Solvent effects on the absorption spectra of potentially pharmacologically active 5-alkyl-5-arylhydantoins: A structure-property relationship study

Article abstract of DOI:10.2298/JSC120719118H

To obtain insight into the interactions of potential anticonvulsant drugs with their surrounding, two series of 5-methyl-5-aryl- and 5-ethyl-5- -arylhydantoins were synthesized and their absorption spectra were recorded in the region from 200 to 400 nm in a set of selected solvents. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions on the absorption maxima shifts were analyzed by means of the linear solvation energy relationship (LSER) concept of Kamlet and Taft. The ratio of the contributions of specific and non-specific solvent-solute interactions were correlated with the corresponding absorption, distribution, metabolism, and excretion (ADME) properties of the studied compounds. The correlation equations were combined with different physicochemical parameters to generate new equations, which demonstrate the reasonable relationships between the solvent- solute interactions and the structure-activity parameters. Copyright (C)2013 SCS.

Full text of DOI:10.2298/JSC120719118H

J. Serb. Chem. Soc. 78 (5) 627–637 (2013)
UDC 547.783+66.081.2:544.351.3:615
JSCS–4444
Original scientific paper
Solvent effects on the absorption spectra of potentially
pharmacologically active 5-alkyl-5-arylhydantoins:
a structure–property relationship study
SLEEM F. HMUDA, NEBOJŠA R. BANJAC, NEMANJA P. TRIŠOVIĆ#,
BOJAN Đ. BOŽIĆ , NATAŠA V. VALENTIĆ and GORDANA S. UŠĆUMLIĆ
#
#
#
*
Department of Organic Chemistry, Faculty of Technology and Metallurgy, University of
Belgrade, Karnegijeva 4, 11120 Belgrade, Serbia
(Received 19 July, revised 22 October 2012)
Abstract: To obtain insight into the interactions of potential anticonvulsant
drugs with their surrounding, two series of 5-methyl-5-aryl- and 5-ethyl-5-
-arylhydantoins were synthesized and their absorption spectra were recorded in
the region from 200 to 400 nm in a set of selected solvents. The effects of sol-
vent dipolarity/polarizability and solvent–solute hydrogen bonding interactions
on the absorption maxima shifts were analyzed by means of the linear solvation
energy relationship (LSER) concept of Kamlet and Taft. The ratio of the con-
tributions of specific and non-specific solvent–solute interactions were corre-
lated with the corresponding absorption, distribution, metabolism, and excre-
tion (ADME) properties of the studied compounds. The correlation equations
were combined with different physicochemical parameters to generate new
equations, which demonstrate the reasonable relationships between the sol-
vent–solute interactions and the structure–activity parameters.
Keywords: hydantoin derivatives; Kamlet–Taft Equation; human intestinal ab-
sorption; lipophilicity, binding affinity.
INTRODUCTION
Hydantoin (imidazolidine-2,4-dione) is the core structure of different biolo-
1
2
gically active compounds, such as antibacterial and antifungal agents, free radi-
3
4
cal scavengers and serotonin and fibrinogen receptor antagonists. 5-Phenylhy-
dantoins are commonly used in the treatment of epilepsy and related disorders.
Phenytoin (5,5-diphenylhydantoin) is one of the oldest non-sedative anticonvul-
sant drugs, whereas mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) is con-
sidered only after other less toxic anticonvulsants have failed. Nirvanol, the 3-
5
6
demethylated metabolite of mephenytoin, was the first hydantoin derivative used
*Corresponding author. E-mail: goca@tmf.bg.ac.rs
# Serbian Chemical Society member.
doi: 10.2298/JSC120719118H
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628
HMUDA et al.
briefly in the treatment of chorea, but it was abandoned due to its hypnotic–
7
sedative effect. Anticonvulsant drugs require long-term application and should
have only minor unfavourable effects. For this reason, the synthesis and model-
ling of the behaviour of new hydantoin derivatives significantly contributes to a
rational search for new anticonvulsant drugs.
