainly liquid–liquid extraction such as octanol–water partitioning
and chromatographic processes [20]. The LSER developed by Kamlet and Taft is one of
the most ambitious and successful quantitative treatments of solvent effects by means of a
multiparameter equation [21–24].
The lipophilic activity of the investigated hydantoins in this work was estimated by the
calculation of log10 P values with the Advanced Chemistry Development (ACD) Software

J Solution Chem (2007) 36: 869–878
871
Solarius V. 4.67. The calculated values of log10 P were correlated with the ratio of the contri-
butions of specific solvent interactions a/b calculated from Eq. 1 and, employing the linear
dependence thus obtained, the pharmacological activity of the studied hydantoin derivatives
is discussed.
2 Experimental
2.1 Chemicals and Materials
All of the investigated 3-alkoxymethyl-5,5-diphenylhydantoins were synthesized by the re-
action of the 5,5-diphenylhydantoin sodium salt suspended in N,N-dimethylformamide
with the corresponding chloromethylalkylether in the presence of base, using a modified
literature procedure [25]. The experimental investigation included modification of the syn-
thetic procedure in terms of catalyst, isolation techniques, as well as purification and identi-
fication of the products.
3-Hydroxymethyl-5,5-diphenylhydantoin was prepared by the reaction of 5,5-diphenyl-
hydantoin (commercial available Fluka) with 37% aqueous formaldehyde in ethyl alcohol
and sodium hydroxide. Isolation of the product from the reaction mixture and the purifica-
tion process are as previously reported [26]. 3-Acetoxymethyl-5,5-diphenylhydantoin was
synthesized by the reaction of 3-hydroxymethyl-5,5-diphenylhydantoin with acetic anhy-
dride [27]. 3-Benzyl-5,5-diphenylhydantoin was prepared by the reaction of 5,5-diphenyl-
hydantoin and benzylchloride in alcoholic solution in the presence of sodium hydrox-
ide [28]. 3-Benzoyl-5,5-diphenylhydantoin was synthesized by the reaction of the 5,5-di-
phenylhydantoin sodium salt and benzoylchloride in dry benzene [29].
2.2 Spectral Analysis
The chemical structures and the purities of the synthesized hydantoins were confirmed by
melting points, 1H NMR, FT-IR and UV spectra. Their full characterization is presented in
Table 1.
FT-IR spectra were recorded with a Bomem MB 100 spectrophotometer. 1H NMR
spectra of DMSO-d6 solutions (TMS as internal standard) were measured with a Varian-
Gemini 200 MHz spectrometer. UV absorption spectra were measured with a Shimadzu
1700 spectrophotometer. The UV spectra were taken in spectroquality solvents (Fluka) at
10−5 mol·L−1 concentration.
2.3 Regression Analysis
The correlation analysis was carried out using Microsoft Excel computer software, 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’s significance test (F).
3 Results and Discussion
The ultraviolet absorption frequencies of the 3-substituted-5,5-diphenylhydantoin in four-
teen protic and aprotic solvents in the range, 200–400 nm, are given in Table 2. The effects

