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

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Journal of Molecular Structure: THEOCHEM

journal homepage: www.elsevier.com/locate/theochem

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

tissues such as heart, vascular smooth and skeletal muscle [7]. As
Diabetes is characterized by disrupted insulin production and newer oral diabetes agents continue to emerge on the market,
sensitivity, leading to high blood glucose and a series of complica- comparative evidence is required to guide appropriate therapy.
tions, such as retinopathy, nephropathy, neuropathy and cardio- Although not all sulfonylureas and glinides have been studied in
vascular disease [1–3]. Sulfonylureas and glinides are effective in randomized controlled trials, they are invariably used in practice
the treatment of non-insulin dependent diabetes mellitus (NDDIM) assuming, probably, a class effect of these pharmacons [8]. A class
[1–4]. It affects about 3–5% of western populations and its preva- effect implies that all drugs in a class exert the same effects,
lence continues to rise [4]. This diabetes of type 2 characterizes whether positive or negative, on their target population [9]. E.g.
both tissue insulin resistance and an insulin secretory deficit the results of the UK Prospective Diabetes Study [10] showed a
[5,6]. Sulfonylureas have been used as hypoglycemic agents since clear risk reduction for the occurrence of microvascular complica-
the mid-1950s, and for many years this class of drugs has been tions by the use of sulfonylurea derivatives, while the risk
one of the mainstays of oral antidiabetic therapy. Compounds in reduction of macrovascular disease was about 16% [11]. Antihyper-
the first generation of this class such as acetohexamide, chlorprop- tensive therapy diminished the risk of macrovascular complica-
amide, tolbutamide and tolazamide are still in use, but are less tions by around 20% [11]. Combined management with both
potent than the more recently introduced second-generation drugs sulfonylurea derivatives and antihypertensives improves the risk
like gliclazide, glimepiride, glipizide and glibenclamide. Glinides, reduction even more [11,12]. The first generation of sulfonylureas
e.g. nateglinide, and repaglinide represent newer group of hypogly- is still in use, but are less potent than the more recently introduced
cemic agents. Both groups of hypoglycemic agents (sulfonylureas second-generation drugs like gliclazide, glimepiride, glipizide and
and glinides) stimulate insulin secretion by closing ATP-sensitive glibenclamide [1,4,8,9]. Glinides (e.g. nateglinide, and repaglinide)
potassium (KATP) channels in pancreatic beta cells, but have have a shorter action than sulfonylurea derivatives, are therefore
associated with lower risk of hypoglycemia, and can also be used
* Tel.: +421 2 50117225; fax: +421 2 50117100. in patients with decreased renal function [13]. Some of the differ-
E-mail address: [email protected] 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- tive orientation of sulfonylurea moiety defined by five dihedral
bility, lipophilicity and acidity), pharmacokinetic (absorption, angles (a, b, c, d, and e, Fig. 1) at the sulfonylurea linkage was taken
protein binding, half-life and metabolic disposition) properties from the experimental data for available X-ray data of chlorprop-
but also in their ability to penetrate and to bind tissue sites [10,11]. amide [32], gliclazide [33], glimepiride [34], and glipizide [35].
Despite a great deal of experimental evidence for the relation- An analysis of the harmonic vibrational frequencies at the HF level
ship between the chemical and biochemical properties of sulfo- of theory of the optimized species revealed that all the structures
nylureas and glinides and their biological activity, there is no obtained were minima (no imaginary frequencies). The Cartesian
single experimental study concerned with the systematic com- coordinates (Å) of all gas-phase oligomers investigated, optimized
parative experimental investigation of the physico-chemical at the B3LYP/6-31G(d) level of theory, are given in Table A of the
and pharmacokinetic parameters of medicinally used sulfonylu- electronic Supporting Information. In order to check the correct-
reas and glinides. The absence of experimental data of sulfonyl- ness of the B3LYP calculated structures using the double-f basis
ureas and glinides presents a challenge to the application of set, we also performed full geometry optimization of the chlor-
computational modeling techniques in order to enhance our propamide, Table A of the Supporting Information, using the basis
understanding of the subtle biological effects of sulfonylureas set of the triple-f quality (B3LYP/6-31++G(d,p) level of theory).
and glinides. In this paper, we have used the results of large- Examination of the space models of the B3LYP computed struc-
scale theoretical calculations for the study of the molecular tures using two basis sets of this drug shows that the increase of
structure, pKa, lipophilicity, solubility, absorption, and polar sur- the basis set gives essentially the same results. The effect of bulk
face area of sulfonylureas and glinides (acetohexamide, tofaza- solvent is treated with two solvation methods (the Onsager [23]
mide, tolbutamide, chlorpropamide, gliclazide, glimepiride, and CPCM [22]) for comparison. Initial calculations were carried
glipizide, glibenclamide, nateglinide, and repaglinide). The results out, for computational reasons, using the SCRF formalism of Wong
of theoretical studies of these drugs were compared with the et al. [36–39]. The radii of the cavities used in this approach were
available experimental data and discussed in relation to the chosen after a volume calculation of each molecule, and the dielec-
present theories of action of these agents. tric constant of water (e = 78.5) was used. The placing of the iso-
lated molecules into a spherical cavity within a dielectric
2. Computational details medium of the Onsager model of solvation does not represent
the realistic situation in the biological medium; it seems helpful
Ab initio calculations of the acetohexamide, tofazamide, tolbuta- in revealing the main role of the solvent in intermolecular electro-
mide, chlorpropamide, gliclazide, glimepiride, glipizide, glibencla- static interactions. The second, CPCM (conductor-like polarizable
