Crystal structure and electronic properties of two nimesulide derivatives: A combined X-ray powder diffraction and quantum mechanical study

Article abstract of DOI:10.1016/j.cplett.2010.05.009

Crystal structures of two nimesulide derivatives, C₁₃H ₁₄O₃N₂S (2) and C₂₁H ₁₆O₅N₂S (3), have been determined from X-ray powder diffraction data and their electronic structures were calculated at the DFT level. The optimized molecular geometries of 2 and 3 correspond closely to that obtained from the crystallographic analysis. Intermolecular hydrogen bonds and π..π stacking interactions form supramolecular assembly in both compounds. The HOMO-LUMO energy gap (>2.2 eV) indicates a high kinetic stability of both compounds. Although the compound 2 does not exhibit any anti-inflammatory activity, 3 can induce 34% edema inhibition in rat paws.

Full text of DOI:10.1016/j.cplett.2010.05.009

Chemical Physics Letters 493 (2010) 151–157
Contents lists available at ScienceDirect
Chemical Physics Letters
journal homepage: www.elsevier.com/locate/cplett
Crystal structure and electronic properties of two nimesulide derivatives: A
combined X-ray powder diffraction and quantum mechanical study
Abir Bhattacharya a, Soumen Ghosh a, Kavitha Kankanala b,c, Vangala Ranga Reddy d, Khagga Mukkanti b,
Sarbani Pal c, Alok K. Mukherjee a,
*
a Department of Physics, Jadavpur University, Jadavpur, Kolkata 700032, India
b JNT University, Kukatpally, Hyderabad 500072, India
c Department of Chemistry, PG Campus, MNR Degree and PG College, Kukatpally, Hyderabad 500085, India
d Dr. Reddy’s Laboratories Ltd., Integrated Product Development Bachupally, Hyderabad 500055, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Crystal structures of two nimesulide derivatives, C13H14O3N2S (2) and C21H16O5N2S (3), have been deter-
mined from X-ray powder diffraction data and their electronic structures were calculated at the DFT
level. The optimized molecular geometries of 2 and 3 correspond closely to that obtained from the crys-
Received 27 January 2010
In final form 7 May 2010
Available online 13 May 2010
tallographic analysis. Intermolecular hydrogen bonds and p. . .p stacking interactions form supramolec-
ular assembly in both compounds. The HOMO–LUMO energy gap (>2.2 eV) indicates a high kinetic
stability of both compounds. Although the compound 2 does not exhibit any anti-inflammatory activity,
3 can induce 34% edema inhibition in rat paws.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
for many materials it can be difficult to grow single crystals of
appropriate size and quality that make them amenable to structure
Nimesulide, N-(4-nitro-2-phenoxyphenyl) methanesulfonam-
ide (1), is an effective non-steroidal anti-inflammatory drug
(NSAID), which can inhibit cyclooxygenase-2 (COX-2) enzyme
selectively [1]. The selective inhibition of COX-2 is attributed
mainly to the presence of methanesulfonamide group, and the
overall molecular conformation of 1 which facilitates strong inter-
actions with the enzyme [2]. In addition to good anti-inflamma-
tory, analgesic, anti-pyretic activities and low gastrointestinal
toxicity, 1 is also useful in a wide range of disorders, which include
various arthritic conditions, gynaecological and urological prob-
lems, post-surgical and cancer pain, and vascular diseases [3]. Sev-
eral analogues of nimesulide (1) aimed at enhancing the anti-
inflammatory activity and reducing its toxicity have been reported
by changing in 1 the R-group of the –NHSO2R moiety, the electron
withdrawing group at the C-4 position and the central aryl ring by
a pyridine or pyridinium moiety [4–6]. The X-ray structure analy-
ses and molecular dynamics simulations of COX-2 complexes with
nimesulide analogues indicate a network of hydrogen bonds in the
COX-2 active site involving the nitrogen and oxygen atoms of the
inhibitor molecule [7,8]. Thus knowledge of crystal structures of
nimesulide derivatives is of key importance for a better under-
standing of their structure–activity relation.
analysis. In such cases, structure determination using X-ray pow-
der diffraction data may be the only viable option for structural
characterization. With the recent developments of the direct-space
strategy for structure solution [9–12], ab initio crystal structure
analysis of organic molecular solids can now be accomplished from
X-ray powder diffraction data. Crystal structures of several molec-
ular compounds have been determined from laboratory X-ray
powder data using the direct-space approaches [13–15].
