Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82

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Journal of Molecular Structure: THEOCHEM

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Theoretical study of molecular structure, pKa, lipophilicity, solubility,

absorption, and polar surface area of some hypoglycemic agents
Milan Remko *
Comenius University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Odbojarov 10, SK-832 32 Bratislava, Slovakia

a r t i c l e i n f o a b s t r a c t

Article history: The methods of theoretical chemistry have been used to elucidate molecular properties of the
Received 14 November 2008 hypoglycemic sulfonylureas and glinides (acetohexamide, tofazamide, tolbutamide, chlorpropamide, gli-
Accepted 25 November 2008 clazide, glimepiride, glipizide, glibenclamide, nateglinide, and repaglinide). The geometries and energies
Available online 7 December 2008
of these drugs have been computed using HF/6-31G(d) and Becke3LYP/6-31G(d) methods. The equilib-
rium structure of the sulfonylureas investigated in the isolated state is determined by the formation of
Keywords: suitable intramolecular hydrogen bonds within the sulfonamide moiety. This specific interaction gives
Sulfonylureas and glinides
rise to the unique overall shape of individual drug conformers. Values of these dihedral angles for indi-
Molecular structure
Solvent effect
vidual drugs are different. Generally, the ab initio SCF and DFT optimized structures in the gas phase fit
Physicochemical properties well one another. Water has a remarkable effect on the geometry of the drugs studied. The pKa values of
Absorption sulfonylurea moiety are in the range of 5.2–6.2 and these drugs are characterized as weak organic acids.
Repaglinide and nateglinide are oral blood glucose-lowering drugs of the glinide class containing acidic
carboxylic group. The pKa values of this carboxylic acid moiety are in the range of 3.5–4.0. Computed par-
tition coefficients (XLOGP2 method) for drugs studied varied between 1.8 and 5.9. Thus these compounds
are described as lipophilic drugs. Although the sulfonylurea and glinidine derivatives studied are only
slightly soluble in water, their computed solubilities from interval between 0.001 and 4 g/L are sufficient
for fast adsorption.
Ó 2008 Elsevier B.V. All rights reserved.

1. Introduction varying cross-reactivity with related channels in extrapancreatic

Diabetes is characterized by disrupted insulin production and
sensitivity, leading to high blood glucose and a series of complica-
tions, such as retinopathy, nephropathy, neuropathy and cardio-
vascular disease [1–3]. Sulfonylureas and glinides are effective in
the treatment of non-insulin dependent diabetes mellitus (NDDIM)
[1–4]. It affects about 3–5% of western populations and its preva-
lence continues to rise [4]. This diabetes of type 2 characterizes
both tissue insulin resistance and an insulin secretory deficit
[5,6]. Sulfonylureas have been used as hypoglycemic agents since
the mid-1950s, and for many years this class of drugs has been
one of the mainstays of oral antidiabetic therapy. Compounds in
the first generation of this class such as acetohexamide, chlorprop-
amide, tolbutamide and tolazamide are still in use, but are less
potent than the more recently introduced second-generation drugs
like gliclazide, glimepiride, glipizide and glibenclamide. Glinides,
e.g. nateglinide, and repaglinide represent newer group of hypogly-
cemic agents. Both groups of hypoglycemic agents (sulfonylureas
and glinides) stimulate insulin secretion by closing ATP-sensitive
potassium (KATP) channels in pancreatic beta cells, but have
* Tel.: +421 2 50117225; fax: +421 2 50117100.
E-mail address: remko@fpharm.uniba.sk
tissues such as heart, vascular smooth and skeletal muscle [7]. As
newer oral diabetes agents continue to emerge on the market,
comparative evidence is required to guide appropriate therapy.
Although not all sulfonylureas and glinides have been studied in
randomized controlled trials, they are invariably used in practice
assuming, probably, a class effect of these pharmacons [8]. A class
effect implies that all drugs in a class exert the same effects,
whether positive or negative, on their target population [9]. E.g.
the results of the UK Prospective Diabetes Study [10] showed a
clear risk reduction for the occurrence of microvascular complica-
tions by the use of sulfonylurea derivatives, while the risk
reduction of macrovascular disease was about 16% [11]. Antihyper-
tensive therapy diminished the risk of macrovascular complica-
tions by around 20% [11]. Combined management with both
sulfonylurea derivatives and antihypertensives improves the risk
reduction even more [11,12]. The first generation of sulfonylureas
is still in use, but are less potent than the more recently introduced
second-generation drugs like gliclazide, glimepiride, glipizide and
glibenclamide [1,4,8,9]. Glinides (e.g. nateglinide, and repaglinide)
have a shorter action than sulfonylurea derivatives, are therefore
associated with lower risk of hypoglycemia, and can also be used
in patients with decreased renal function [13]. Some of the differ-
ent pharmacological and adverse effects exerted by sulfonylureas