The anticonvulsant activity of hydantoin derivatives is mediated by their
+
8
interaction with and inhibition of the brain Na channels. Their common phar-
macophore core contains at least one aromatic ring at C5, which forms aromatic–
aromatic interactions, and a polar imide group, which interacts with the receptor
site through a low-energy amino–aromatic hydrogen bond. Poupaert et al. tested
a limited series of compounds structurally related to phenytoin and observed that
the anticonvulsant activity decreased with a reduction in their ability to form
9
hydrogen bonds. Brouillette et al. demonstrated that 5-alkyl-5-phenylhydantoins
+
have an affinity for Na channels comparable to that of phenytoin, with the opti-
10,11
mal length of the aliphatic chain corresponding to pentyl, hexyl or heptyl.
In
this context, it was proposed that the structure–activity and structure–property re-
lationships of hydantoin anticonvulsants have molecular size and hydrogen bond-
12–14
ing as their primary determinants.
Since most drug candidates fail in preclinical and clinical trials because of
their unfavourable ADME (absorption, distribution, metabolism and excretion)
properties, ADME modelling has attracted significant attention over the last two
decades. The lipophilicity of drugs, as expressed by their octanol–water parti-
tioning coefficient (log P), has been proven to be the most important parameter in
the study of transport phenomena in vivo and through biological membranes. In-
sufficient lipophilicity results in poor membrane permeability of a drug, whereas
excessive lipophilicity is a common cause of poor solubility that could lead to in-
15
complete absorption following oral administration. Concerning central nervous
system (CNS) active drugs, the ideal candidates must be able to penetrate the
blood–brain barrier (BBB) effectively. It was suggested that the optimum log P
16
value for diffusion into the brain is around 2.
In this work, two series of 5-methyl-5-aryl- and 5-ethyl-5-arylhydantoins
were assembled (Fig. 1) as a part of a larger investigation on the contribution of
hydrogen bonding to the pharmacologically relevant properties of hydantoin deri-
vatives and their potential application as anticonvulsant drugs. Kleinpeter et al.
estimated the lipophilicities of a representative number of hydantoins using RP-
17
HPLC and concluded that some of the derivatives studied in this work (1, 5, 6,
7, 9, 10 and 11) are expected to interact with and penetrate native membranes and
be bioactive.
A first insight into the interactions of the investigated molecules with their
surrounding can be derived from solvatochromic studies in which specific and
18
non-specific interactions can be separated. Hereto, their absorption spectra
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STRUCTURE–PROPERTY RELATIONSHIP STUDY OF 5-ALKYL-5-ARYLHYDANTOINS
629
have been recorded in the region 200–400 nm in twelve solvents. The effects of
solvent dipolarity/polarizabilty (non-specific solvent–solute interactions) and
hydrogen bonding (specific solvent–solute interactions) on the absorption spectra
19
shifts were interpreted using the Kamlet–Taft equation in the form:
ν = ν + sπ* + bβ + aα
(1)
0
where v is the wavenumber, π* is an index of the solvent dipolarity/polarizabilty,
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 ν is the
0
regression value of this solute property in cyclohexane as the reference solvent.
The regression coefficients s, b and a in Eq. (1) measure the relative suscepti-
bilities of the absorption maxima shift to the indicated solvent parameters.
Fig. 1. Structures of the investigated 5-methyl-5-(4-substituted phenyl)- and
5-ethyl-5-(4-substituted phenyl)hydantoins.
To analyze the role of hydrogen bonding in their ADME properties, octanol–
–water partitioning coefficient (log P), human intestinal absorption (Abs) and
protein binding affinity (k ) data have been correlated with the regression coef-
A
ficients from Eq. (1). The obtained correlation equations demonstrate reasonable
relationships between solvent–solute interactions and structure–property parame-
ters.