mide, nateglinide, and repaglinide (Fig. 1) were carried out with model), defines the cavity by the envelope of spheres centered
the Gaussian 03 computer code [14] at the ab initio SCF (HF [15]) on the atoms or the atomic groups [22].
and density functional theory (DFT, Becke3LYP [16–20]) levels of According to the recent high-level ab initio calculations [40,41]
theory using the 6-31G(d) basis set. In order to evaluate the confor- of the structurally related sulfonamides, these compounds exist in
mational behavior of these systems in solvent, we carried out opti- two stable forms. The basic difference between these two struc-
mization calculations in the presence of water. The methodology tures arises from the arrangement of –NH2 group syn or anti with
used in this work is centered on two solvation methods, CPCM respect to the –SO2 group. The syn isomer of the substituted
[21,22] and Onsager [23] models. The structures of all gas-phase sulfonamide derivatives was found to be the most stable structure
species were fully optimized at the HF/6-31G(d) and Becke3LYP/ [40]. Thus, the calculations of sulfonylurea drugs studied were car-
6-31G(d) levels of theory without any geometrical constraint. In ried out for syn structures of the sulfonamide moiety only. Impor-
order to check the correctness of the B3LYP calculated geometries tant geometrical parameters of the sulfonylurea linkage are given
using the double-f basis set, we also performed calculations of the in Tables 1 and 2. Some trends are apparent: (i) there are no major
sulfonylurea species, using the basis set of the triple-f quality differences between the HF/6-31G(d) and B3LYP/6-31G(d) geome-
(B3LYP/6-31++G(d,p) level of theory) implemented in the Gaussian tries. B3LYP geometries, as expected, have bond lengths 0.03 Å
03 package of computer codes [14,15]. The structures of all con- longer. (ii) The S–N bond length in sulfonylureas (1.70 Å) is
densed-phase (SCRF) species were fully optimized without any shorter than the S–N single bond distance 1.75 Å [42]. (iii) The
geometrical constraint at the B3LYP/6-31G(d) level of theory. valence bond angles of the sulfonylurea grouping are within a ser-
The calculations of the macroscopic pKa of sulfonylureas and ies of drugs studied almost the same. Exceptions are tofazamide
glinides investigated were performed using the program AB/pKa and glimepiride. The valence angle S(3)–N(4)–C(5) is by about
module of the Pharma Algorithms [24]. Lipophilicity and water 10° longer that angle in the rest of the drugs studied (Table 1).
solubility calculations were carried out using web-based VCCLAB (iv) Comparison of the B3LYP structures of chlorpropamide com-
[25–27]. For calculations of molecular polar surface areas the frag- puted using two basis sets shows that the increase of the basis
ment-based method of Ertl and coworkers [28,29] incorporated in set gives essentially the same geometries (Tables 1 and 2). Thus,
the Molinspiration Cheminformatics software [30] was used. for purposes of determining reasonable geometries of large sys-
tems the B3LYP/6-31G(d) should be considered the method of
choice.
3. Results and discussion The sulfonylurea drugs studied possess the same aryl-sulfonyl-
urea functionality. In these structures the relative molecular orienta-
3.1. Molecular structures 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
Conformational search using theoretical methods for such large sulfonylurea drugs are given in Table 2. The equilibrium structure of
systems was in the past limited to use some of the available force- the sulfonylureas investigated in the isolated state is determined by
field methods [31]. It is common in the computational study of the formation of suitable intramolecular hydrogen bonds within the
drugs to use structural data obtained from X-ray crystallography sulfonamide moiety. This specific interaction gives rise to the unique
or NMR spectroscopy as guides to the quality of theoretical compu- overall shape of individual drug conformers (Fig. 2), and is mani-
tations. Initial conformations to use in the theoretical calculations fested by the computed values of the a, b, c, d, and e dihedral angles
of the sulfonylureas and glinides studied were constructed by of the sulfonylurea linkage. Values of these dihedral angles for
means of the Gauss View graphical interface of Gaussian. The rela- 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 moment (Table 3). The larger dipole moments of the second-gener-
C(2)–S(3) bond length of about 1.79 Å (DFT method) is a single bond ation drugs like gliclazide, glimepiride, glipizide and glibenclamide
length between the sp2 hybridized carbon atom and sulfur because provide an additional stabilization in the solvent media when com-
the sulfonamide group and aromatic rings are approximately per- pared to those of the others. The energy difference between gas
pendicular (dihedral angle a[C(1)–C(2)–S(3)–N(4)]). On the other phase and solvated phase was significant for the two solvation
hand, the dihedral angles b, c, d, and e change considerably upon sub- models employed in this work. The CPCM provided substantially
stitution. Generally, the ab initio SCF and DFT optimized structures in more stable structures than Onsager’s model (Table 3).
the gas phase fit well one another (within 5°). In the absence of gas-phase data, the geometry of the parent
Water has a remarkable effect on the geometry of the title drugs sulfonylureas only can be compared with available published X-
studied. Table 3 shows the results obtained for calculations per- ray data of the drugs studied. Although both methods are based
formed in both, vacuum and that based on the solvation method. on different models, the computed geometry for sulfonylureas
According to Table 3, the hypoglycemic agents exhibit the largest (Table 2) is in good agreement with the experimentally determined
stability in solvent as expected, since they hold considerable dipole 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 formed by proton acceptor and proton donor (N–H) groups of two
of these compounds and their derivatives to exist in two or more neighboring molecules.
polymorphic forms [43,44]. The solid-state properties of these
compounds are influenced by their propensity for hydrogen bond- 3.1.2. Tofazamide
ing [45,46], which can give rise to polymorphism. Because the Gas-phase geometry of tofazamide is stabilized via intramolec-
geometries of the sulfonamides in the crystalline phase are con- ular hydrogen bonding system of the S@O