0166-1280/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.theochem.2008.11.021
74 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82
and glinides may depend on the different physico-chemical (solu-
bility, lipophilicity and acidity), pharmacokinetic (absorption,
protein binding, half-life and metabolic disposition) properties
but also in their ability to penetrate and to bind tissue sites [10,11].
Despite a great deal of experimental evidence for the relation-
ship between the chemical and biochemical properties of sulfo-
nylureas and glinides and their biological activity, there is no
single experimental study concerned with the systematic com-
parative experimental investigation of the physico-chemical
and pharmacokinetic parameters of medicinally used sulfonylu-
reas and glinides. The absence of experimental data of sulfonyl-
ureas and glinides presents a challenge to the application of
computational modeling techniques in order to enhance our
understanding of the subtle biological effects of sulfonylureas
and glinides. In this paper, we have used the results of large-
scale theoretical calculations for the study of the molecular
structure, pKa, lipophilicity, solubility, absorption, and polar sur-
face area of sulfonylureas and glinides (acetohexamide, tofaza-
mide, tolbutamide, chlorpropamide, gliclazide, glimepiride,
glipizide, glibenclamide, nateglinide, and repaglinide). The results
of theoretical studies of these drugs were compared with the
available experimental data and discussed in relation to the
present theories of action of these agents.
2. Computational details
Ab initio calculations of the acetohexamide, tofazamide, tolbuta-
mide, chlorpropamide, gliclazide, glimepiride, glipizide, glibencla-
mide, nateglinide, and repaglinide (Fig. 1) were carried out with
the Gaussian 03 computer code [14] at the ab initio SCF (HF [15])
and density functional theory (DFT, Becke3LYP [16–20]) levels of
theory using the 6-31G(d) basis set. In order to evaluate the confor-
mational behavior of these systems in solvent, we carried out opti-
mization calculations in the presence of water. The methodology
used in this work is centered on two solvation methods, CPCM
[21,22] and Onsager [23] models. The structures of all gas-phase
species were fully optimized at the HF/6-31G(d) and Becke3LYP/
6-31G(d) levels of theory without any geometrical constraint. In
order to check the correctness of the B3LYP calculated geometries
using the double-f basis set, we also performed calculations of the
sulfonylurea species, using the basis set of the triple-f quality
(B3LYP/6-31++G(d,p) level of theory) implemented in the Gaussian
03 package of computer codes [14,15]. The structures of all con-
densed-phase (SCRF) species were fully optimized without any
geometrical constraint at the B3LYP/6-31G(d) level of theory.
The calculations of the macroscopic pKa of sulfonylureas and
glinides investigated were performed using the program AB/pKa
module of the Pharma Algorithms [24]. Lipophilicity and water
solubility calculations were carried out using web-based VCCLAB
[25–27]. For calculations of molecular polar surface areas the frag-
ment-based method of Ertl and coworkers [28,29] incorporated in
the Molinspiration Cheminformatics software [30] was used.
3. Results and discussion
3.1. Molecular structures
Conformational search using theoretical methods for such large
systems was in the past limited to use some of the available force-
field methods [31]. It is common in the computational study of
drugs to use structural data obtained from X-ray crystallography
or NMR spectroscopy as guides to the quality of theoretical compu-
tations. Initial conformations to use in the theoretical calculations
of the sulfonylureas and glinides studied were constructed by
means of the Gauss View graphical interface of Gaussian. The rela-
tive orientation of sulfonylurea moiety defined by five dihedral
angles (a, b, c, d, and e, Fig. 1) at the sulfonylurea linkage was taken
from the experimental data for available X-ray data of chlorprop-
amide [32], gliclazide [33], glimepiride [34], and glipizide [35].
An analysis of the harmonic vibrational frequencies at the HF level
of theory of the optimized species revealed that all the structures
obtained were minima (no imaginary frequencies). The Cartesian
coordinates (Å) of all gas-phase oligomers investigated, optimized
at the B3LYP/6-31G(d) level of theory, are given in Table A of the
electronic Supporting Information. In order to check the correct-
ness of the B3LYP calculated structures using the double-f basis
set, we also performed full geometry optimization of the chlor-
propamide, Table A of the Supporting Information, using the basis
set of the triple-f quality (B3LYP/6-31++G(d,p) level of theory).
Examination of the space models of the B3LYP computed struc-
tures using two basis sets of this drug shows that the increase of
the basis set gives essentially the same results. The effect of bulk
solvent is treated with two solvation methods (the Onsager [23]
and CPCM [22]) for comparison. Initial calculations were carried
out, for computational reasons, using the SCRF formalism of Wong
et al. [36–39]. The radii of the cavities used in this approach were
chosen after a volume calculation of each molecule, and the dielec-
tric constant of water (e = 78.5) was used. The placing of the iso-
lated molecules into a spherical cavity within a dielectric
medium of the Onsager model of solvation does not represent
the realistic situation in the biological medium; it seems helpful
in revealing the main role of the solvent in intermolecular electro-
static interactions. The second, CPCM (conductor-like polarizable
model), defines the cavity by the envelope of spheres centered
on the atoms or the atomic groups [22].
According to the recent high-level ab initio calculations [40,41]
of the structurally related sulfonamides, these compounds exist in
two stable forms. The basic difference between these two struc-
tures arises from the arrangement of –NH2 group syn or anti with
respect to the –SO2 group. The syn isomer of the substituted
sulfonamide derivatives was found to be the most stable structure
[40]. Thus, the calculations of sulfonylurea drugs studied were car-
ried out for syn structures of the sulfonamide moiety only. Impor-
tant geometrical parameters of the sulfonylurea linkage are given
in Tables 1 and 2. Some trends are apparent: (i) there are no major
differences between the HF/6-31G(d) and B3LYP/6-31G(d) geome-
tries. B3LYP geometries, as expected, have bond lengths 0.03 Å
longer. (ii) The S–N bond length in sulfonylureas (1.70 Å) is
shorter than the S–N single bond distance 1.75 Å [42]. (iii) The
valence bond angles of the sulfonylurea grouping are within a ser-
ies of drugs studied almost the same. Exceptions are tofazamide
and glimepiride. The valence angle S(3)–N(4)–C(5) is by about
10° longer that angle in the rest of the drugs studied (Table 1).
(iv) Comparison of the B3LYP structures of chlorpropamide com-
puted using two basis sets shows that the increase of the basis
set gives essentially the same geometries (Tables 1 and 2). Thus,
for purposes of determining reasonable geometries of large sys-
tems the B3LYP/6-31G(d) should be considered the method of
choice.
The sulfonylurea drugs studied possess the same aryl-sulfonyl-
urea functionality. In these structures the relative molecular orienta-
tion is described by five dihedral angles at the sulfonylurea linkage,
denoted a, b, c, d, and e. These dihedral angles of the fully optimized
sulfonylurea drugs are given in Table 2. The equilibrium structure of
the sulfonylureas investigated in the isolated state is determined by
the formation of suitable intramolecular hydrogen bonds within the
sulfonamide moiety. This specific interaction gives rise to the unique
overall shape of individual drug conformers (Fig. 2), and is mani-
fested by the computed values of the a, b, c, d, and e dihedral angles
of the sulfonylurea linkage. Values of these dihedral angles for
individual drugs are different (Table 2). However, some general con-
 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82 75

O O 9 O 10 O O
S H3C S
2 O7 O
3 4
H3C N N
1 5 H
H 6
N 8 N N
H H

Acetazolamide Tofazamide
O O O O
H3C S Cl S
O O
N N
H H CH3
N CH3 N
H H
Tolbutamide Chlorpropamide
O O
H3C S O
N
H
H3C N N
Gliclazide H
H
N O O
N
S O
H3C O
O N
H
Glimepiride N CH3
H
H3C N H
N O O
N S O
O
N
H
Glipizide
Cl N
H
H
N O O
S O
O
N
O H
Glibenclamide N
H3C
H