The present Letter reports the synthesis and structural
characterization of two nimesulide derivatives, N-(4-amino-2-
phenoxyphenyl) methanesulfonamide (2) and N-[4-(1,3-dioxo-
1,3-dihydroisoindol-2-yl)-2-phenoxyphenyl] methanesulfonamide
(3), along with the DFT calculations to investigate the molecular
geometry and the electronic structure. To the best of our knowl-
edge, this is the first example of structure determination of
nimesulide analogues from X-ray powder diffraction data.
2. Materials and methods
2.1. Synthesis
N-(4-amino-2-phenoxyphenyl) methanesulfonamide (2) was
synthesized by catalytic hydrogenation of a magnetically stirred
solution of nimesulide 1 (9 g, 28.1 mmol) in dry ethyl acetate
(50 mL) using 5% Pd–C. The reaction was carried out at room tem-
perature (27 °C) for 3 h. After completion of the reaction, as indi-
cated by the thin layer chromatography (TLC), the solution was
In general, single-crystal X-ray diffractometry is the method of
choice when it comes to crystal structure determination; although
* Corresponding author. Fax: +91 33 24146484.
E-mail address: akm_ju@rediffmail.com (A.K. Mukherjee).
0009-2614/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.cplett.2010.05.009

152
A. Bhattacharya et al. / Chemical Physics Letters 493 (2010) 151–157
filtered and the filtrate was concentrated under reduced pressure
to obtain 2 (a reduced form of nimesulide 1) in quantitative yield.
The crude product was purified by recrystallization from methanol
and chloroform mixture to afford light brown coloured microcrys-
talline powder of N-(4-amino-2-phenoxyphenyl) methanesulfon-
amide (2). Mp 198(2) °C. Elemental analysis: found C 56.25, H
5.07, N 10.26%; calculated for C13H14N2O3S: C 56.10, H 5.07, N
10.06%.
crystalline powder of N-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-
2-phenoxyphenyl] methanesulfonamide (3) (yield 70%).
Microwave assisted method: a mixture of compound 2 (278 mg,
1.0 mmol), phthalic anhydride (1.0 mmol) and sodium acetate
(100 mg) was exposed to microwave irradiation in a domestic
microwave oven operating at 2450 MHz. After completion of reac-
tion, the mixture was diluted with cold water (50 mL), stirred vig-
orously, filtered and dried to obtain the desired product 3 (yield
73%). Mp 231(2) °C. Elemental analysis: found C 61.70, H 3.94, N
6.89%, calculated for C21H16N2O5S: C 61.75, H 3.5, N 6.86%.
Elemental analyses (C, H, N) were performed using a Perkin–El-
mer 240 C analyzer.
The cyclic amide, N-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-
phenoxyphenyl] methanesulfonamide (3), was synthesized as fol-
lows. Anhydrous sodium acetate (100 mg) was added to a mixture
of compound
2 (278 mg, 1.0 mmol) and phthalic anhydride
(1.0 mmol) in glacial acetic acid (3 mL) and the mixture was allowed
to reflux for 10 min. After completion of the reaction, the mixture
was poured into crushed ice (50 g) and stirred. The solid separated
was filtered and dried. The crude product on purification by column
chromatography and crystallization from methanol yielded micro-
2.2. X-ray structure analysis
X-ray powder diffraction data were recorded at ambient tem-
perature on a Bruker D8 Advance diffractometer operating in the
Fig. 1. Final Rietveld plots and molecular views of (a) C13H14O3N2S (2) and (b) C21H16O5N2S (3) with atom numbering scheme. Red crosses: observed pattern, green curve:
calculated pattern, pink curve: difference curve. The vertical scale of the 40–100° (2h) portion of the profiles has been multiplied by a factor of 10. (For interpretation of the
references in colour in this figure legend, the reader is referred to the web version of this article.)

