Solvent effects on the structure-activity relationship of phenytoin-like anticonvulsant drugs

Article abstract of DOI:10.1007/s10953-008-9367-y

The absorption spectra of nine compounds structurally related to phenytoin (5,5-diphenylhydantoin) were recorded in twelve solvents over the range of 200 to 400 nm. The effects of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions were 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 calculation of their log ₁₀ P values. The calculated values of log ₁₀ P were correlated with the ratio of the contributions of specific and non-specific solute/solvent interactions. The correlation equations were combined with the corresponding ED₅₀ values to generate new equations that demonstrate exact relationship between solute/solvent interactions and the structure-activity parameters.

Full text of DOI:10.1007/s10953-008-9367-y

J Solution Chem (2009) 38: 199–208
DOI 10.1007/s10953-008-9367-y
Solvent Effects on the Structure-Activity Relationship
of Phenytoin-like Anticonvulsant Drugs
Nemanja Trišovi c´ · Nebojša Banjac · Nataša Valenti c´ ·
Gordana Uš c´ umli c´
Received: 23 July 2008 / Accepted: 7 October 2008 / Published online: 28 November 2008
©
Springer Science+Business Media, LLC 2008
Abstract The absorption spectra of nine compounds structurally related to phenytoin (5,5-
diphenylhydantoin) were recorded in twelve solvents over the range of 200 to 400 nm. The
effects of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions
were analyzed by means of the linear solvation energy relationship (LSER) concept pro-
posed by Kamlet and Taft. The lipophilic activity of the investigated hydantoins was es-
timated by calculation of their log P values. The calculated values of log P were cor-
1
0
10
related with the ratio of the contributions of specific and non-specific solute/solvent inter-
actions. The correlation equations were combined with the corresponding ED50 values to
generate new equations that demonstrate exact relationship between solute/solvent interac-
tions and the structure-activity parameters.
Keywords Phenytoin · Absorption frequencies · Solvent effect · Kamlet-Taft equation ·
Lipophilicity parameter · Specific and non-specific solvent interactions ·
Pharmacological activity
1
Introduction
Phenytoin (5,5-diphenylhydantoin) is the most widely used anticonvulsant [1, 2]. It targets
the neuronal voltage-gated sodium channels (NVSC) to reproduce the normal ion poten-
tial [3]. Studies of compounds that are structurally related to phenytoin could provide im-
portant knowledge and allow us to predict how to enhance binding sites for NVSC. The
exact location of these sites and their structural requirements for optimal binding have not
yet been determined. Regarding the molecular mode of action of phenytoin, Smythies [4]
suggested that it forms an array of molecules stacked on a β-turn segment of the proteic part
of the putative receptor site, through formation of hydrogen bonds with the carbonyl group
in position 2 and the NH group in position 3.
N. Trišovi c´ · N. Banjac · N. Valenti c´ (ꢀ) · G. Uš c´ umli c´
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 (2009) 38: 199–208
Transport phenomena occur in vivo and through membranes that are dependent on
lipophilic contributions [5]. The more lipophilic is the compound, the better is its ability
to penetrate lipid membranes to reach an appropriate receptor site. The partition coefficient
in n-octanol/water systems proved to be a simple model for lipophilic-hydrophilic balance
and hydrogen-bonding interactions. For anticonvulsant assays, the optimal lipophilicity for
penetration through the blood-brain barrier appears to exist at about log10 P = 2 [6].
The basic requirement for determining a structure-activity relationship is the selection of
an ideal property as a descriptor that correlates well with the physical and biological proper-
ties of the group of analyzed compounds. It is necessary that the descriptor be highly specific
and accurate. Phenytoin has two alternate C(=O)NH edges and two prochiral phenyl groups
that are connected to the quaternary carbon in position 5. This arrangement makes it partic-
ularly receptive towards various hydrogen-bonding donors and acceptors. Usually, the func-
tional relationships between solvent parameters and various solvent-dependent processes
take the form of a linear solvation energy relationship (LSER). The LSER concept devel-
oped by Kamlet and Taft [7], in the form of a multiparameter equation, is one of the most
ambitious and successful quantitative treatments of solvent effects.
For structure-activity modeling, we have selected a set of nine compounds that are struc-
turally related to phenytoin (Fig. 1) which have measured maximal electroshock seizure
(MES) activities in mice and rats following oral administration. For details of these biologi-
cal tests, the original articles should be consulted [8, 9].
Poupaert et al. [8] tested a limited series of compounds that are structurally related to
phenytoin with the MES test, in order to determine the impact of reducing their ability to
form hydrogen bonds on their anticonvulsant activity. Decreasing the ability of the investi-
gated compounds to form hydrogen bonds was found to reduce their anticonvulsant activi-
ties. The focus of our research has been to determine the behavior of compounds structurally
related to phenytoin, in different solvents, using UV/Vis spectroscopic methods. UV absorp-
tion spectra have been recorded in the region of 200 to 400 nm in selected solvents having
different polarity. The effects of solvent dipolarity/polarizability and hydrogen bonding on
the absorption spectra are interpreted by means of a linear solvation relationship using the
Kamlet-Taft equation [7] in the following form:
∗
ν = ν0 + sπ + bβ + aα
(1)
∗
where π is an index of the solvent dipolarity/polarizability [10], β is a measure of the
solvent hydrogen-bonding acceptor (HBA) basicity [11], α is a measure of the solvent
hydrogen-bonding donor (HBD) acidity [12], and ν0 is the value of this solvent property
in cyclohexane as the reference solvent, based on regression of experimental results. The
regression coefficients s, b and a of Eq. 1 are measures of the relative susceptibilities of the
solvent-dependent solute property (absorption frequencies) to the indicated solvent parame-
ters.
We estimated the lipophilicities of the investigated compounds by calculation of their
log P values using the Advanced Chemistry Development (ACD) Software Solaris V.4.67.
1
0
The calculated values of log P were correlated with the ratio of the contributions of spe-
1
0
cific and non-specific solute/solvent interactions. The correlation equations were combined
with the corresponding ED50 values (the effective dose required to protect mice against
spasms induced by the maximum electric shock), to generate new equations that demonstrate
exact relationships between solute/solvent interactions and structure-activity parameters.