H3C O HO
O
H3C N
H3C N
H H
O N

HO O CH3

O CH3
Repaglinide Nateglinide

Fig. 1. Structure and atom labeling in the hypoglycemic drugs studied.

clusions about aryl-sulfonylurea functionality can be deduced. The
C(2)–S(3) bond length of about 1.79 Å (DFT method) is a single bond
length between the sp2 hybridized carbon atom and sulfur because
the sulfonamide group and aromatic rings are approximately per-
pendicular (dihedral angle a[C(1)–C(2)–S(3)–N(4)]). On the other
hand, the dihedral angles b, c, d, and e change considerably upon sub-
stitution. Generally, the ab initio SCF and DFT optimized structures in
the gas phase fit well one another (within 5°).
Water has a remarkable effect on the geometry of the title drugs
studied. Table 3 shows the results obtained for calculations per-
formed in both, vacuum and that based on the solvation method.
According to Table 3, the hypoglycemic agents exhibit the largest
stability in solvent as expected, since they hold considerable dipole
moment (Table 3). The larger dipole moments of the second-gener-
ation drugs like gliclazide, glimepiride, glipizide and glibenclamide
provide an additional stabilization in the solvent media when com-
pared to those of the others. The energy difference between gas
phase and solvated phase was significant for the two solvation
models employed in this work. The CPCM provided substantially
more stable structures than Onsager’s model (Table 3).
In the absence of gas-phase data, the geometry of the parent
sulfonylureas only can be compared with available published X-
ray data of the drugs studied. Although both methods are based
on different models, the computed geometry for sulfonylureas
(Table 2) is in good agreement with the experimentally determined
X-ray structures of these compounds. Sulfonamides exhibit inter-
76 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82

Table 1
Optimized relevant bond lengths (Å), and bond angles (degrees) of the sulfonylurea drugs studied.
Parametera Acetohexamide Tofazamide Tolbutamide Chlorpropamide
HF DFT DFT HF DFT DFT HF DFT DFT HF DFT DFT DFT
CPCM CPCM CPCM High levelb CPCM
d[C(2)–S(3)] 1.769 1.795 1.794 1.764 1.791 1.783 1.764 1.791 1.786 1.763 1.788 1.791 1.786
d[S(3)–O(9)] 1.430 1.465 1.469 1.426 1.461 1.467 1.427 1.462 1.469 1.422 1.457 1.458 1.465
d[S(3)–O(10)] 1.420 1.455 1.464 1.431 1.468 1.470 1.425 1.461 1.466 1.430 1.465 1.468 1.468
d[S(3)–N(4)] 1.659 1.703 1.683 1.650 1.695 1.691 1.667 1.722 1.709 1.665 1.716 1.713 1.686
d[N(4)–C(5)] 1.392 1.409 1.416 1.408 1.429 1.423 1.415 1.434 1.441 1.392 1.409 1.408 1.410
d[C(5)–N(6)] 1.353 1.371 1.353 1.354 1.369 1.362 1.351 1.366 1.352 1.349 1.371 1.367 1.353
d[C(5)–O(7)] 1.195 1.220 1.230 1.190 1.214 1.223 1.196 1.221 1.228 1.197 1.221 1.223 1.230
d[N(6)–X(8)] 1.460 1.467 1.466 1.383 1.395 1.399 1.464 1.470 1.468 1.455 1.461 1.462 1.459
d[N(4)–H] 0.997 1.013 1.032 0.999 1.015 1.033 1.001 1.018 1.034 0.998 1.016 1.014 1.032
d[N(6)–H] 0.996 1.013 1.026 1.001 1.021 1.022 0.998 1.014 1.026 0.994 1.011 1.009 1.023
H[C(2)–S(3)–O(9)] 108.3 108.1 108.2 108.4 108.2 109.0 108.6 108.5 109.1 108.6 108.7 108.8 108.3
H[C(2)–S(3)–O(10)] 108.5 108.4 108.4 107.9 107.7 108.4 108.0 107.9 108.2 108.8 108.8 108.7 108.6
H[C(2)–S(3)–N(4)] 106.3 106.1 107.2 106.7 106.8 107.4 106.2 106.1 107.0 105.4 104.0 104.6 105.4
H[S(3)–N(4)–C(5)] 125.5 125.2 123.1 131.2 130.4 129.1 125.4 123.9 121.7 124.6 123.0 123.8 123.0
H[N(4)–C(5)–N(6)] 113.2 112.8 113.1 114.7 114.0 115.4 116.8 116.0 116.2 113.9 113.6 114.0 113.4
H[N(4)–C(5)–O(7)] 121.7 122.4 121.4 118.5 118.9 118.4 119.2 119.9 119.5 121.5 122.2 121.7 121.4
H[C(5)–N(6)–X(8)] 121.2 120.6 122.1 118.6 118.7 119.0 126.8 126.9 128.0 121.6 120.4 121.6 122.0

Parametera Gliclazide Glimepiride Glipizide Glibenclamide

HF DFT DFT HF DFT DFT HF DFT DFT HF DFT DFT
CPCM CPCM CPCM CPCM
d[C(2)–S(3)] 1.761 1.787 1.781 1.765 1.791 1.785 1.763 1.789 1.785 1.762 1.789 1.785
d[S(3)–O(9)] 1.423 1.459 1.466 1.431 1.468 1.470 1.432 1.465 1.470 1.432 1.466 1.471
d[S(3)–O(10)] 1.431 1.465 1.469 1.425 1.461 1.467 1.422 1.456 1.465 1.422 1.456 1.466
d[S(3)–N(4)] 1.661 1.704 1.683 1.649 1.694 1.692 1.662 1.707 1.690 1.663 1.707 1.686
d[N(4)–C(5)] 1.377 1.391 1.396 1.407 1.428 1.429 1.391 1.407 1.416 1.391 1.407 1.411
d[C(5)–N(6)] 1.364 1.387 1.368 1.343 1.357 1.349 1.354 1.374 1.353 1.356 1.374 1.356
d[C(5)–O(7)] 1.195 1.219 1.228 1.197 1.221 1.229 1.196 1.221 1.230 1.196 1.220 1.231
d[N(6)–X(8)] 1.381 1.399 1.402 1.457 1.464 1.467 1.459 1.465 1.465 1.459 1.467 1.466
d[N(4)–H] 0.999 1.017 1.034 0.999 1.015 1.032 0.997 1.014 1.033 0.997 1.014 1.031
d[N(6)–H] 1.001 1.020 1.038 0.997 1.015 1.018 0.996 1.013 1.025 0.996 1.013 1.025
H[C(2)–S(3)–O(9)] 108.7 108.7 108.2 107.9 107.9 108.3 108.5 108.3 108.5 108.5 108.3 108.5
H[C(2)–S(3)–O(10)] 108.9 109.0 108.3 108.3 108.0 109.0 108.8 108.7 108.9 108.8 108.7 108.6
H[C(2)–S(3)–N(4)] 105.8 104.4 106.0 106.7 106.7 107.3 106.7 106.5 107.5 106.7 106.5 107.6
H[S(3)–N(4)–C(5)] 125.3 124.7 124.0 130.9 130.0 127.1 125.3 125.1 122.7 125.6 125.1 123.7
H[N(4)–C(5)–N(6)] 113.9 112.8 113.6 116.3 115.7 116.0 113.2 112.8 113.1 113.2 112.7 113.2
H[N(4)–C(5)–O(7)] 123.8 124.9 123.3 118.1 118.4 118.3 122.0 122.7 121.4 122.0 122.7 121.5
H[C(5)–N(6)–X(8)] 121.9 121.1 121.2 121.0 120.9 121.9 121.2 120.3 122.7 121.2 120.4 121.8
a
X = N, C.
b
Becke3LYP/6-31++G(d,p) method.