A. Bhattacharya et al. / Chemical Physics Letters 493 (2010) 151–157
153
reflection mode and using CuK radiation (k = 1.5406 Å) selected
with a germanium (1 1 1) incident-beam monochromator for 2,
program FOX [20]. The initial molecular geometry input in FOX
was determined by the MOPAC 5.0 program [21].
a
1
and CuK radiation (k = 1.5418 Å) for 3. The indexing of X-ray pow-
The atomic coordinates obtained from FOX were used as the
starting model for the Rietveld refinement using the GSAS program
package [22] with an EXPGUI [23] interface. The lattice parameters,
background coefficients and profile parameters were refined
initially followed by the refinement of positional coordinates of
all non-hydrogen atoms with soft constraints on bond lengths
and bond angles, and planar restraints on the phenyl and isoin-
dol-2-yl moieties. The background was described by the shifted
Chebyshev function of first kind with 10 points regularly distrib-
uted over the entire 2h range. A common isotropic displacement
parameter has been refined for all non-hydrogen atoms in 2 and
3. Hydrogen atoms were placed at the calculated positions with a
fixed value of isotropic displacement parameter (0.08 Å2). In the fi-
nal stage of refinement, preferred orientation correction was ap-
plied using the generalized spherical harmonic model. The
powder sample of 2 was textured and the order of spherical har-
monics necessary to describe the preferred orientation was 18
(texture index = 1.60). In 3, however, spherical harmonics of order
four was found to be adequate. The Rietveld refinement of 2 and 3
yielded good quality of fits (Fig. 1) with Rp = 0.0553, Rwp = 0.0758
a
der pattern of 2 using the program NTREOR [16] indicated a mono-
clinic unit cell with a = 14.423(3), b = 12.514(4), c = 7.661(5) Å
and b = 100.11(1)° [M(20) = 17, F(20) = 35 (0.011 605, 50)]. In 3,
the indexing result showed a triclinic unit cell with a = 8.643(4),
b = 19.910(2), c = 5.616(4) Å,
a = 90.40(3), b = 95.62(1) and
c
= 91.81(2)° [M(20) = 38, F(20) = 75 (0.012 955, 89)]. Statistical
analysis of powder patterns using the EXPO 2004 [17] indicated
ꢀ
the most probable space group as P21/a for 2, and P1 for 3, which
were used for structure solution. The full pattern decomposition
was performed in each case with EXPO 2004 following the Le Bail
algorithm and using a Pearson VII peak profile function [18]. Good
quality Le Bail fits, Rp = 0.085 in 2 and Rp = 0.065 in 3, indicated the
correctness of unit cells and the estimates of profile parameters for
subsequent structure solution. The structures of 2 and 3 were
solved by global optimization of structural models in direct-space
based on a Monte Carlo search using the simulated annealing tech-
nique [19] (in parallel tempering mode), as implemented in the
and R2F = 0.1432 for
2
and Rp = 0.0464, Rwp = 0.0634 and
Table 1
Crystal data and structure refinement parameters of
C
13H14O3N2S (2) and
R2F = 0.0498 for 3. Relevant crystal data for 2 and 3 are summarized
C21H16O5N2S (3).
in Table 1.