J Solution Chem (2009) 38: 199–208
201
Fig. 1 Structure of investigated phenytoin(1)-like anticonvulsant drugs
2
Experimental
2.1 Chemicals and Materials
All of the studied 3-alkyl-5,5-diphenylhydantoins (compounds 2, 3 and 6) were synthe-
sized by the reaction of 5,5-diphenylhydantoin (commercially available from Fluka) with
the corresponding alkyl bromide in alcoholic solution in the presence of sodium hydrox-
ide [13]. 3-Alkoxy-5,5-diphenylhydantoins (compounds 4 and 7) were prepared by reaction
of the 5,5-diphenylhydantoin sodium salt, suspended in N,N-dimethylformamide, with the
corresponding alkyl ether in the presence of base using a modification of the literature pro-
cedure [9]. The experimental investigation included modification of the synthetic procedure
in terms of catalysts, isolation techniques, as well as purification and identification of the
products. 3-Acetoxymethyl-5,5-diphenylhydantoin (compound 5) was synthesized by reac-

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J Solution Chem (2009) 38: 199–208
tion of 3-hydroxymethyl-5,5-diphenylhydantoin with acetic anhydride [14]. Diphenylpyrro-
lidinone (compound 8) was synthesized by reaction of 5,5-diphenyl-2-thiohydantoin [15] in
ethanol containing Raney nickel [16]. 3,3-Diphenylsuccinimide (compound 9) was prepared
according to the procedure of Miller and Long [17].
Diphenyl substituted acetonitrile was alkylated with ethylbromoacetate to give the corre-
sponding cyano-ester. Hydrolysis and ring closure results from the anhydride interactions.
The anhydride was dissolved in dry ether, and ammonia was passed through the solution
until precipitation was complete. The succinamic acid was filtered, dried and refluxed with
acetyl chloride to yield 3,3-diphenylsuccinimide.
2.2 Spectral Analysis
The chemical structures and purities of the synthesized compounds were confirmed by their
1
1
melting points, H NMR, FT-IR and UV spectra. The H NMR spectra of DMSO-d6 solu-
tions (TMS as internal standard) were measured with a Varian-Gemini 200 MHz spectrome-
ter. 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
−
5
−1
.
in spectro quality solvents (Fluka) at a fixed concentration of 1 × 10 mol·L
.3 Regression Analysis
2
The correlation analysis was carried out using Microsoft Excel software that consider the
5% confidence level. The goodness of fit is discussed using the correlation coefficient (R),
the standard error of the estimate (S), and Fisher’s significance test (F).
9
3
Results and Discussion
The ultraviolet absorption frequencies of the studied compounds, that are structurally related
to phenytoin, are given in the Table 1 for twelve solvents. The effects of the solvent dipo-
larity/polarizability and hydrogen bonding are interpreted by means of the LSER concept
using Eq. 1. The solvent parameters are shown in the Table 2. Correlation of the spectro-
scopic data was carried out in terms of multiple linear regression. It was found that the
absorption frequencies of the studied compounds, in these twelve selected solvents, show a
∗
satisfactory correlation with the π , β and α parameters (Tables 3 and 4). The regression
values of ν0, s, b and a fit at the 95% confidence level are presented in Table 3. The degree
of success of Eq. 1 is shown in Fig. 2, by means of a plot of νmax (calculated) versus νmax
(observed) in different solvents.
The negative signs of the s and b coefficients in the solvatochromic equation (Ta-
ble 3) indicate that there is a bathochromic shift, with both increasing solvent dipolar-
ity/polarizability and solvent hydrogen-bond basicity. This information suggests that stabi-
lization of the electronic excited state occurs relative to the ground state. The positive sign of
the a coefficient for all compounds indicates that a hypsochromic shift occurs with increas-
ing solvent hydrogen-bond acidity. This conclusion implies stabilization of the ground state
relative to the excited electronic state. The red shift of the absorption band, when the solvent
∗
polarity is decreased, supports its n-π nature, because in protic solvents the n-electrons are
+
expected to be blocked by the solvent H ions through intermolecular hydrogen bonds and,
consequently, the excitation of n-electrons is difficult. These results are in accordance with
our previously published data for 3-substituted-5,5-diphenylhydantoins [18].