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J Solution Chem (2007) 36: 869–878
a
Table 1 Physical and spectroscopic data for 3-substituted-5,5-diphenylhydantoins
b
b
1
No. Substituent
X
mp
Lit. mp.
IR (KBr)
H NMR (DMSO-d6)
(cm ) δ (ppm)
−1
(cm ) ν
NH
−1
(°C) (°C)
ν
C=O
1
2
H
293–5 293–5
3273
3208
1773
1742
1769
1708
9.17 [s, 2H, (N-1)H],
7.30 [s, 10H, 2Ph]
CH OH
184–6 184–6 [26] 3337
126–7 127–8 [25] 3181
9.67 [s, 1H, (N-1)H],
7.27–7.51 [m, 10H, 2Ph],
6.30–6.49 [t, 1H, OH],
2
4.84–4.87 [d, 2H, N–CH ]
2
3
4
CH OCH
1781
1741
9.82 [s, 1H, (N-1)H],
2
3
7.26–7.46 [m, 10H, 2Ph],
4.83 [s, 2H, N–CH ],
2
3.22 [s, 3H, CH ]
3
CH OC H
2 5
127–9
3174
1778
1726
9.82 [s, 1H, (N-1)H],
2
7.26–7.46 [m, 10H, 2Ph],
4.87 [s, 2H, N–CH ],
2
3.41–3.52 [q, 2H, OCH ],
2
1.01–1.08 [t, 3H, CH ]
3
5
6
CH OCOCH
161–2 162–3 [27] 3380
1789
1737
1728
9.96 [s, 1H, (N-1)H],
2
3
7.28–7.52 [m, 10H, 2Ph],
5.48 [s, 2H, N–CH ],
2
2.0 [s, 3H, COCH ]
3
CH OCH C H 150–2 151–2 [25] 3174
1777
1715
9.85 [s, 1H, (N-1)H],
2
2 6 5
7.20–7.46 [m, 15H, 2Ph + CH Ph],
2
4.98 [s, 2H, N–CH ],
2
4.54 [s, 2H, OCH ]
2
7
8
CH C H
6 5
145–6 145–6 [28] 3275
150–1 149–51 [29] 3335
1760
1715
9.84 [s, 1H, (N-1)H],
2
7.23–7.42 [m, 15H, 2Ph + CH Ph],
2
4.66 [s, 2H, N–CH ]
2
COC H
1797
1748
1718
10.27 [s, 1H, (N-1)H],
6
5
7.34–7.83 [m, 15H, 2Ph + CH Ph]
2
a
The 5,5-diphenylhydantoins was commercially available (Fluka)
Melting point, mp
b
of the solvent dipolarity/polarizability (nonspecific solvent interactions) and hydrogen bond-
ing (specific solvent interactions) on the investigated hydantoins are interpreted by means
of the LSER concept using Eq. 1. The solvent parameters [30] are given in Table 3. Cor-
relation of the spectroscopic data was carried out by means of a multiple linear regression
analysis. It was found that absorption frequencies for hydantoin derivatives in eleven se-
lected solvents (except chloroform, acetonitrile and dioxane) show a satisfactory correla-
tion with the π∗, β and α parameters. These results are in accordance with our unpublished
data for 3-(4-substituted benzyl)- and 3-(4-substituted benzoyl)-5,5-diphenylhydantoins and
Kamlet–Taft’s conclusion [31] that differences between the solvent dipolarity/polarizability
are significantly greater between different solvent classes than within the individual classes.

J Solution Chem (2007) 36: 869–878
873

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J Solution Chem (2007) 36: 869–878
Table 3 Solvent parameters [30]
∗
Solvent
π
α
β
Methanol
0.60
0.54
0.52
0.48
0.47
0.55
0.27
0.58
0.88
0.88
0.71
0.58
0.75
0.55
0.93
0.83
0.78
0.76
0.79
0
0.62
0.77
0.83
0.95
0.88
0.45
0.49
0.55
0.76
0.69
0.48
0
Ethanol
Propan-1-ol
Propan-2-ol
Butan-1-ol
Ethyl acetate
Diisopropyl ether
Tetrahydrofuran
N,N-Dimethylacetamide
N,N-Dimethylformamide
Acetone
0
0
0
0
0.08
0.44
0.19
0
Chloroform
Acetonitrile
0.31
0.37
Dioxane
a
Table 4 Regression fits to the solvatochromic parameters (Eq. 1)
b
c
d
No. Substituent X
ν
s
a
b
R
S
F
0
−3
−1
−3
−1
−3
−1
−3
−1
(10 cm
)
(10 cm
)
(10 cm
)
(10 cm )
1
2
3
4
5
6
7
8
H
43.83
−4.02
9.54
−4.27
0.989 0.68 109
0.993 0.51 171
0.993 0.51 159
0.993 0.49 161
0.992 0.55 142
0.977 1.06 48
0.969 1.07 36
0.993 0.68 165
(
1.14)
(
1.36)
(
0.77)
( 1.78)
CH OH
2
43.95
−3.94
9.05
−4.49
(
0.86)
(
1.02)
(
0.58)
(
1.33)
CH OCH
2
43.47
−4.37
8.19
−2.96
3
(
0.84)
(
1.00)
(
0.57)
(
1.32)
CH OC H
2 5
43.62
−4.28
8.18
−3.46
2
(
0.82)
(
0.98)
(
0.56)
(
1.28)
CH OCOCH
43.44
−4.52
8.33
−3.14
2
3
(
0.91)
(
1.09)
(
0.62)
(
1.42)
CH OCH C H 45.47441
−5.82
9.72
−6.04
2
2 6 5
(
1.76)
(
2.11)
(
1.19)
(
2.76)
CH C H
6 5
41.52
−6.16
6.22
3.51
2
(
1.79)
(
2.13)
(
1.21)
(
2.79)
COC H
41.56
−8.68
8.50
4.17
6
5
(
1.13)
(
1.35)
(
0.76)
( 1.76)
a
Chloroform, acetonitrile and dioxane were excluded from the correlation set
b
c
Correlation coefficient
Standard error of the estimate
d
Fisher’s test
The results of the multiple regressions are presented in Tables 4 and 5. The coefficient values
νo, s, b and a fit at the 95% confidence level are given in Table 4. The degree of success of