Compound
C13H14O3N2S
(2)
C21H16O5N2S
(3)
C13H12O5N2S
(1)a
2.3. Computational details
Formula weight
Temperature (K)
Crystal system
Wavelength (Å)
Space group
a (Å)
278.33
293(2)
Monoclinic
1.5406
P 21/a
14.427(1)
12.521(1)
7.658(1)
90.0
100.14(1)
90.0
1361.8(3)
4
408.43
293(2)
Triclinic
1.5418
308.31
293(2)
Monoclinic
1.5418
C 2/c
33.657(3)
5.131(1)
16.082(1)
90.0
92.37(1)
90.0
2774.5(3)
8
Density functional theory (DFT) calculations have been carried
out in the solid state (periodic) for 2 and 3 with the DMOL3 code
[24] in the framework of a generalized-gradient approximation
(GGA) [25]. The geometry optimization was performed using the
BLYP density functional [26,27] and a double numeric plus polari-
zation (DNP) basis set. The atomic coordinates were taken from the
final X-ray refinement cycle. Geometry optimizations were carried
out without any structural constraints. The electronic structures
were also calculated at the same level.
ꢀ
P1
8.659(3)
19.949(8)
5.629(2)
90.40(1)
95.64(1)
91.79(1)
967.2(11)
2
b (Å)
c (Å)
a
(°)
b (°)
(°)
c
Volume (Å3)
Z
Density (calculated)
1.358
1.403
1.476
g cmÀ3
2.4. Anti-inflammatory property evaluation
2h interval (°)
Step size (°)
Counting time (s)
No. of variable
parameters
No. of background
points
3–100
0.02
25
5–100
0.02
50
5–115
–
–
194
Male adult albino Wister rats (100–200 g) were divided into
separate groups of six animals each. The anti-inflammatory activity
of compounds 2 and 3 was evaluated following the method de-
scribed by Winter et al. [28]. The pedal inflammation in rat paws
was induced by sub plantar injection of 0.1 ml carrageenan
(0.2%) suspension in gum acacia into the right hind of rats. The
rat paw thickness was measured with a vernier calipers before
and 1 h after the carrageenan injection. The compounds 2 and 3
were injected (100 mg/kg) intraperitoneally to separate groups of
181
123
10
10
–
Rp/R1
0.0553
0.0758
0.1432
0.0464
0.0634
0.0498
0.0401
0.1146
–
Rwp/wR
RF2
v2/S
3.10
8.23
1.25
a
Structural data of C13H12O5N2S (1) are taken from Dupont [29].
Table 2
Hydrogen bond geometries (Å, °) in C13H14O3N2S (2) and C21H16O5N2S (3).
D–H. . .A
d(D–H)
d(H. . .A)
d(D. . .A)
<(DHA)
Symmetry
C13H14O3N2S (2)
N1–HN1A. . .O3
N1–HN1B. . .O2
N2–HN2. . .N1
0.87
0.87
0.88
2.44
2.42
2.34
3.274(4)
3.179(4)
2.923(6)
161.7
146.6
124.2
x + 1/2, Ày + 1/2, z
Àx + 1/2, y + 1/2, Àz + 1
Àx + 1/2, yÀ1/2, Àz
C21H16O5N2S (3)
N2–HN2. . .O3
C18–H18. . .O4
C21–H21. . .O5
C13–H13B. . .O2
Cg(4)–Cg(4)
0.91
0.97
0.97
0.98
–
2.26
2.60
2.54
2.61
–
3.060(2)
3.441(2)
3.324(2)
3.510(2)
4.576(8)
4.623(8)
146.8
145.1
137.8
152.4
–
Àx + 2, Ày + 2, Àz + 1
Àx + 1, Ày + 1, Àz
Àx + 2, Ày + 1, Àz + 2
Àx + 1, Ày + 2, Àz + 1
Àx + 1, Ày + 1, Àz + 1
Àx + 2, Ày + 1, Àz + 1
Cg(4)–Cg(4)
–
–
–
Cg(4) is the centroid of the (C15/C16/C18–C21) phenyl ring.