esting solid-state properties, among which is the ability for many
of these compounds and their derivatives to exist in two or more
polymorphic forms [43,44]. The solid-state properties of these
compounds are influenced by their propensity for hydrogen bond-
ing [45,46], which can give rise to polymorphism. Because the
geometries of the sulfonamides in the crystalline phase are con-
trolled by intermolecular hydrogen bonds, they are not exactly
comparable with those of the free molecules.
3.1.1. Acetohexamide
Optimized molecular conformation of acetohexamide at the
B3LYP level of the DFT theory (Fig. 2) is stabilized by means of
the intramolecular hydrogen bond of the S@O


H–N type with
the length 2.458 Å which is less than the sum of the van der Waals
radii [47] of hydrogen and oxygen atoms (2.7 Å). The cyclohexane
ring exists in a chair conformation. The calculated aryl-sulfonyl-
urea geometry of acetohexamide in H2O is quite different. The dif-
ference in dihedral angles b[C(2)–S(3)–N(4)–C(5)], c[S(3)–N(4)–
C(5)–N(6)] and d[S(3)–N(4)–C(5)–O(7)] can be as large as 15°
(Table 2). Stephenson et al. [48] investigated solid-state tautomer-
ism of acetohexamide. On the basis of X-ray data and solid-state
NMR spectroscopy this drug in solid state may exist in two poly-
morphic (A and B) keto-forms [48]. The form A of acetohexamide
is in the crystal structure stabilized by means of network of inter-
molecular hydrogen bonds of the S@O


H–N and C@O


H–N types
formed by proton acceptor and proton donor (N–H) groups of two
neighboring molecules.
3.1.2. Tofazamide
Gas-phase geometry of tofazamide is stabilized via intramolec-
ular hydrogen bonding system of the S@O


H–N and C@O


H–N
types (Fig. 2). The aryl-sulfonylurea geometry is, on the contrary
to the acetohydroxamide, stabilized through the short N(6)–
H


O@S interaction with length of 2.08 Å. The optimal bond
lengths, bond angles, and dihedral angles of tofazamide computed
with the self-consistent reaction field methods and solvent water
do not considerably differ from those obtained for isolated mole-
cule (Tables 1 and 2).
3.1.3. Tolbutamide
The 3D structure of fully optimized tolbutamide is stabilized by
the system of intramolecular hydrogen bonds within the sulfon-
amide moiety. Of the three hydrogen bonds, two are bifurcated
hydrogen bonds of the sulfonamide N–H group (Fig. 2). Optimized
geometry of tolbutamide in water solution changed only slightly.
3.1.4. Chlorpropamide
Chlorpropamide may exist in several polymorphs [49]. As a
starting geometry for ab initio calculations we used X-ray structure
of recently discovered new polymorph of this drug (ß-chlorprop-
 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82 77

Table 2
Optimized dihedral anglesa of the drugs studied.

No Drug Method a[C(1)–C(2)–S(3)– b[C(2)–S(3)–N(4)– c[S(3)–N(4)–C(5)– d[S(3)–N(4)–C(5)– e[N(4)–C(5)–N(6)–

N(4)] C(5)] N(6)] O(7)] X(8)]b
1 Acetohexamide HF 90.2 68.2 169.8 12.2 176.1
DFT 83.4 66.8 173.8 8.2 175.1
DFT–Onsager 92.5 59.8 177.2 1.6 176.0
DFT–CPCM 95.5 59.7 174.4 5.2 173.9
2 Tofazamide HF 98.5 69.8 22.1 158.2 175.4
DFT 92.9 69.5 25.1 155.5 174.3
DFT–Onsager 95.4 67.6 24.7 156.2 176.4
DFT–CPCM 100.9 64.7 27.7 153.2 176.9
3 Tolbutamide HF 95.1 50.8 58.5 121.2 36.5
DFT 90.9 47.9 62.5 117.5 33.6
DFT–Onsager 99.8 37.5 60.3 119.4 34.6
DFT–CPCM 96.5 47.6 68.8 111.4 27.5
4 Chlorpropamide X-ray 75.7 62.9 168.8 10.3 178.6
HF 89.5 70.5 166.6 14.2 174.5
DFT 96.3 75.1 162.4 18.2 170.5
DFT–High level 93.4 74.4 160.2 20.8 172.4
DFT–Onsager 97.8 72.4 168.0 12.1 171.2
DFT–CPCM 97.5 74.2 165.6 14.6 172.2
5 Gliclazide X-ray 86.1 69.2 171.7 11.2 19.8
HF 90.3 69.7 170.6 12.0 15.3
DFT 97.2 74.2 166.5 17.0 18.2
DFT–Onsager 94.8 60.3 169.0 13.0 17.5
DFT–CPCM 94.1 71.4 170.5 12.7 14.6
6 Glimepiride X-ray 93.3 94.7 6.2 174.2 170.8
HF 94.8 73.2 21.0 159.1 174.9
DFT 86.0 73.6 24.8 156.0 173.6
DFT–Onsager 88.5 74.0 21.7 159.3 175.3
DFT–CPCM 103.2 62.6 34.2 146.9 177.1
7 Glipizide X-ray 94.5 67.0 163.8 5.9 173.8
HF 90.2 67.5 170.8 11.1 175.7
DFT 84.2 65.8 174.1 7.6 174.3
DFT–Onsager 90.6 57.3 168.3 11.0 176.6
DFT–CPCM 97.9 58.3 169.0 11.1 174.4
8 Glibenclamide HF 90.5 67.6 170.6 11.3 175.6
DFT 85.2 65.5 174.0 7.7 174.6
DFT–Onsager 87.8 58.7 172.0 7.1 176.9
DFT–CPCM 95.1 62.7 176.6 2.9 172.1
a
For definition of dihedral angles see Fig. 1.
b
X = C, N.