J Solution Chem (2007) 36: 869–878
875
(%)
Table 5 Percentage
contributions of the
solvatochromic parameters
No.
Substituent X
H
P
∗ (%)
P
(%)
P
β
α
π
1
2
3
4
5
6
7
8
22.55
22.54
28.16
26.88
28.27
26.97
38.77
40.65
53.50
51.77
52.77
51.38
52.09
45.04
39.14
39.81
23.95
25.69
19.07
21.74
19.64
27.99
22.09
19.54
CH OH
2
CH OCH
2
3
CH OC H
2 5
2
CH OCOCH
2
3
CH OCH C H
2 6 5
2
CH C H
6 5
2
COC H
6
5
Fig. 2 Plot of ν
observed
max
against ν
calculated from
max
Eq. 1 for 3-substituted-
5,5-diphenylhydantoins
Eq. 1 is shown in Fig. 2 by means of a plot of νmax calculated versus νmax observed in differ-
ent solvents. The negative signs of the s and b coefficients in the total solvatochromic equa-
tion (Table 4) for all 3-substituted-5,5-diphenylhydantoins (excluding the positive sign of the
b coefficient for CH2C6H5 and COC6H5 groups as substituents) indicates a bathochromic
shift with both increasing solvent polarity and solvent hydrogen bond acceptor basicity.
This suggests that stabilization of the electron’s excited state relative to the ground state
occurs. The positive sign of the a coefficient for all hydantoins indicates a hypsochromic
shift with increasing solvent hydrogen bond donor acidity. This implies stabilization of the
ground state relative to the electronic excited state. The percentage contributions of the sol-
vatochromic parameters (Table 5) for the investigated hydantoins show that most of the
solvatochromism is due to solvent basicity and acidity (specific solute–solvent interactions)
rather than to the solvent dipolarity/polarizability (nonspecific solute–solvent interactions).
These results are in accordance with the preferred existence of the hydantoins as their lactam
tautomer [5] and the previously reported hypothesis by Poupaert et al. [13] that hydrogen
bonding is an essential factor in the anticonvulsant action of 5,5-diphenylhydantoin deriva-
tives.
The results of our previous investigation of the solvent effects on the absorption frequen-
cies of 5,5-dimethylhydantoin [32] and 1,3-bis-substituted-5,5-dimethylhydantoins [32]
showed that multiple linear regression of the νmax and π∗, α and β solvent parameters gave
poor results for all 5,5-dimethylhydantoins because the β parameter is not significant in
these correlations. This can be explained by the ability of these hydantoins to create a strong
intermolecular hydrogen bond that decreases the hydrogen-bond accepting influence of the
solvent and lipophilic activity of the molecules. These results are in accordance with the
extensive study of 5,5-dialkylhydantoin derivatives [33] and the conclusion about the non-
activity of these molecules.