154
A. Bhattacharya et al. / Chemical Physics Letters 493 (2010) 151–157
Fig. 2. Two-dimensional molecular assembly built with R4(12) and R4(36) rings in C13H14O3N2S (2).
4
4
rats 1 h after the carrageenan injection. The control groups re-
ceived the vehicle (5% gum acacia), while diclofenac sodium at a
dose of 10 mg/kg was injected to the reference group. The differ-
ence between the thickness of two paws before and 1 h after the
injection of the test compound (2 or 3) was taken as a measure
of edema inhibition.
NHSO2CH3 moiety, the sulfur–oxygen bond distances in 2 and 3
[1.427(7)–1.452(8) Å] are consistent with S@O distance and are
similar to those found in related compounds [31–33]. These obser-
vations are supported by the DFT structure optimizations.
The crystal packing in 2 and 3 is stabilized by a combination of
intermolecular N–H. . .O and C–H. . .O hydrogen bonds, and
p. . .p
stacking interactions (Table 2). The supramolecular assembly in
the compounds can be readily analyzed in terms of substructures
of lower dimensionality with dimeric or tetrameric unit as the
building block. Two pairs of intermolecular N–H. . .O hydrogen
bonds in 2 (Table 2) with the amine N1 atom in the molecule at
(x, y, z) acting as a double donor to the sulfonamide oxygen atoms
O2 at (1/2 À x, 1/2 + y, 1 À z) and O3 at (1/2 + x, 1/2 À y, z) connect
sets of four molecules into two types of rectangular motifs of inner
core dimensions 4.5 Â 4.4 Å2 and 8.9 Â 10.5 Å2, respectively
(Fig. 2). In terms of the graph set notation [34], these can be de-
scribed as R44(12) and R44(36) rings. Adjacent R44(12) and R44(36) rings
are edge fused to produce a two-dimensional supramolecular
assembly in 2 (Fig. 2).
In 3, a pair of intermolecular C–H. . .O hydrogen bonds (Table 2)
between the centrosymmetrically related molecules involving the
dioxoisoindol-2-yl atoms, C18 at (x, y, z) and O4 at (1 À x, 1 À y,
Àz), generates an R22(10) dimeric ring (M), Fig. 3, centered at (1/2,
1/2, 0). Similarly, pairs of intermolecular C21–H21. . .O5 hydrogen
bonds (Table 2) form another type of R22(10) ring (N), Fig. 3, cen-
tered at (1, 1/2, 1). The two types of R22(10) rings are linked alter-
nately to produce a C(13) chain [34] along the [1 0 2] direction
with a MNMN. . . sequence (Fig. 3). The parallel C(13) chains are
joined through pairs of N2–HN2. . .O3 hydrogen bonds to form a
rectangular two-dimensional grid of dimension 21.8 Â 10.7 Å2.
The stacking of rectangular grids along the [1 0 0] direction via
3. Results and discussion
3.1. Crystal and molecular structure
The molecular views of 2 and 3 with atom labeling scheme are
shown in Fig. 1. The compounds 2 and 3 are the first structurally
characterized nimesulide derivatives with substitution in the nitro
group. The essential difference between the nimesulide (1) and the
compounds 2 and 3 is that the nitro group in 1 is replaced by an
amino group in 2 and dioxoisoindol-2-yl moiety in 3. The overall
molecular conformation in 2 and 3 can be described in terms of
dihedral angle between the oxygen-bridged phenyl rings, (C1–
C6) and (C7–C12), of 66.4(2)° in 2 and 65.8(6)° in 3, and the orien-
tation of the methanesulfonamide group, which restricts any intra-
molecular C–H. . .O hydrogen bond. In the nimesulide (1) structure
[29], the oxygen-bridged phenyl rings are inclined to each other by
74.69(8)°. The displacement of the oxygen atoms of the sulfon-
amide group prevents any hydrogen bond inside the COX-2 active
site and consequently forms a less stable enzyme–ligand complex.