amide) [32]. The equilibrium geometry of this compound is stabi-
lized by means of intramolecular hydrogen bond of the S@O


H–N
type (Fig. 2). This hydrogen bond is also preserved in crystal. The
main difference between calculated and experimental structures
is in the relative orientation of the aromatic ring and the sulfonyl-
urea moieties. For this difference the pattern of intermolecular
hydrogen bonds in the ß-polymorph is mainly responsible. Upon
hydration the structure of the sulfonylurea chain of chlorprop-
amide does not change importantly (Table 2).
3.1.5. Gliclazide
The B3LYP optimized structure of gliclazide is stabilized by the
system of three hydrogen bonds (Fig. 2). An additional basic nitro-
gen of the perhydrocyclopenta[c]pyrrole group is linked with the
sulfonamide –NH group by the N


H–N hydrogen bond with the
length of 2.217 Å. This interaction was also observed experimen-
tally [33] with slightly greater bond length of 2.335 Å. The fused
five-membered rings of the perhydrocyclopenta[c]pyrrole moiety
adopt envelope conformation. The computed dihedral angles of
the flexible aryl-sulfonylurea functionality using two theoretical
methods are in very good agreement with the experimental so-
lid-state geometric parameters of the fully extended conformation
of gliclazide. The suitable orientation of the flexible aryl-sulfonyl-
urea moiety of gliclazide is particularly important for the mode
of action of gliclazide. The action of gliclazide is mediated through
its calcium transportation across the membrane of the beta cell
[31]. Release of insulin evoked by oral hypoglycemic sulfonylureas
is due to the accumulation of calcium in the pancreatic beta cell.
The complexation of calcium dication by two molecules of glicla-
zide is only possible when the gliclazide molecule is fully extended
[31] (Fig. 2). Therefore the computed extended structure of glicla-
zide will represent the biologically active conformation. Since in
water solution its gas-phase molecular structure changes only
slightly, the fully extended conformation of gliclazide will also be
present in water (Table 2).
3.1.6. Glimepiride
The B3LYP optimized structure of glimepiride is shown in Fig. 2.
The bond lengths and bond angles of the sulfonylurea moiety (Table
1) are in agreement with values computed for other sulfonylureas
studied. Optimized structure is stabilized by means of three intra-
molecular hydrogen bonds (Fig. 2). The S@O


H–N(C8) hydrogen
bond with bond length 2.043 Å stabilizes a unique conformation of
aryl-sulfonylurea moiety. This hydrogen bonding system is also
present in the solid state [34]. However, the difference in dihedral
angles b[C(2)–S(3)–N(4)–C(5)], c[S(3)–N(4)–C(5)–N(6)] and
d[S(3)–N(4)–C(5)–O(7)] between solid-state conformation and
gas-phase can be as large as 20° (Table 2). The molecular conforma-
tion of glimepiride in water is considerably different to those ob-
served in crystal. The difference in dihedral angles b[C(2)–S(3)–
N(4)–C(5)], c[S(3)–N(4)–C(5)–N(6)] and d[S(3)–N(4)–C(5)–O(7)]
can be as large as 30° (Table 2).
3.1.7. Glipizide
The molecular structure of glipizide optimized at the B3LYP
level of theory is stabilized by means of weak intramolecular
78 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82

Fig. 2. B3LYP/6-31G(d) optimized structures of the hypoglycemic drugs investigated.

Table 3
The Becke3LYP/6-31G(d) solvent stability of the hypoglycemic agents investigateda.

No. Drug DEc DE c Gas-phase dipole momentd

Cavity valueb (a0) Onsager CPCM
1 Acetohexamide 5.02 12.8 96.3 6.01
2 Tofazamide 5.27 6.6 66.1 4.88
3 Tolbutamide 5.08 4.7 72.8 3.79
4 Chlorpropamide 4.82 9.6 89.9 5.28
5 Gliclazide 5.23 14.0 80.9 5.63
6 Glimepiride 6.17 11.3 95.2 7.86
7 Glipizide 5.72 12.8 142.2 6.59
8 Glibenclamide 5.85 14.4 134.9 8.07
9 Repaglinide 6.15 0.9 80.5 1.84
10 Nateglinide 5.60 1.1 77.9 2.26
a
water as solvent.
b
Ångström (Å).
c
kJ/mol.
d
Debye (D).

hydrogen bond of the S@O


H–N type (Fig. 2). Comparison with
the X-ray structure [35] shows large difference between gas-
phase and solid state structures, especially in the sulfonylurea–
cyclohexane moiety (dihedral angles c[S(3)–N(4)–C(5)–N(6)],
d[S(3)–N(4)–C(5)–O(7), and e[N(4)–C(5)–N(6)–C(8)]) and the 5-
methylpyrazine substituent of the amido linker. Hydration
caused appreciable geometry changes in the overall structure
of glipizide (Table 2).
3.1.8. Glibenclamide
The molecular structure of glibenclamide differs from glipizide
just in the kind of the substituent of the amido linker. The 5-methyl-
pyrazine is in glibenclamide substituted by 5-chloro-2-methoxy-
benzene (Fig. 2). In both, gas-phase and in water solution,
aryl-sulfonylurea part of these two drugs possesses almost the same
conformation (Table 2). The 3D structure is stabilized by means of
weak intramolecular hydrogen bond of the S@O


H–N type (Fig. 2).
 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82 79

Table 4
Experimental and the AB/pKa calculated pKa values of the hypoglycemic agents
investigated.