EXPERIMENTAL
Synthesis of the investigated compounds
All of the investigated 5-methyl-5-aryl- and 5-ethyl-5-arylhydantoins were synthesized
by a modification of the method of Bucherer20 (Scheme 1). The appropriate ketone (0.020
mol) was dissolved in 50 % ethanol (50 cm3) and ammonium carbonate (7.70 g, 80.0 mmol)
plus potassium cyanide (2.60 g, 40.0 mmol) were added. This mixture was warmed under a
condenser at 60 °C for 15 h, after which the solution was concentrated to approximately two-
thirds of its initial volume and chilled in an ice-bath. The mass was filtered on a Büchner fun-
nel. The product was dissolved in 5 % sodium hydroxide solution, filtered from unreacted
ketone and reprecipitated by acidification with hydrochloric acid. Recrystallization of the
white solid from 60 % ethanol yielded a crystalline product. The ketones used in these prepa-
rations were commercially available (Fluka). The chemical structure and the purities of the
1
synthesized compounds were confirmed by their melting points and H-NMR, 13C-NMR,
FT-IR and UV spectra.
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630
HMUDA et al.
Scheme 1. Synthetic route to the investigated 5-alkyl-5-(4-substituted phenyl)hydantoins.
Spectroscopic measurements
1
The H- and 13C-NMR spectra were recorded on a Bruker AC 250 spectrometer at 200
1
MHz for the H-NMR and 50 MHz for the 13C-NMR spectra. The spectra were recorded at
room temperature in DMSO-d6. The chemical shifts are expressed in ppm referred to TMS
(δH = 0 ppm) in the 1H-NMR and the residual solvent signal (δH = 39.5 ppm) in the 13C-NMR
spectra. The FT-IR spectra were recorded on a Bomem MB 100 spectrometer. The absorption
spectra were measured in spectroquality solvents (Fluka) at 10-5 mol dm-3 concentration using
a Shimadzu 1700 spectrophotometer. All melting points are uncorrected and are presented in
°C. Mass spectra were obtained on Agilent technologies 6210 TOF LC/MS (HRMS) ins-
trument (LC: series 1200). Elemental analysis was performed using a Vario EL III elemental
analyzer.
Physicochemical characterization of the investigated compounds
The physicochemical characterization of compounds 1–6 has already been reported,21
whereas the yields and the characterization of compounds 7–12 are given in the Supplemen-
tary material to this paper.
Methods of calculation
The correlation analysis was realised using Microsoft Excel 2003, which considers the
95% confidence level. The goodness-of-fit is discussed using the correlation coefficient (R),
standard error of the estimate (S) and the Fisher’s criterion (F).
In the absence of appropriate experimental data in the literature, computer methods were
used to predict the ADME properties of the investigated hydantoin derivatives. Their lipo-
philicity was estimated by calculation of their log P values with Advanced Chemistry Deve-
lopment (ACD) software Solaris, v. 4.67. The human intestinal absorption data (Abs) and
protein binding values (fb) were obtained with the ChemSilico program.23
The corresponding physicochemical characteristics and ADME data of the investigated
molecules are collected in Table I.
TABLE I. Physicochemical properties and ADME data of the investigated molecules
b
e
No.
R
X
σIa
σR
log Pc
Absd / %
fbd / %
log kA
1
2
3
4
5
Me
Me
Me
Me MeO
Me Cl
H
OH
Me
0
0
0.999
0.263
1.459
0.914
1.594
91.8
89.4
93.3
89.4
93.7
37.435
40.823
67.904
52.849
69.988
2.71
2.85
3.97
3.33
4.07
0.24
–0.01
0.3
–0.43
–0.13
–0.43
–0.16
0.47
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STRUCTURE–PROPERTY RELATIONSHIP STUDY OF 5-ALKYL-5-ARYLHYDANTOINS
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TABLE I. Continued
b
e
No.