J Solution Chem (2009) 38: 199–208
203
Table 1 Ultraviolet absorption frequencies of the studied compounds structurally related to phenytoin
−
3
−1
Solvent/
νmax × 10 (cm
)
Compound
1
2
3
4
5
6
7
8
9
Ethanol
49.16 48.08 47.85 47.71 48.17 48.03 47.66 48.22 47.72
47.94 47.80 47.80 48.26 47.94 47.85 47.66 47.94 48.16
47.08 47.39 46.95 46.95 47.30 46.86 47.04 47.48 47.06
46.34 46.43 46.34 46.47 46.43 46.34 46.30 46.51 46.40
48.12 48.92 48.31 48.69 49.26 49.16 49.41 48.54 48.64
41.70 41.95 41.63 41.46 41.63 41.63 41.56 41.77 41.36
41.53 41.77 41.43 41.32 41.39 41.53 41.36 41.43 41.28
38.67 38.73 38.76 38.70 38.40 37.88 38.52 38.43 38.58
39.94 40.06 39.94 40.19 39.22 39.18 38.79 39.75 39.84
39.87 39.87 39.90 39.84 39.94 39.97 39.71 39.81 39.65
Propan-1-ol
Propan-2-ol
Butan-1-ol
Ethylene glycol
Diisopropyl ether
Tetrahydrofuran
Dimethyl sulfoxide
Methyl acetate
Ethyl acetate
N,N-Dimethylformamide 37.71 37.76 37.71 37.65 37.76 37.68 37.82 37.68 37.56
N,N-Dimethylacetamide 37.45 37.37 37.34 37.48 37.45 37.43 37.54 37.48 37.38
Table 2 Solvent parameters [7]
∗
Solvent
π
β
α
Ethanol
0.54
0.52
0.48
0.47
0.92
0.27
0.58
1.00
0.60
0.55
0.88
0.88
0.77
0.83
0.95
0.88
0.52
0.49
0.55
0.76
0.42
0.45
0.69
0.76
0.83
0.78
0.76
0.79
0.90
0
Propan-1-ol
Propan-2-ol
Butan-1-ol
Ethylene glycol
Diisopropyl ether
Tetrahydrofuran
Dimethyl sulfoxide
Methyl acetate
Ethyl acetate
0
0
0
0
N,N-Dimethylformamide
N,N-Dimethylacetamide
0
0
The percentage contributions of the solvatochromic parameters (Table 4) for the studied
compounds (that are structurally related to phenytoin) show that most of the solvatochromic
effect is due to the solvent basicity and acidity (specific solute-solvent interactions), rather
than to the solvent dipolarity/polarizability (nonspecific solute-solvent interactions). The
specific solvent-solute interactions show that the dominant effect is the solvent-hydrogen
bond donor acidity. These results are in accordance with the preferred existence of all of the
studied molecules being in their keto tautomer. Results obtained in this work show that the
increase of the ratio of relative contributions from specific and non-specific solute/solvent
interactions reduces the anticonvulsant activities of the studied compounds. Poupaert et al.
[8] previously reported that progressive reduction of the ability to form hydrogen bonds,
via the replacement of a carbonyl group or an NH by a methylene group, produces com-
pounds with less anti-MES activity than phenytoin. A net stepwise decrease of their anti-
convulsant activity was observed when the hydantoin ring structure was changed to pyrro-
lidinone (compound 8) and succinimide (compound 9), or when it was N-methylated (com-