No. Drug pKa, exp pKa, % Ionized form % Ionized form

calc (exp) (calc)
1 Acetohexamide 5.60 98.4
2 Tofazamide 5.60 98.4
a b
3 Tolbutamide 5.3 ; 5.16 5.20 99.2; 99.4 99.4
4 Chlorpropamide 4.60 99.8
5 Gliclazide 5.8c 5.60 97.5 98.4
6 Glimepiride 6.2d 5.20 94.1 99.4
7 Glipizide 5.9d 5.20 96.9 99.4
8 Glibenclamide 6.8a; 6.0d 5.20 79.9; 96.2 99.4
9 Repaglinide 3.96e 3.80 100 99.9
10 Nateglinide 3.50 99.9
a
Ref. [51].
b
Ref. [52].
c
Ref. [31].
d
Ref. [53].
e
Ref. [54].
Fig. 3. A molecular superimposition of the minimum energy conformations of the
repaglinide (blue) and in solution optimized repaglinide (green).(For interpretation with pK expa as the independent variable the following regression
of color mentioned in this figure legend, the reader is referred to the web version of equation was obtained:
the article.)
pK exp
a = 1.178 pK calc
a + 0.893, (n = 6, R2 = 0.7990). The pKa values
of sulfonylurea moiety in the hypoglycemic drugs studied are in
3.1.9. Repaglinide and nateglinide the range of 5.2–6.2 and are characterized, like parent sulfona-
Repaglinide and nateglinide are two short-acting glinide insulin mides [55,56], as weak organic acids. However, at physiological
secretagogues. Repaglinide is most active representative of a series pH 7.4 sulfonylamide group of these drugs is completely ionized.
of these novel hypoglycemic benzoic acid derivatives [1]. The Repaglinide and nateglinide are oral blood glucose-lowering drugs
B3LYP optimized structure of this drug is shown in Fig. 2. Solvent of the glinide class containing acidic carboxylic group. The pKa val-
(water) treated within the self-consistent CPCM method apprecia- ues of this carboxylic acid moiety in the glinide drugs studied are
bly changes its conformation (Fig. 3). The stable conformation of in the range of 3.5–4.0. At physiological pH 7.4 this group is com-
the structurally related nateglinide is in the gas-phase stabilized pletely ionized. Aromatic amino group of repaglinide is weakly
through intramolecular hydrogen bond of the N–H


O type basic with experimental pKa value of 6.20 [54]. Our calculated
(Fig. 2). This hydrogen bond is also present in solvated nateglinide. AB/pKa value of 6.40 is in good agreement with the experimental
The solvent does not considerably change its computed gas-phase one. Both sulfonylurea and glinide drugs stimulate insulin secre-
equilibrium geometry. Tessler and Goldberg have been investi- tion by closing ATP-sensitive potassium (KATP) channels in pancre-
gated crystal and molecular structure of bis(nateglinide) hydro- atic beta cells [7,57]. The receptor site (SUR1) is located at the
nium chloride [50]. In the crystal the asymmetric unit of this cytoplasmic face of the plasma membrane and interacts with the
drug forms hydrogen bonded carboxylic acid dimmers and final anionic (dissociated) forms of sulfonylureas and analogues [58].
hexameric aggregate is further interlinked via N–H


Cl, O–H


Cl The acidity (or basicity) of a drug can influence its bioavailabil-
and O–H


O (hydroxonium ion) hydrogen bonds [50]. However, ity. Yoshida and Topliss [59] find that Brønsted acids have a better
due to the crystal packing forces and the coordination of nategli- oral bioavailability than neutral species, and that Brønsted bases
nide with hydrated hydrochloric acid, the solid state and DFT opti- have lower bioavailability than neutral species. It is further shown
mized structures of this drug are different. It is therefore probable that for strong Brønsted acids and bases, the rate constant for
that upon binding of this drug on its receptor the ‘‘active conforma- absorption of ionic species is close to that for absorption of the cor-
tion” will be closer to those computed by us in water solution. responding neutral species, so that to a first approximation the
percentage of internal absorption can be calculated from the prop-
3.2. Dissociation constants erties of neutral species [60]. However, human bioavailability of a
drug influence is determined by additional physico-chemical
Dissociation plays an important role in both partition and parameters (lipophilicity, solubility, molecular weight, counts of
receptor binding processes of drug action. It is therefore, important hydrogen bond acceptors and donors in molecule. . .). These param-
to know if drug molecules exist predominantly in the basic or eters serve as important molecular predictors [60] of good oral bio-
protonated forms. Acetohexamide, tofazamide, tolbutamide, chlor- availability. Thus computed and/or experimentally determined
propamide, gliclazide, glimepiride, glipizide, glibenclamide, nate- physico-chemical parameters of clinically useful sulfonylurea and
glinide, and repaglinide contain an acidic function (N–H group of glinide drugs represent a yardstick for the design of new com-
the sulfonamide moiety and/or COOH group, respectively) and pounds with improved pharmacological activity and pharmacoki-
are classified as weak acids. Repaglinide possesses also one weakly netic profiles.
basic group resulting in the ampholitic nature of the molecule in
the aqueous solution. In solution dissociation constant or the pKa 3.3. Lipophilicity
is a measure of the strength of an acid or a base. Therefore this
parameter is very useful in understanding the behavior of drug Poor solubility and poor permeability are among the main
molecules at the site of action. We used the pKa’s predictor imple- causes for failure during drug development [61–63]. It is therefore,
mented in the software AB/pKa [24] to compute the theoretical pKa important to determine these physico-chemical properties associ-
values of studied drugs in condensed-phase (water). The calculated ated with a drug, before synthetic work is undertaken. The com-
macroscopic pKa values are listed in Table 4. The computed pKa val- puted log P values (P is the partition coefficient of the molecule
ues correlate well with the available experimental pKa values in the water–octanol system), together with the experimental data,
found in the literature [31,51–54]. Using the regression analysis are shown in Table 5. The ALOGPS method is part of the ALOGPS
80 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82

Table 5 Table 6
Calculated partition coefficients of the hypoglycemic agents investigated. Calculated solubilities of the hypoglycemic agents studied.