R
X
σIa
σR
log Pc
Absd / %
fbd / %
log kA
6
7
8
9
10
11
12
Me
Et
Et
Et
Et
Et
Et
Br
H
OH
Me
MeO
Cl
0.47
0
–0.16
0
1.771
1.530
0.794
1.991
1.446
2.126
2.302
94.0
92.8
91.0
93.9
90.8
94.3
94.4
75.079
48.188
49.223
74.736
61.883
76.844
80.989
4.32
3.15
3.19
4.30
3.70
4.42
4.67
0.24
–0.01
0.3
0.47
0.47
–0.43
–0.13
–0.43
–0.16
–0.16
Br
aInductive substituent parameter;24 bresonance substituent parameter;24 ccalculated with ACD Solaris, v. 4.67;
dcalculated with ChemSilico; ethe protein binding affinities were obtained by Eq. (3)
RESULTS AND DISCUSSION
Absorption spectra of the investigated molecules were recorded in twelve
solvents of different polarities and the corresponding absorption maxima are pre-
sented in Table II. The absorption spectra were characterized by one band with a
weak low-energy shoulder, which is typical for 5-phenylhydantoins. The main
absorptions resulted from an intramolecular charge transfer (ICT), corresponding
to a migration of electron density from the hydantoin moiety to the phenyl ring.
The bathochromic shift of the absorption bands with increasing solvent dipola-
12–14
rity/polarizability is in accordance with previously published data.
TABLE II. Absorption maxima of the investigated molecules in the set of selected solvents
ν
max×10-3 / cm-1
Compound/
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
Methanol
Ethanol
47.89 44.56 45.80 44.80 45.21 44.96 46.51 43.63 45.83 44.17 45.00 44.76
47.48 44.52 45.66 44.76 45.16 44.92 47.13 44.44 45.75 45.21 45.33 45.04
47.50 44.62 45.45 45.00 44.88 45.51 47.08 44.60 45.87 45.21 44.68 44.56
47.94 44.90 46.21 44.80 45.00 44.82 48.17 45.70 47.57 46.59 45.21 45.05
47.60 44.85 46.00 45.44 46.00 45.33 47.04 44.96 45.83 45.45 45.63 44.13
40.62 40.42 40.91 40.52 40.55 40.52 40.88 40.75 40.72 40.45 40.49 40.39
41.77 39.03 41.28 40.25 41.28 41.18 41.77 41.67 41.74 41.70 41.18 41.02
1-Propanol
2-Propanol
1-Butanol
Diethyl ether
Disopropyl
ether
Tetrahydro-
furan
Dimethyl
sulfoxide
Ethyl acetate
39.18 38.79 39.15 39.09 39.12 39.06 39.43 39.31 39.28 39.34 39.28 39.25
37.45 36.05 36.76 36.39 37.26 37.20 37.48 36.37 36.74 36.98 37.28 37.34
38.58 36.39 38.66 36.60 38.46 38.28 39.62 36.51 39.28 36.88 38.76 38.32
N,N-Dimethyl- 37.79 36.20 37.73 37.51 37.76 37.70 37.65 36.18 36.79 36.39 37.31 38.71
formamide
N,N-Dimethyl- 37.12 36.07 36.79 36.41 37.7 37.37 37.57 36.18 37.15 36.50 37.25 37.43
acetamide
The effects of the solvent dipolarity/polarizability and hydrogen bonding on
the absorption maxima shifts were evaluated by multiple regression analysis
using the solvent parameter set of Kamlet and Taft (Table III). It was found that
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632
HMUDA et al.
absorption maxima of the investigated molecules in selected solvents show a
satisfactory correlation with the π*, β and α parameters. The fitted regression
values of ν , s, b and a at the 95 % confidence level are presented in Table IV.
0
The success degree of Eq. (1) is shown in Fig. 2 by means of a plot of ν
cal-
max
culated versus ν
observed in different solvents (R = 0.991, S = 0.50, F = 8048).
max
TABLE III. Solvent parameters19
Solvent
π*
β
α
Methanol
Ethanol
1-Propanol
2-Propanol
1-Butanol
Diethyl ether
Diisopropyl ether
Tetrahydrofuran
Dimethyl sulfoxide
Ethyl acetate
N,N-Dimethylformamide
N,N-Dimethylacetamide
0.60
0.54
0.52
0.48
0.47
0.27
0.27
0.58
1.00
0.55
0.88
0.88
0.62
0.77
0.83
0.95
0.88
0.47
0.49
0.55
0.76
0.45
0.69
0.76
0.93
0.83
0.78
0.76
0.79
0.00
0.00
0.00
0.00
0.00
0.00
0.00
Fig. 2. Experimental vs. calculated values of ν from Eq. (1).