H–N and C@O


H–N
trolled by intermolecular hydrogen bonds, they are not exactly types (Fig. 2). The aryl-sulfonylurea geometry is, on the contrary
comparable with those of the free molecules. to the acetohydroxamide, stabilized through the short N(6)–
H


O@S interaction with length of 2.08 Å. The optimal bond
3.1.1. Acetohexamide lengths, bond angles, and dihedral angles of tofazamide computed
Optimized molecular conformation of acetohexamide at the with the self-consistent reaction field methods and solvent water
B3LYP level of the DFT theory (Fig. 2) is stabilized by means of do not considerably differ from those obtained for isolated mole-
the intramolecular hydrogen bond of the S@O


H–N type with cule (Tables 1 and 2).
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 3.1.3. Tolbutamide
ring exists in a chair conformation. The calculated aryl-sulfonyl- The 3D structure of fully optimized tolbutamide is stabilized by
urea geometry of acetohexamide in H2O is quite different. The dif- the system of intramolecular hydrogen bonds within the sulfon-
ference in dihedral angles b[C(2)–S(3)–N(4)–C(5)], c[S(3)–N(4)– amide moiety. Of the three hydrogen bonds, two are bifurcated
C(5)–N(6)] and d[S(3)–N(4)–C(5)–O(7)] can be as large as 15° hydrogen bonds of the sulfonamide N–H group (Fig. 2). Optimized
(Table 2). Stephenson et al. [48] investigated solid-state tautomer- geometry of tolbutamide in water solution changed only slightly.
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- 3.1.4. Chlorpropamide
morphic (A and B) keto-forms [48]. The form A of acetohexamide Chlorpropamide may exist in several polymorphs [49]. As a
is in the crystal structure stabilized by means of network of inter- starting geometry for ab initio calculations we used X-ray structure
molecular hydrogen bonds of the S@O


H–N and C@O


H–N types 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- The complexation of calcium dication by two molecules of glicla-
lized by means of intramolecular hydrogen bond of the S@O