Significant differences in the orientation of the methyl group with
respect to the C6–N2 bond in the structures are established by the
torsion angle C6–N2–S1–C13 of À56.1(5)° in 2 and À78.0(9)° in 3.
A
comparison of C6–N2 [1.397(8)–1.419(6) Å] and N2–S1
[1.631(6)–1.658(7) Å] bond lengths in 2 and 3 (Supplementary Ta-
ble 1) with that of nimesulide (1), 1.409(4) Å and 1.640(2) Å, where
the sulfonamide group is not deprotonated, indicates that the com-
pounds 2 and 3 are in the neutral form; the corresponding C6–N2
and N2–S1 distances in the zwitterionic form of nimesulide ana-
logue are 1.354(2) Å and 1.609(1) Å, respectively [30]. For the –
p. . .p interactions between the aryl rings of isoindol-2-yl groups
results into a three-dimensional supramolecular structure in 3.
Within the stack, the phenyl rings (C15/C16/C18–C21) of the mol-
ecules at (x, y, z) and (1 À x, 1 À y, 1 À z), (2 À x, 1 À y, 1 À z) are
strictly parallel with interplanar spacings of 3.98 and 3.64 Å,

A. Bhattacharya et al. / Chemical Physics Letters 493 (2010) 151–157
155
Fig. 3. A view of R2(10) rings and formation of two-dimensional grid in C21H16O5N2S (3).
2
3.5 Å). The evaluated
DEHB energies in 2 and 3 are 9.24 and
10.79 kcal molÀ1, respectively.
3.2. Electronic structure
The superposition of molecular geometries of 2 and 3 as estab-
lished by the quantum mechanical calculations and the X-ray
structure analyses shows excellent agreements (Fig. 4). Our DFT
calculations concur that the observed molecular conformation is
very close to that obtained via geometry optimization with regard
to orientation of the methanesulfonamide group and also the twist
of the phenyl ring (C7–C12) about the O1–C7 bond. The molecular
energies of the X-ray analyzed and DFT calculated structures were
À148.80 and À157.23 eV in 2, and À221.89 and À230.04 eV in 3.
The r.m.s. deviations between the geometrically optimized bond
lengths, bond angles and the corresponding crystallographically
determined values are 0.016 Å, 3.6° in 2, and 0.022 Å, 3.1° in 3.
The net charges of atoms and dipoles calculated at the BLYP le-
vel (Supplementary Table 2) indicate that all oxygen and nitrogen
atoms in the molecules of 2 and 3 bear negative charges, and the
sulfur atom (S1) of the methanesulfonamide group and the carbon
atoms of the oxygen-bridged phenyl rings having substitutions
(C3, C5, C6 and C7) bear positive charges; the remaining carbon
atoms (except C14–C17 atoms in 3) bear negative charges. Due
to this charge redistribution, the dipole of the molecule becomes
2.84 a.u. for 2 and 2.81 a.u. for 3, respectively.
Fig. 4. Superposition of molecular conformation as obtained from X-ray structure
analysis (blue) and solid state DFT calculation (red) for (a) C13H14O3N2S (2) and (b)
C21H16O5N2S (3). (For interpretation of the references in colour in this figure legend,
the reader is referred to the web version of this article.)
respectively; the corresponding ring offset and ring centroid sepa-
rations are 2.27/4.576(8) Å and 2.85/4.623(8) Å, respectively.
Hydrogen bond energies have been calculated for 2 and 3 as the
energy difference,
DEHB, between the molecular packing with
(D. . .A < 3.5 Å) and without hydrogen bond interaction (D. . .A >

156
A. Bhattacharya et al. / Chemical Physics Letters 493 (2010) 151–157
Fig. 5. Charge density of (a) HOMO and (b) LUMO orbitals of C13H14O3N2S (2) calculated by DFT method.
Fig. 6. Charge density of (a) HOMO and (b) LUMO orbitals of C21H16O5N2S (3) calculated by DFT method.