The investigated compounds showed positive solvatochromism with regards
to π* (as indicated by the negative s coefficients in Table IV), which indicates
that the dipole moment of the excited state is higher than in the ground state.
Thus, considerable differences between the dipole moments in the ground and
excited state are characteristic for ICT processes. The positive a and b coeffi-
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STRUCTURE–PROPERTY RELATIONSHIP STUDY OF 5-ALKYL-5-ARYLHYDANTOINS
633
cients indicate hypsochromic shifts of absorption maxima with increasing solvent
hydrogen bond acidity and basicity (Table IV). This can be explained by the
hydrogen bond formation between protic solvents and the hydantoin carbonyl
moieties, which reduced their electron density and thus decreased the ICT cha-
racter of the chromophoric system. On the other hand, the interactions of the NH
groups played only a minor role, which is represented by the small percentage
contribution of the b coefficient compared to those of a and s (Table V). These
results are also in accordance with the preferred existence of the investigated
molecules in their imido tautomer.
TABLE IV. Regression fits to the solvatochromic parameters
No.
1
R
Me
X
H
ν0×10-3 / cm-1 s×10-3 / cm-1 b×10-3 / cm-1 a×10-3 / cm-1 Ra
41.51(±0.68) –6.51(±0.80) 2.59(±1.34) 9.15(±0.52) 0.996 0.48 351
Sb Fc
2
3
4
5
Me OH 39.80(±1.02) –6.56(±1.20) 3.22(±2.01) 6.99(±0.78) 0.988 0.72 106
Me Me 41.85(±0.49) –6.88(±0.58) 2.11(±0.97) 7.16(±0.74) 0.997 0.34 463
Me MeO 40.29(±1.08) –6.55(±1.26) 3.28(±2.11) 6.65(±0.82) 0.985 0.76 89
Me Cl 41.22(±0.54) –5.89(±0.63) 2.30(±1.06) 6.41(±0.41) 0.998 0.38 310
Me Br 41.18(±0.61) –6.45(±0.72) 2.60(±1.06) 6.36(±0.46) 0.994 0.43 238
6
7
Et
H
41.43(±0.63) –7.43(±0.74) 4.16(±1.24) 7.65(±0.48) 0.996 0.44 346
8
9
10
11
12
Et OH 40.47(±1.13) –9.67(±1.32) 6.34(±2.22) 5.04(±0.86) 0.984 0.79 83
Et Me 41.79(±0.89) –8.06(±0.95) 3.57(±1.59) 6.96(±0.62) 0.993 0.57 187
Et MeO 39.96(±1.11) –9.14(±1.30) 6.94(±2.19) 5.53(±0.85) 0.986 0.78 92
Et Cl 41.49(±0.47) –6.13(±0.55) 1.98(±0.93) 6.45(±0.36) 0.997 0.33 409
Et Br 41.29(±0.40) –5.73(±0.47) 1.88(±0.79) 6.19(±0.31) 0.997 0.28 505
aCorrelation coefficient; bstandard error; cFisher’s test
Table V. Percentage contribution of the solvatochromic effects
No.
R
X
Pπ* / %
Pβ / %
Pα / %
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
H
OH
Me
MeO
Cl
Br
H
OH
Me
MeO
Cl
35.67
39.12
42.60
39.75
40.30
41.86
38.62
45.94
43.36
42.30
42.10
41.52
14.19
19.20
13.07
19.90
15.76
16.87
21.62
30.12
19.20
32.11
13.60
13.62
50.14
41.68
44.33
40.35
43.93
41.27
39.76
23.94
37.44
25.59
44.30
44.86
9
10
11
12
Et
Br
To investigate the importance of various types of interactions in determining
the anticonvulsant potencies of the investigated compounds, a multiple regression
approach was applied to analyze the factors which govern their ADME proper-
ties. ADME data, whether experimentally measured or computationally pre-
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634
HMUDA et al.
dicted, provide key insights into how a drug will ultimately be treated or accepted
by the body.