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J Solution Chem (2009) 38: 199–208
Table 3 Regression fits to the solvatochromic parameters
a
b
c
F
No.
ν
0
s
b
a
R
S
−
3
−1
−3
−1
−3
−1
−3
−1
(
10 cm
)
(10 cm
)
(10 cm
)
(10 cm )
1
2
3
4
5
6
7
8
9
44.32
± 1.43)
44.67
± 1.42)
44.21
± 1.29)
44.20
± 1.28)
44.07
± 1.37)
44.53
± 1.34)
43.59
± 1.59)
44.22
± 1.28)
43.90
± 1.31)
−4.02
−3.46
10.47
0.982
0.982
0.984
0.985
0.984
0.985
0.981
0.986
0.985
0.98
0.98
0.88
0.88
0.94
0.92
1.03
0.88
0.90
72
72
84
88
83
85
67
92
86
(
(± 1.36)
−3.61
(± 1.97)
−4.36
(± 0.86)
10.61
(
(± 1.35)
−3.61
(± 1.96)
−3.78
(± 0.85)
10.27
(
(± 1.22)
−3.31
(± 1.77)
−4.12
(± 0.77)
10.60
(
(± 1.21)
−3.18
(± 1.76)
−4.27
(± 0.76)
11.07
(
(± 1.30)
−3.43
(± 1.89)
−4.89
(± 0.82)
11.08
(
(± 1.28)
−2.62
(± 1.85)
−4.22
(± 0.81)
10.96
(
(± 1.42)
−3.93
(± 2.06)
−3.52
(± 0.90)
10.60
(
(± 1.21)
−3.35
(± 1.76)
−3.82
(± 0.76)
10.68
(
(± 1.25)
(± 1.81)
(± 0.79)
a
Correlation coefficient
b
c
Standard error
Fisher’s test
Table 4 Percentage contribution
P ) to the solvatochromic effects
No.
Pπ∗(%)
Pβ(%)
Pα(%)
(
1
2
3
4
5
6
7
8
9
22.40
19.43
20.44
18.36
17.17
17.68
14.72
21.77
18.72
19.28
23.47
21.40
22.85
23.06
25.21
23.71
19.50
21.41
58.33
57.10
58.15
58.79
59.77
57.11
61.57
58.73
61.57
pound 2). Vida et al. [9] reported that both 3-acetoxymethyl and 1,3-bis(acetoxymethyl)-
,5-diphenylhydantoin showed good activity against maximal electroshock seizures (MES
5
test). They also reported [19] that the 3-alkoxymethyl derivatives of 5,5-diphenylhydantoin
possess activity against maximal electroshock seizures, but, unlike non-substituted hydan-
toin, they were also effective against chemoshock. The results of all of these studies are
summarized in Table 5.

J Solution Chem (2009) 38: 199–208
205
Fig. 2 Plot of νmax observed versus νmax calculated from Eq. 1 for the phenytoin-like anticonvulsant drugs
Table 5 Values of the ratios of
a
b
No.
(a + |b|)/|s|
log
P
ED
50
contributions of specific and
non-specific solute/solvent
interactions (a + /|b/|)/|s/|, the
10
(mg·kg 1
−
)
lipophilic parameter, log
P
10
1
2
3
4
5
6
7
8
9
3.47
4.15
3.89
4.45
4.82
4.66
5.79
3.59
4.33
2.52
2.03
2.56
1.98
2.24
3.89
4.18
0.81
2.71
7.5
39.6
–
and ED
50
a
Calculated with the Advanced
Chemistry Development
Software Solaris V.4.67
6
12.5
200
25
b
The effective dose required to
protect mice against spasms
induced by maximum electric
shock, pharmacological activity
test reported [8, 19]
30.7
26.9
The results of our previous investigation of solvent effects on the structure-activity
relationship of pharmacologically-active 3-substituted-5,5-diphenylhydantoins [18] and
5-methyl-5-(4-substituted phenyl)hydantoins [20] showed that correlation of calculated
log P values, with the ratio of the contributions of specific solvent interactions, gave satis-
1
0
factory results. In this work, additional evidence for solvent effects on the structure-activity
relationship of compounds that are structurally related to phenytoin has been obtained by
correlation of the calculated log P values with the ratio of the relative contribution of
1
0
the specific and non-specific solvent/solute interactions ((a + |b|)/|s|). All parameters de-
pend on the structural characteristics of the studied compounds (Table 5). The results of the
correlation are shown in Fig. 3.
The poor correlation result presented in Fig. 3 is due to the different structural character-
istics of the investigated compounds. The plot of the log P values against ((a + |b|)/|s|)
1
0
yields a good linear correlation (excluding the points of compounds 1, 3 and 6) that can be