H–N zide is only possible when the gliclazide molecule is fully extended
type (Fig. 2). This hydrogen bond is also preserved in crystal. The [31] (Fig. 2). Therefore the computed extended structure of glicla-
main difference between calculated and experimental structures zide will represent the biologically active conformation. Since in
is in the relative orientation of the aromatic ring and the sulfonyl- water solution its gas-phase molecular structure changes only
urea moieties. For this difference the pattern of intermolecular slightly, the fully extended conformation of gliclazide will also be
hydrogen bonds in the ß-polymorph is mainly responsible. Upon present in water (Table 2).
hydration the structure of the sulfonylurea chain of chlorprop-
amide does not change importantly (Table 2). 3.1.6. Glimepiride
The B3LYP optimized structure of glimepiride is shown in Fig. 2.
3.1.5. Gliclazide The bond lengths and bond angles of the sulfonylurea moiety (Table
The B3LYP optimized structure of gliclazide is stabilized by the 1) are in agreement with values computed for other sulfonylureas
system of three hydrogen bonds (Fig. 2). An additional basic nitro- studied. Optimized structure is stabilized by means of three intra-
gen of the perhydrocyclopenta[c]pyrrole group is linked with the molecular hydrogen bonds (Fig. 2). The S@O


H–N(C8) hydrogen
sulfonamide –NH group by the N


H–N hydrogen bond with the bond with bond length 2.043 Å stabilizes a unique conformation of
length of 2.217 Å. This interaction was also observed experimen- aryl-sulfonylurea moiety. This hydrogen bonding system is also
tally [33] with slightly greater bond length of 2.335 Å. The fused present in the solid state [34]. However, the difference in dihedral
five-membered rings of the perhydrocyclopenta[c]pyrrole moiety angles b[C(2)–S(3)–N(4)–C(5)], c[S(3)–N(4)–C(5)–N(6)] and
adopt envelope conformation. The computed dihedral angles of d[S(3)–N(4)–C(5)–O(7)] between solid-state conformation and
the flexible aryl-sulfonylurea functionality using two theoretical gas-phase can be as large as 20° (Table 2). The molecular conforma-
methods are in very good agreement with the experimental so- tion of glimepiride in water is considerably different to those ob-
lid-state geometric parameters of the fully extended conformation served in crystal. The difference in dihedral angles b[C(2)–S(3)–
of gliclazide. The suitable orientation of the flexible aryl-sulfonyl- N(4)–C(5)], c[S(3)–N(4)–C(5)–N(6)] and d[S(3)–N(4)–C(5)–O(7)]
urea moiety of gliclazide is particularly important for the mode can be as large as 30° (Table 2).
of action of gliclazide. The action of gliclazide is mediated through
its calcium transportation across the membrane of the beta cell 3.1.7. Glipizide
[31]. Release of insulin evoked by oral hypoglycemic sulfonylureas The molecular structure of glipizide optimized at the B3LYP
is due to the accumulation of calcium in the pancreatic beta cell. 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 3.1.8. Glibenclamide
the X-ray structure [35] shows large difference between gas- The molecular structure of glibenclamide differs from glipizide
phase and solid state structures, especially in the sulfonylurea– just in the kind of the substituent of the amido linker. The 5-methyl-
cyclohexane moiety (dihedral angles c[S(3)–N(4)–C(5)–N(6)], pyrazine is in glibenclamide substituted by 5-chloro-2-methoxy-
d[S(3)–N(4)–C(5)–O(7), and e[N(4)–C(5)–N(6)–C(8)]) and the 5- benzene (Fig. 2). In both, gas-phase and in water solution,
methylpyrazine substituent of the amido linker. Hydration aryl-sulfonylurea part of these two drugs possesses almost the same
caused appreciable geometry changes in the overall structure conformation (Table 2). The 3D structure is stabilized by means of
of glipizide (Table 2). 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].