No. Drug Log Pa (exp.) ALOGPS KoWWIN XLOGP2 No. Drug Solubilitya (exp.) Log S (exp.) ALOGPS
1 Acetohexamide 2.7 1.72 2.44 2.71 1 Acetohexamide 3430 mg/L 2.06 3.83 (48.3 mg/L)
2 Tofazamide 1.40 2.23 2.48 2 Tofazamide 3.01 (0.31 g/L)
3 Tolbutamide 2.2 2.04 2.41 2.18 3 Tolbutamide 109 mg/L 3.39 3.13 (0.20 g/L)
4 Chlorpropamide 1.8 2.15 2.01 1.80 4 Chlorpropamide 2.2 g/L 3.03 3.25 (0.16 g/L)
5 Gliclazide 2.6 1.52 2.12 2.59 5 Gliclazide 3.23 (0.19 g/L)
6 Glimepiride 3.5 2.09 4.21 2.65 6 Glimepiride 3.99 (48.6 mg/L)
7 Glipizide 2.5 1.83 3.35 2.53 7 Glipizide 37.2 mg/L 4.08 4.43 (16.4 mg/L)
8 Glibenclamide 4.7 3.78 4.79 4.68 8 Glibenclamide 4 mg/L 5.09 5.38 (2.1 mg/L)
9 Repaglinide 5.9 5.05 6.19 5.94 9 Repaglinide 5.19 (2.9 mg/L)
10 Nateglinide 2.4 3.59 4.70 4.56 10 Nateglinide 4.57 (8.5 mg/L)
a a
Ref. [52]. Ref. [52].

2.1 program [64] used to predict lipophilicity [65] and aqueous
solubility [66,67] of compounds. The lipophilicity calculations
within this program are based on the associative neural network
approach and the efficient partition algorithm. The LogKow (Kow-
WIN) program [68] estimates the log octanol/water partition coef-
ficient (log P) of organic chemicals and drugs using an atom/
fragment contribution method developed at Syracuse Research
Corporation [69]. The XLOGP2 is atom-additive method applying
corrections [70,71]. Available experimental log P values of the sul-
fonylurea and glinide drugs were extracted from the literature
[52]. The available experimental partition coefficients of drugs
investigated are best reproduced by atom/fragment methods
XLOGP2 and KoWWIN. The associative neural network ALOGPS
method also performs well (Table 5).
Computed partition coefficients (XLOGP2 method) for drugs
studied varied between 1.8 and 5.9. Thus, these compounds are
described as lipophilic drugs. The first generation of sulfonylureas
(acetohexamide, tofazamide, tolbutamide and chlorpropamide)
exhibits slightly lower lipophilicity. Second-generation sulfonylu-
reas gliclazide, glimepiride, glipizide, and glibenclamide due to
their greater hydrophobic character are effective over a longer
duration of action [1]. The lipophilicity of sulfonylurea drugs qual-
itatively well correlates with their ability to interact with sulfonyl-
urea receptors (SUR). Giannaccini et al. carried out the
displacement experiments using pancreatic islet sulfonylurea
receptors [72]. They found following rang order of potency of the
oral sulfonylureas tested: glibenclamide = glimepiride > tolbuta-
mide > chlorpropamide, which correlates well with the lipophilic-
ity of these drugs (Table 5). Moreover, lipophilic substitution on
their urea group is also responsible for their selectivity for sulfo-
nylurea receptor subtype SUR1 over SUR2 [58]. E.g. highly lipo-
philic glibenclamide (log P = 4.7) bound to the SUR2 isoforms
(SUR2 receptors of the ATP-sensitive K+ (KATP) channels found in
heart) with 300- to 500-fold lower affinity than to SUR1 [58].
3.4. Solubility
Log S – an intrinsic solubility in neutral state is indicative of a
compound’s solubility (S). As the experimental solubilities of most
compounds under study are not known, the log S values were cal-
culated using ALOGPS as a predictor. This method uses E-state
indices as descriptors and a neural network [66] as the modeling
‘‘engine”. The computed solubilities are presented in Table 6. Pre-
vious calculations of chemically different biologically active com-
pounds have been shown, that these methods well reproduce
known experimental solubilities [73,74]. Drug solubility is one of
the important factors, which affect the movement of a drug from
a site of administration into the blood. Knowing of drug solubility
is important. It is well known that insufficient solubility of drugs
can lead to poor absorption [75]. Investigation of the rate-limited
steps of human oral absorption of 238 drugs (including tolbuta-
mide, gliclazide and glibenclamide) has been shown [75] that the
absorption of a drug is usually very low if the calculated solubility
is <0.0001 mg/L. Although the sulfonylurea and glinidine deriva-
tives studied are only slightly soluble in water, their computed sol-
ubilities from interval between 0.001 and 4 g/L are sufficient for
fast adsorption. Glibenclamide exhibits the lowest solubility
(about 2 mg/L). Very high lipophilicity, low solubility and extended
molecular structure of glibenclamide are probably responsible for
its high selectivity for SUR2 receptors of the ATP-sensitive K+ (KATP)
channels found in heart [76]. Mitochondrial ATP-sensitive K+ chan-
nel plays a key role in cardioprotection. Hence, a sulfonylurea that
does not block these channels would be desirable to avoid damage
to the heart [76]. It is known, that the treatment with the long sul-
fonylurea glibenclamide (drug that possesses both sulfonylurea
and non-sulfonylurea moieties, Fig. 1) could be associated with
higher mortality for cardiovascular diseases and malignancies, in
comparison with the short sulfonylurea derivative gliclazide [77],
which could be explained by greater selectivity of gliclazide for
pancreatic, rather than myocardial sulfonylurea receptors [78].
3.5. Absorption, polar surface area, and ‘‘rule of five” properties
High oral bioavailability is an important factor for the develop-
ment of bioactive molecules as therapeutic agents. Passive intestinal
absorption, reduced molecular flexibility (measured by the number
of rotatable bonds), low polar surface area or total hydrogen bond
count (sum of donors and acceptors), are important predictors of
good oral bioavailability [79,80]. Properties of molecules such as bio-
availability or membrane permeability have often been connected to
simple molecular descriptors such as log P (partition coefficient),
molecular weight (MW), or counts of hydrogen bond acceptors and
donors in molecule [81]. Lipinski et al. [82] used these molecular
properties in formulating his ‘‘Rule of Five”. The rule states that most
molecules with good membrane permeability have log P 6 5, molec-
ular weight 6500, number of hydrogen bond acceptors 610, and
number of hydrogen bond donors 65. This rule is widely used as a fil-
ter for drug-like properties. Table 7 contains calculated percentage
of absorption (%ABS), molecular polar surface area (PSA) and Lipinski
parameters of the hypoglycemic drugs investigated. Magnitude of
absorption is expressed by the percentage of absorption. Absorption
percent was calculated [75] using the expression: %ABS =
109 0.345 PSA. Polar surface area (PSA) was determined by the frag-
ment-based method of Ertl and coworkers [29,30].
The long sulfonylureas (drugs that possess both sulfonylurea
and non-sulfonylurea moieties, Fig. 1) glimepiride, glipizide and
glibenclamide possess higher number (11–12) of proton acceptor
and proton donor groups to ensure efficient interaction with the
hydrogen bonding groups of the subcompartments A and B of the
SUR receptor [83]. Hydrogen-bonding capacity has been also iden-
tified as an important parameter for describing drug permeability
[80]. Its abnormal increase may result in considerably lowered
absorption of these ligands. High number of hydrogen bond donors
 M. Remko / Journal of Molecular Structure: THEOCHEM 897 (2009) 73–82 81

Table 7
Calculated absorption (%ABS), polar surface area (PSA) and Lipinski parameters of the hypoglycemic drugs studied.