206
J Solution Chem (2009) 38: 199–208
Fig. 3 Correlation of the log P values with the ratios of contributions of the specific and nonspecific
10
solvent/solute interactions for the studied compounds structurally related to phenytoin
Fig. 4 Hydrogen-bonding
among the neighboring
molecules of 5,5-disubstituted
hydantoins
represented by Eq. 2:
log P = 1.38(± 0.28)[(a + |b|)/|s|] − 3.91(± 1.26)
1
0
(R = 0.930, S = 0.46, F = 25, n = 6)
(2)
This correlation is evidence for the proportionality between the lipophilicity parameter and
the ratio of the contributions of specific and non-specific solute/solvent interactions.
The previously reported results [22] clearly confirm the hypothesis that the position of
hydrogen-donor or electron-donor atoms, in combination with an aromatic ring in a spe-
cific orientation, is an important factor in determining the hydantoin drug pharmacological
site action. 5,5-Disubstituted hydantoins proved to be hydrogen bonded to two neighboring
groups (Fig. 4). The ability of hydantoins to create a strong intermolecular hydrogen bond
decreases the hydrogen bond acceptor effect of the solvent.
The results presented in this work show that introduction of substituents in position 3
produces compounds with reduced capability for forming solute-solute hydrogen bonds (rel-
ative to phenytoin), generally increases their ability to interact with solvent molecules, and
decreases their anticonvulsant activity (Tables 4 and 5).
The anticonvulsant activity depends parabolically on log P , with an optimum value
1
0
of 2 [21]. This agrees well with values found empirically for central nervous system de-
pressants. In this work, the correlation of log P values with the pharmacological activity
1
0

J Solution Chem (2009) 38: 199–208
207
parameter log (1/ED50) (Table 5), for the studied compounds (excluding the data for mole-
1
0
cules 2, 7 and 8), gave a satisfactory result as described by Eq. 3:
log (1/ED50) = −0.80(± 0.13)log P + 0.84(± 0.37)
1
0
10
(R = 0.958, S = 0.20, F = 34, n = 5)
(3)
A negative proportionality coefficient of −0.80 in Eq. 3 indicates that modification of the
structure of the compounds included in this correlation is unfavorable for their anticonvul-
sant activity.
Much better correlation results were obtained for the same correlation set as in Eq. 3,
when the pharmacological activity parameter log (1/ED50) was correlated with the sum of
1
0
log P and (a + |b|)/|s| (Eq. 4):
1
0
log (1/ED50) = −0.76(± 0.06)log P − 0.37(± 0.08)[(a + |b|)/|s|] + 2.21(± 0.38)
1
0
10
(R = 0.995, S = 0.09, F = 98, n = 5)
(4)
The existence of these correlations has been interpreted as evidence for the significant
role of the ratio of relative contributions from specific and non-specific solute/solvent inter-
actions on the anticonvulsant activity of the studied compounds, and shows that increasing
the ratio of the relative contributions of the specific and non-specific solute/solvent interac-
tions reduces the anticonvulsant activity of the studied compounds.
The satisfactory correlation of the ultraviolet absorption frequencies of the studied com-
pounds that are structurally related to phenytoin, with Eq. 1, indicates that the correct model
was selected. This means that this model gives a correct interpretation of the linear solvation
energy relationship for the complex system containing phenytoin-like compounds in the se-
lected solvents. In this case, where both solvents and substrates are hydrogen-bond donors
and acceptors, it is quite difficult to untangle the solvent dipolarity/polarizability, hydrogen-
bond basicity and hydrogen-bond acidity properties. For these reasons, we consider that
the results presented in this work can be utilized to quantitatively estimate and separate the
overall solvent effects into specific and non-specific contributions using a LSER equation.
The excellent correlation of the pharmacological activity parameter log (1/ED50), for
1
0
the selected set of compounds, with the lipophilic parameter log P , and the ratio of contri-
1
0
butions of specific and non-specific solute/solvent interactions, supports the previously re-
ported pharmacological model [22] that is based on the hydrogen-bond acceptor, hydrogen
bond-donor and an electronegative group being a large hydrophobic part of the molecule.
Following the approach proposed in this work, the anticonvulsant activity of some pheny-
toin derivatives can be explained and the corresponding potential activity/nonactivity of new
synthesized ones can be predicted.
Acknowledgements The authors acknowledge the financial support of the Ministry of Science of the Re-
public of Serbia (Project 142 063).
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