mide, gliclazide and glibenclamide) has been shown [75] that the
2.1 program [64] used to predict lipophilicity [65] and aqueous absorption of a drug is usually very low if the calculated solubility
solubility [66,67] of compounds. The lipophilicity calculations is <0.0001 mg/L. Although the sulfonylurea and glinidine deriva-
within this program are based on the associative neural network tives studied are only slightly soluble in water, their computed sol-
approach and the efficient partition algorithm. The LogKow (Kow- ubilities from interval between 0.001 and 4 g/L are sufficient for
WIN) program [68] estimates the log octanol/water partition coef- fast adsorption. Glibenclamide exhibits the lowest solubility
ficient (log P) of organic chemicals and drugs using an atom/ (about 2 mg/L). Very high lipophilicity, low solubility and extended
fragment contribution method developed at Syracuse Research molecular structure of glibenclamide are probably responsible for
Corporation [69]. The XLOGP2 is atom-additive method applying its high selectivity for SUR2 receptors of the ATP-sensitive K+ (KATP)
corrections [70,71]. Available experimental log P values of the sul- channels found in heart [76]. Mitochondrial ATP-sensitive K+ chan-
fonylurea and glinide drugs were extracted from the literature nel plays a key role in cardioprotection. Hence, a sulfonylurea that
[52]. The available experimental partition coefficients of drugs does not block these channels would be desirable to avoid damage
investigated are best reproduced by atom/fragment methods to the heart [76]. It is known, that the treatment with the long sul-
XLOGP2 and KoWWIN. The associative neural network ALOGPS fonylurea glibenclamide (drug that possesses both sulfonylurea
method also performs well (Table 5). and non-sulfonylurea moieties, Fig. 1) could be associated with
Computed partition coefficients (XLOGP2 method) for drugs higher mortality for cardiovascular diseases and malignancies, in
studied varied between 1.8 and 5.9. Thus, these compounds are comparison with the short sulfonylurea derivative gliclazide [77],
described as lipophilic drugs. The first generation of sulfonylureas which could be explained by greater selectivity of gliclazide for
(acetohexamide, tofazamide, tolbutamide and chlorpropamide) pancreatic, rather than myocardial sulfonylurea receptors [78].
exhibits slightly lower lipophilicity. Second-generation sulfonylu-
reas gliclazide, glimepiride, glipizide, and glibenclamide due to 3.5. Absorption, polar surface area, and ‘‘rule of five” properties
their greater hydrophobic character are effective over a longer
duration of action [1]. The lipophilicity of sulfonylurea drugs qual- High oral bioavailability is an important factor for the develop-
itatively well correlates with their ability to interact with sulfonyl- ment of bioactive molecules as therapeutic agents. Passive intestinal
urea receptors (SUR). Giannaccini et al. carried out the absorption, reduced molecular flexibility (measured by the number
displacement experiments using pancreatic islet sulfonylurea of rotatable bonds), low polar surface area or total hydrogen bond
receptors [72]. They found following rang order of potency of the count (sum of donors and acceptors), are important predictors of
oral sulfonylureas tested: glibenclamide = glimepiride > tolbuta- good oral bioavailability [79,80]. Properties of molecules such as bio-
mide > chlorpropamide, which correlates well with the lipophilic- availability or membrane permeability have often been connected to
ity of these drugs (Table 5). Moreover, lipophilic substitution on simple molecular descriptors such as log P (partition coefficient),
their urea group is also responsible for their selectivity for sulfo- molecular weight (MW), or counts of hydrogen bond acceptors and
nylurea receptor subtype SUR1 over SUR2 [58]. E.g. highly lipo- donors in molecule [81]. Lipinski et al. [82] used these molecular
philic glibenclamide (log P = 4.7) bound to the SUR2 isoforms properties in formulating his ‘‘Rule of Five”. The rule states that most
(SUR2 receptors of the ATP-sensitive K+ (KATP) channels found in molecules with good membrane permeability have log P 6 5, molec-
heart) with 300- to 500-fold lower affinity than to SUR1 [58]. ular weight 6500, number of hydrogen bond acceptors 610, and
number of hydrogen bond donors 65. This rule is widely used as a fil-
3.4. Solubility ter for drug-like properties. Table 7 contains calculated percentage
of absorption (%ABS), molecular polar surface area (PSA) and Lipinski
Log S – an intrinsic solubility in neutral state is indicative of a parameters of the hypoglycemic drugs investigated. Magnitude of
compound’s solubility (S). As the experimental solubilities of most absorption is expressed by the percentage of absorption. Absorption
compounds under study are not known, the log S values were cal- percent was calculated [75] using the expression: %ABS =
culated using ALOGPS as a predictor. This method uses E-state 109 0.345 PSA. Polar surface area (PSA) was determined by the frag-
indices as descriptors and a neural network [66] as the modeling ment-based method of Ertl and coworkers [29,30].
‘‘engine”. The computed solubilities are presented in Table 6. Pre- The long sulfonylureas (drugs that possess both sulfonylurea