The evidence for solvent effects on the structure–property relationships of
the investigated molecules was first demonstrated by plotting the calculated
human intestinal absorption (HIA) values against the ratio a/|s| as a convenient
measure of the relative contributions of the dominant modes of solvation (Fig. 3).
The HIA values (Abs) calculated by the ChemSilico program are expressed as the
percentage of a drug absorbed by the intestine (Table I). The plot of the Abs
values versus a/|s| reveals that the molecules, where OH and MeO are attached to
the phenyl ring (2, 4, 8 and 10), behave differently and their intestinal absorption
percentages when compared to the others are somewhat lower. This can be ex-
pected, because these substituents may act as an additional site for hydrogen-
bonding with the surrounding solvent molecules.
Fig. 3. Correlation between the Abs values and the ratio of the contributions of the specific
and non-specific solvent–solute interactions (a/|s|).
The improved correlation, which includes all of the investigated molecules,
was derived through the additional inclusion of the resonance (σ ) and inductive
R
(σ ) constants of substituents in para position of the phenyl group (Eq. 2):
I
Abs = 98.05(±1.65) – 3.94(±1.38)a/|s| + 4.68(±1.28)σ +13.45(±2.02)σ (2)
I
R
(R = 0.928, S = 0.81, F = 16, n = 12)
It can be seen that Eq. (2) has a meaning similar to the corresponding model
25
of Abraham, when one realizes that the a and s coefficients refer to the hyd-
rogen bond basicity and dipolarity/polarizability of the investigated molecules,
respectively. The Abraham approach is based on the theoretical cavity model of
solvent–solute interactions and successfully correlates different physicochemical
26
properties of solutes. Eq. (2) shows that the hydrogen bond basicity of the
investigated molecules decreases intestinal absorption, whereas the dipolarity/po-
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STRUCTURE–PROPERTY RELATIONSHIP STUDY OF 5-ALKYL-5-ARYLHYDANTOINS
635
larizability enhances it. Generally, substituents on the phenyl ring at C5 exhibit
two opposing effects: the conjugative electron donation, which decreases drug in-
testinal absorption, and the inductive electron withdrawal, which acts in the op-
posite direction.
Furthermore, the same approach was applied in the analysis of factors that
determine octanol–water partitioning (log P) and protein binding affinity (k ).
A
The log P parameter, calculated with Advanced Chemistry Development (ACD)
software Solaris, v. 4.67 (Table I), is a solvational characteristic, since it is di-
rectly related to the change in the Gibbs energy of solvation of a drug between
27
octanol and water. The protein binding values (f , fraction bound) are given as
b
the percentage of the total plasma concentration of a drug that is bound to all
plasma proteins (Table I). Human serum albumin (HSA), the most abundant pro-
tein in blood plasma (concentration 0.53–0.75 mM), has multiple hydrophobic
28
binding sites and binds diverse drugs. The percentage data were converted into
an equivalent binding affinity k using the following formula (Eq. (3)) derived
A
from the mass law. k is the binding affinity to HSA under the assumption that
A
binding occurs exclusively to HSA, a binary complex is formed, and an excess of
albumin (concentration 0.6 mM, [HSA]) is present compared to the concentration
29
of the drug:
fb
[
]
− log HSA
log k = log
(3)
[
]
A
1− fb
[
]
Reasonable statistics were obtained for 10 compounds with the exclusion of
compounds 3 and 9 bearing substituents with electron-donating inductive effect
(Eqs. (4) and (5)):
log P = 2.56(±0.75) – 1.08(±0.58)a/|s| +2.34(±0.61)σ + 3.43(±0.84)σ (4)
I
R
(R = 0.907, S = 0.33, F = 9, n = 10)
log k = 3.88(±0.51) – 0.79(±0.40)a/|s| +3.60(±0.41)σ + 2.21(±0.57)σ (5)
A
I
R
(R = 0.965, S = 0.22, F = 27, n = 10)
Evidently, all equations ((2), (4) and (5)) show clear similarities. It should be
pointed out that parameters a/|s|, σ and σ are not normalized to each other, so
I
R
the regression coefficients in these equations do not provide adequate measures
of the relative contributions of the indicated types of solvent–solute interactions
and substituent effects to the analyzed ADME properties. On the other hand, they
all interpret the contribution of the hydrogen bond basicity and dipolarity/pola-
rizability to the lipophilicity and intestinal absorption of the investigated mole-
26,30
cules in the same manner as the Abraham models.