The HOMO (highest occupied molecular orbital) and LUMO
a low-lying HOMO [36]. In the present work, the HOMO–LUMO en-
ergy gap in 3 (2.21 eV) is found to be smaller than that in 2
(3.42 eV), which suggests that the compound 3 is likely to be more
reactive than compound 2. The differences between the orbital
energies corresponding to HOMOÀ1 and HOMOÀ2 of 0.67 eV in
2 and 0.54 eV in 3 are much larger than 0.05 eV, which indicate
that the HOMOÀ1 and HOMOÀ2 energy levels in compounds 2
and 3 are non-degenerate. Similar conclusion can be drawn
from the LUMO+1 and LUMO+2 orbital energy calculations in 2
and 3.
According to the molecular orbital theory, HOMO and LUMO are
two important factors influencing the bioactivity of a compound.
Preliminary results of anti-inflammatory activity test using the
rat carrageenan paw edema model indicate that compound 3 can
induce 34% edema inhibition in the rat paws, while compound 2
does not exhibit any anti-inflammatory activity; the corresponding
edema inhibition with diclofenac sodium (reference drug) is 66%.
The interaction between compound 3 and the receptor cells of in-
(lowest unoccupied molecular orbital) wave functions in mole-
cules of 2 and 3 are quite different, and the charge densities for
the HOMO and LUMO in 2 (Fig. 5) and 3 (Fig. 6) indicate very little
charge accumulation on the hydrogen atoms. In 2, the HOMO is
primarily localized on the electron-rich amino and methanesulfon-
amide groups at the C3 and C6 positions of the phenyl ring A (C1–
C6) as well as on the bridging oxygen atom (O1) with hardly any
population on the phenyl ring B (C7–C12). In the HOMO of 2, the
benzene ring (A) atoms have equal contribution and show bond-
ing–antibonding patterns characteristic of phenyl ring system. It
is worth pointing out that the corresponding HOMO population
in 3 is associated with both oxy-bridged phenyl rings A and B,
the nitrogen (N1 and N2) and oxygen (O1) atoms. The LUMO in 2
is populated on the carbon atoms of phenyl rings A and B with only
minor population localized on the bridging oxygen (O1) and amide
nitrogen (N1) atoms. In 3, however, the LUMO population is lo-
cated mainly on the dioxo-1,3-dihydroisoindol-2-yl part of the
molecule with almost no charge accumulation on the phenoxyphe-
nyl methanesulfonamide fragment.
flamed tissue in animal models can be dominated by
p. . .p or
hydrophobic interactions among the frontier orbitals. The negative
charges in 3, mainly located on the nitrogen and oxygen atoms of
the sulfonamide and dioxoisoindol-2-yl groups, are likely to inter-
act with the positive part of the receptor. The most positively
charged parts of 3, on the contrary, will interact quite easily with
the negatively charged part of the receptor. The anti-inflammatory
activity of 3 can possibly be attributed to the presence of additional
oxygen acceptor atoms in the dioxoisoindol-2-yl part of the mole-
The orbital energy level analysis at the BLYP level shows EHOMO
and ELUMO values of À4.86 and À1.44 eV for 2, and À5.52 and
À3.31 eV for 3, respectively. The HOMO–LUMO energy separation
has been used as an indicator of kinetic stability of the molecule
[35,36]. A large HOMO–LUMO gap implies a high kinetic stability
and low chemical reactivity, because it is energetically unfavorable
to add electrons to a high-lying LUMO or to extract electrons from

A. Bhattacharya et al. / Chemical Physics Letters 493 (2010) 151–157
157
cule and the molecular conformation which facilitate
ing interaction.
p. . .
p
stack-
data associated with this article can be found, in the online version,
at doi:10.1016/j.cplett.2010.05.009.
References
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Financial support from the University Grants Commission, New
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Crystallographic data for the structures C13H14O3N2S (2) and
C21H16O5N2S (3) reported in this article have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 761790 and 761791. Supplementary