vious calculations of chemically different biologically active com- and non-sulfonylurea moieties, Fig. 1) glimepiride, glipizide and
pounds have been shown, that these methods well reproduce glibenclamide possess higher number (11–12) of proton acceptor
known experimental solubilities [73,74]. Drug solubility is one of and proton donor groups to ensure efficient interaction with the
the important factors, which affect the movement of a drug from hydrogen bonding groups of the subcompartments A and B of the
a site of administration into the blood. Knowing of drug solubility SUR receptor [83]. Hydrogen-bonding capacity has been also iden-
is important. It is well known that insufficient solubility of drugs tified as an important parameter for describing drug permeability
can lead to poor absorption [75]. Investigation of the rate-limited [80]. Its abnormal increase may result in considerably lowered
steps of human oral absorption of 238 drugs (including tolbuta- 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 completely ionized. Repaglinide and nateglinide are oral blood glu-
in their reduced absorption in comparison with the short sulfonyl- cose-lowering drugs of the glinide class containing acidic carbox-
urea gliclazide. Gliclazide is the second-generation sulfonylurea ylic group. The pKa values of this carboxylic acid moiety in the
with reduced hydrogen bond capacity and exhibits largest absorp- glinide drugs studied are in the range of 3.5–4.0. At physiological
tion. Analogous absorption to gliclazide exhibit also the first gener- pH 7.4 this group is completely ionized.
ation sulfonyluras (acetohexamide, tofazamide, tolbutamide, The available experimental partition coefficients of hypoglyce-
chlorpropamide) and glinides (Table 7). mics investigated are best reproduced by atom/fragment methods
The low number of rotatable bonds (3) in gliclazide indicates XLOGP2 and KoWWIN. Computed partition coefficients (XLOGP2
that this ligand upon binding to a channel containing SUR recep- method) for drugs studied varied between 1.8 and 5.9. Thus, these
tors changes its conformation only slightly. Somewhat larger con- compounds are described as lipophilic drugs. The lipophilicity of
formational change is possible with the substantially more flexible sulfonylurea drugs qualitatively well correlates with their ability
glimepiride, glipizide, glibenclamide and repaglinide species stud- to interact with sulfonylurea receptors (SUR). Although the sulfo-
ied. These drugs possess high number of rotatable bonds (7–10) nylurea and glinide derivatives studied are only slightly soluble
and therefore, exhibit large conformational flexibility. The geome- in water, their computed solubilities from interval between 0.001
try analysis of the B3LYP computed conformations of gliclazide, and 4 g/L are sufficient for fast adsorption. Gliclazide is the sec-
glimepiride, glipizide and glibenclamide points out a constant rel- ond-generation sulfonylurea with reduced hydrogen bond capacity
ative orientation of their benzenesulfonamide moiety regardless of and exhibits largest absorption. Analogous absorption to gliclazide
the molecular environment. However, the urea part of the pharma- exhibit also the first generation sulfonyluras (acetohexamide, tof-
cophore unit is in these drugs oriented differently (dihedral angles azamide, tolbutamide, chlorpropamide) and glinides.
c and e, Table 2). It means that the lipophilic N-substituent accom- This work yields quantities that may be inaccessible or comple-
modates a different space in the cavity of the SUR receptor. Thus, it mentary to experiments and represents the first theoretical
is probable that suitable acidity, lipophilicity, solubility, and approach in which both the gas-phase and solvated phase proper-
absorption are more important factors for the designing of highly ties of clinically useful sulfonylureas and glinides were evaluated.
active ligands selectively acting on individual SUR receptors. Such investigations may be, due to the present recognition of the
important potential commercial value of accurate prediction of
4. Conclusions acidity, lipophilicity, solubility and absorption as very important
factors for the designing of highly active ligands selectively acting
This theoretical study set out to determine stable conforma- on individual SUR receptors, useful in design of new drugs in the
tions, solvent effect, pKa, lipophilicity, solubility, absorption and treatment of non-insulin dependent diabetes mellitus with
polar surface area of 10 ligands acting on sulfonylurea receptors improved properties and intellectual property value.
for which a relatively small amount of experimental physicochem-
ical data exist, considering its pharmacological importance. Using
Appendix A. Supplementary data
the theoretical methods the following conclusions can be drawn.
The equilibrium structure of the sulfonylureas investigated in the
Supplementary data associated with this article can be found, in
isolated state is determined by the formation of suitable intramolec-
the online version, at doi:10.1016/j.theochem.2008.11.021.
ular hydrogen bonds within the sulfonamide moiety. This specific
interaction gives rise to the unique overall shape of individual drug
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