The obtained correlations
also suggest that the introduction of an electron-withdrawing substituent at the
para position of the phenyl group at C5 may produce derivatives with improved
pharmacokinetic properties.
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636
HMUDA et al.
CONCLUSIONS
The reasonable correlations of absorption maxima of 5-methyl-5-aryl- and 5-
ethyl-5-arylhydantoins with the solvent parameter set of Kamlet and Taft indi-
cated that the selected model interpreted their LSER correctly. In this case, where
both solvent and solute are hydrogen bond donors and acceptors, it was quite
difficult to quantitatively estimate and separate the overall solvent effect into the
contributions of specific and non-specific interactions. However, such a sepa-
ration provided further possibility to establish the structure–property relation-
ships of the investigated molecules. The obtained models represented how va-
rious types of interactions and electronic effects of substituents on the phenyl
ring at C5 influenced their biological partitioning and binding to plasma proteins.
The approach proposed in this work provided the means to analyze pharmaco-
kinetic properties of hydantoin derivatives, not yet pharmacologically tested,
which are difficult to determine experimentally.
SUPPLEMENTARY MATERIAL
Physical and spectral data for compounds 7–12 are available electronically from
http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgements. The authors acknowledge the financial support of the Ministry of
Education, Science and Technological Development of the Republic of Serbia (Project No.
172 013).
И З В О Д
УТИЦАЈ РАСТВАРАЧА НА АПСОРПЦИОНЕ СПЕКТРЕ ПОТЕНЦИЈАЛНО
ФАРМАКОЛОШКИ АКТИВНИХ 5-АЛКИЛ-5-АРИЛХИДАНТОИНА: ПРОУЧАВАЊЕ
ОДНОСА СТРУКТУРЕ И СВОЈСТАВА
SLEEM F. HMUDA, НЕБОЈША Р. БАЊАЦ, НЕМАЊА П. ТРИШОВИЋ, БОЈАН Ђ. БОЖИЋ,
НАТАША В. ВАЛЕНТИЋ и ГОРДАНА С. УШЋУМЛИЋ
Катедра за органску хемију, Технолошко–металуршки факултет, Универзитет у Београду,
Карнегијева 4, 11120 Београд
Да би се проценио начин на који потенцијални антиконвулзивни лекови интерагују
са својим окружењем, две серије 5-метил-5-(4-супституисаних фенил)- и 5-етил-5-(4-
супституисаних фенил)хидантоина су синтетисане и њихови апсорпциони спектри су
снимљени у интервалу таласних дужина од 200 до 400 nm у сету изабраних растварача.
Ефекти диполарности/поларизабилности растварача и водоничног везивања између мо-
лекула растварача и растворене супстанце на померање апсорпционих максимума ана-
лизирани су применом метода линеарне корелације енергије солватације (LSER), од-
носно Камлет–Тафтовом једначином. Однос доприноса специфичних и неспецифичних
интеракција између молекула растварача и растворене супстанце корелисани су са одго-
варајућим АДМЕ својствима проучаваних једињења. Корелационе једначине су даље
комбиноване са различитим физичко–хемијским параметрима при чему су добијене
нове једначине које на задовољавајући начин описују односе између интеракција између
молекула растварача и растворене супстанце и својстава која одређују њихову активност
у организму.
(Примљено 19. јула, ревидирано 22. октобра 2012)
Available online at www.shd.org.rs/JSCS/
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STRUCTURE–PROPERTY RELATIONSHIP STUDY OF 5-ALKYL-5-ARYLHYDANTOINS
637
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