No. Drug %ABS Volume PSA NROTB n ON acceptors n OHNH donors Log P, calcda Formula weight
1 Acetohexamide 77.14 284.80 92.33 4 6 2 2.29 324.40
2 Tofazamide 81.91 278.58 78.51 3 6 2 2.03 311.41
3 Tolbutamide 83.03 242.79 75.26 5 5 2 2.21 270.35
4 Chlorpropamide 83.03 222.96 75.27 4 5 2 1.98 276.75
5 Gliclazide 81.91 284.59 78.51 3 6 2 2.07 323.42
6 Glimepiride 65.98 445.90 124.67 7 9 3 2.98 490.62
7 Glipizide 64.09 393.91 130.15 7 9 3 2.57 445.55
8 Glibenclamide 69.81 424.74 113.60 8 8 3 4.41 424.74
9 Repaglinide 81.79 442.52 78.87 10 6 2 5.72 452.59
10 Nateglinide 86.09 316.03 66.39 6 4 2 4.28 317.43
a
Range of log P values obtained by three theoretical methods (Table 3) (ALOGPS, KoWWIN, XLogP2).

and acceptors in glimepiride, glipizide and glibenclamide resulted
in their reduced absorption in comparison with the short sulfonyl-
urea gliclazide. Gliclazide is the second-generation sulfonylurea
with reduced hydrogen bond capacity and exhibits largest absorp-
tion. Analogous absorption to gliclazide exhibit also the first gener-
ation sulfonyluras (acetohexamide, tofazamide, tolbutamide,
chlorpropamide) and glinides (Table 7).
The low number of rotatable bonds (3) in gliclazide indicates
that this ligand upon binding to a channel containing SUR recep-
tors changes its conformation only slightly. Somewhat larger con-
formational change is possible with the substantially more flexible
glimepiride, glipizide, glibenclamide and repaglinide species stud-
ied. These drugs possess high number of rotatable bonds (7–10)
and therefore, exhibit large conformational flexibility. The geome-
try analysis of the B3LYP computed conformations of gliclazide,
glimepiride, glipizide and glibenclamide points out a constant rel-
ative orientation of their benzenesulfonamide moiety regardless of
the molecular environment. However, the urea part of the pharma-
cophore unit is in these drugs oriented differently (dihedral angles
c and e, Table 2). It means that the lipophilic N-substituent accom-
modates a different space in the cavity of the SUR receptor. Thus, it
is probable that suitable acidity, lipophilicity, solubility, and
absorption are more important factors for the designing of highly
active ligands selectively acting on individual SUR receptors.
4. Conclusions
This theoretical study set out to determine stable conforma-
tions, solvent effect, pKa, lipophilicity, solubility, absorption and
polar surface area of 10 ligands acting on sulfonylurea receptors
for which a relatively small amount of experimental physicochem-
ical data exist, considering its pharmacological importance. Using
the theoretical methods the following conclusions can be drawn.
The equilibrium structure of the sulfonylureas investigated in the
isolated state is determined by the formation of suitable intramolec-
ular hydrogen bonds within the sulfonamide moiety. This specific
interaction gives rise to the unique overall shape of individual drug
conformers. Values of these dihedral angles for individual drugs
are different. Generally, the ab initio SCF and DFT optimized struc-
tures in the gas phase fit well one another. Water has a remarkable
effect on the geometry of the drugs studied. These hypoglycemic
agents exhibit the largest stability in solvent as expected, since they
hold considerable dipole moment. The energy difference between
gas phase and solvated phase was significant for the two solvation
models employed in this work. The CPCM provided substantially
more stable structures than Onsager’s model.
The computed pKa values correlate well with the available
experimental pKa values found in the literature. The pKa values of
sulfonylurea moiety in the hypoglycemic drugs studied are in the
range of 5.2–6.2 and are characterized as weak organic acids. How-
ever, at physiological pH 7.4 sulfonylamide group of these drugs is
completely ionized. Repaglinide and nateglinide are oral blood glu-
cose-lowering drugs of the glinide class containing acidic carbox-
ylic group. The pKa values of this carboxylic acid moiety in the
glinide drugs studied are in the range of 3.5–4.0. At physiological
pH 7.4 this group is completely ionized.
The available experimental partition coefficients of hypoglyce-
mics investigated are best reproduced by atom/fragment methods
XLOGP2 and KoWWIN. Computed partition coefficients (XLOGP2
method) for drugs studied varied between 1.8 and 5.9. Thus, these
compounds are described as lipophilic drugs. The lipophilicity of
sulfonylurea drugs qualitatively well correlates with their ability
to interact with sulfonylurea receptors (SUR). Although the sulfo-
nylurea and glinide derivatives studied are only slightly soluble
in water, their computed solubilities from interval between 0.001
and 4 g/L are sufficient for fast adsorption. Gliclazide is the sec-
ond-generation sulfonylurea with reduced hydrogen bond capacity
and exhibits largest absorption. Analogous absorption to gliclazide
exhibit also the first generation sulfonyluras (acetohexamide, tof-
azamide, tolbutamide, chlorpropamide) and glinides.
This work yields quantities that may be inaccessible or comple-
mentary to experiments and represents the first theoretical
approach in which both the gas-phase and solvated phase proper-
ties of clinically useful sulfonylureas and glinides were evaluated.
Such investigations may be, due to the present recognition of the
important potential commercial value of accurate prediction of
acidity, lipophilicity, solubility and absorption as very important
factors for the designing of highly active ligands selectively acting
on individual SUR receptors, useful in design of new drugs in the
treatment of non-insulin dependent diabetes mellitus with
improved properties and intellectual property value.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.theochem.2008.11.021.
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