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Table 6 Values of the ratios of
the solvatochromic coefficients
a
b
No.
Substituent X
a/b
log
P
MES
10
−1
a/b, lipophilic parameter log
and pharmacologic activity
parameter MES for 3-substituted-
5,5-diphenylhydantoins
P
ED , mg·kg
50
10
(activity reported)
1
2
3
4
5
6
7
8
H
2.23
2.02
2.77
2.36
2.65
1.61
1.77
2.04
2.52
1.34
1.98
2.84
2.24
4.18
3.89
3.40
∼7.5
–
CH OH
2
CH OCH
2
∼6
3
CH OC H
2 5
–
2
a
Values of ACD log
P
10
CH OCOCH
<12.5
>25
>200
–
2
3
calculated by the Advanced
Chemistry Development
Software Solaris V.4.67
CH OCH C H
2 6 5
2
CH C H
6 5
2
b
Maximal electroshock seizures
COC H
6
5
(pharmacological test) [25, 34]
Fig. 3 Correlation of log
P
10
values with ratios of contribution
of specific solvent interactions
a/b for 3-substi-
tuted-5,5-diphenylhydantoins
Vida et al. [25] earlier reported that both 3-acetoxymethyl and 1,3-bis(acetoxymethyl)-
5,5-diphenylhydantoin showed good activity against maximal electroshock seizures (MES
test). They also reported [34] that 3-alkoxymethyl derivatives of diphenylhydantoin possess
activity against maximal electroshock seizures but, unlike the non-substituted diphenylhy-
dantoin, were also effective against chemoshock. The results of these studies have been
summarized in Table 6 for some of the compounds investigated in our present work.
Additional evidence for solvent effects on the structure-activity relationship of hydantoin
derivatives was obtained by the correlation of calculated lipophilic log10 P values with the
ratio of the contributions of specific solvent interactions a/b, with both parameters being
dependent on the structural characteristics of the investigated hydantoins (Table 6). The
results of the correlation are shown in Fig. 3. The plot of log10 P values versus a/b gives
a satisfactory linear correlation (excluding the point of CH2OH substituent) that can be
represented by Eq. 2:
log10 P = −1.89( 0.20)(a/b) + 7.18( 0.45)
(2)
(R = 0.972,
S = 0.21,
F = 87,
n = 7).
The data for 3-hydroxymethyl-5,5-diphenylhydantoin (a very important intermediate in the
preparation of the phenytoin prodrug) did not follow Eq. 2. The existence of this correla-
tion (Fig. 3) is strong evidence for the proportionality between the lipophilic parameters and
the specific solvatochromic effect of the investigated 3-substituted-5,5-diphenylhydantoins
that show good activity against maximal electroshock seizures as reported previously

J Solution Chem (2007) 36: 869–878
877
[25, 34] (Table 6). The correlation of log10 P with a/b values for 3-substituted-5,5-
diphenylhydantoins, excluding the data of both 3-hydroxymethyl-5,5-diphenylhydantoin
and 5,5-diphenylhydantoin (unsubstituted molecule), gave excellent results as presented by
Eq. 3:
log10 P = −1.88( 0.03)(a/b) + 7.23( 0.07)
(3)
(R = 0.999,
S = 0.03,
F = 3442,
n = 6).
The satisfactory correlation of the ultraviolet absorption frequencies of the investigated 3-
substituted-5,5-diphenylhydantoins with Eq. 1 indicates that the correct model was selected.
This means that this model gives a correct interpretation of the linear solvation energy re-
lationships for the complex system of hydantoin derivatives in the selected solvents. In this
case, where both solvents and substrates are hydrogen-bond donors and acceptors, it has
proven to be quite difficult to untangle the solvent dipolarity/polarizability, hydrogen bond
donor acidity and hydrogen bond acceptor basicity properties. For these reasons, we con-
sider that the results presented in this work may be utilized to quantitatively estimate and
separate the overall solvent effect into specific and nonspecific contributions using a LSER
method. The satisfactory correlation of the lipophilic parameters, log10 P , of the investigated
pharmacological active hydantoins with the ratio of the contributions of the specific solvent-
solute interactions supports the previously reported [12] pharmacophore model, which is
based on a hydrogen-bond acceptor, a hydrogen-bond donor, and an electronegative group
with a large hydrophobic part of the molecule.
Following the model proposed in this work, the pharmacological activity of some hydan-
toin derivatives can be explained and the corresponding potential activity/nonactivity of the
studied hydantoins, not yet pharmacologically tested, may be predicted.
Acknowledgements The authors acknowledge the financial support of the Ministry of Science and Envi-
ronmental Protection of the Republic of Serbia (Project 142 063).
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