Synthesis, structure, theoretical calculations and biological activity of sulfonate active ester new derivatives

Article abstract of DOI:10.1016/j.molstruc.2013.04.025

A series of naphthyl and tolyl sulfonate ester were synthesized and characterized by H NMR. X-ray single crystal diffraction experiments established the molecular structure of three new sulfonate esters derivatives, and spectral data agree with these in solution. The observed hydrogen bonding is discussed on the basis of crystal structural analyses and DFT/MP2 geometry optimization quantum calculations. Antimicrobial activities were screened for selected compounds against three human cancer cell lines and Mosquito Culex pipiens larvae.

Full text of DOI:10.1016/j.molstruc.2013.04.025

Journal of Molecular Structure 1046 (2013) 147–152
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, structure, theoretical calculations and biological activity of
sulfonate active ester new derivatives
b
c
c
Mohamed Ghazzali a, , Sherine A.N. Khattab , Yasser A. Elnakady , Fahd A. Al-Mekhlafi ,
⇑
Khalid Al-Farhan a, Ayman El-Faham a,b
a Department of Chemistry, College of Science, King Saud University, P.O. 2455, 11451 Riyadh, Saudi Arabia
b Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, 21321 Alexandria, Egypt
c Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
Three structural determinations of
new active ester derivatives are
presented.
ꢀ
ꢀ
Intermolecular interactions were
investigated by DFT-B3LYP theory.
Biological activities were studied for
selected compounds.
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of naphthyl and tolyl sulfonate ester were synthesized and characterized by H NMR. X-ray single
crystal diffraction experiments established the molecular structure of three new sulfonate esters deriva-
tives, and spectral data agree with these in solution. The observed hydrogen bonding is discussed on the
basis of crystal structural analyses and DFT/MP2 geometry optimization quantum calculations. Antimi-
crobial activities were screened for selected compounds against three human cancer cell lines and Mos-
quito Culex pipiens larvae.
Received 6 February 2013
Received in revised form 19 March 2013
Accepted 11 April 2013
Available online 25 April 2013
Keywords:
Ó 2013 Elsevier B.V. All rights reserved.
Sulfonate active ester
N-protected amino acid
X-ray single crystal diffraction
Biological activity
DFT/MP2 calculations
1. Introduction
combine with amine groups when both are mixed. The so-called
peptide coupling reagents are then responsible for activation of
The active esters are well known precursors in peptide bond
reaction for both liquid- and solid-state synthesis [1,2]. An impor-
tant step in peptide bond formation is the development of N-pro-
tected amino acid derivatives that are reactive enough to
amino acids during the condensation step [3]. A major class of pep-
tide coupling reagents is based on sulfonate ester derivatives of
both 1-hydroxy benzotriazole, abbreviated afterwards as HOBt
(1–5 in Fig. 1) and 7-aza-1-hydroxy benzotriazole, abbreviated
afterwards as HOAt (6–10 in Fig. 1) [4]. The reactivity of such sul-
fonate esters was shown to be directly related to the presence of
⇑
Corresponding author. Tel.: +966 14673734.
E-mail addresses: mghazzali@ksu.edu.sa, m.ghazzali@gmail.com (M. Ghazzali).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.04.025

148
M. Ghazzali et al. / Journal of Molecular Structure 1046 (2013) 147–152
Fig. 1. Library of sulfonate active esters derived from HOBt (1–5), HOAt (6–10), Ethyl cyanoglyoxylate-2-oxime 11, 12 and 1-hydroxypyridin-2-one 13.
electron withdrawing substituents in both benzotriazole and sulfo-
nate moieties [5].
30 min and then at room temperature for 2 h. After dilution with
30 mL of CH2Cl2, the organic phase was washed with water and
dried over anhydrous Na2SO4. After solvent evaporation, the resi-
due was recrystallized from CH2Cl2/hexane to give the correspond-
ing sulfonate esters.
However, the use of sulfonate esters are showing a scarce prac-
tice, since it is depending on the basicity of the amine component,
while the in situ coupling method via the active ester intermediate
is often compromised with a formation of sulfonamide byproduct
[6]. Because of the explosive character of HOBt and it derivatives
[7], one of us recently reported [8] the synthesis of sulfonate esters
based on ethyl cyanoglyoxylate-2-oxime 11 and 12 as well 1-hy-
droxy-2-pryridinone 13 (Fig. 1) as new coupling agents. These
derivatives showed some advantages over those of HOBt or HOAt
in terms of yield, racemization-free reactivity with byproduct min-
imization. We are reporting here the synthesis, spectral character-
ization and molecular structure elucidation of three new sulfonate
ester derivatives, evincing the O-form configuration of synthesized
esters. We are extending the work to the structural and theoretical
calculations of intermolecular interactions, existing in the solid
phase of these compounds. The biological activity studies of some
selected derivatives showed a moderate anti-proliferative effect
against human cancer cell line SW756 for two compounds, while
one derivative showed a strong growth inhibition for mosquito
Culex pipiens 4th instar larvae.
2.1.1. 1H-benzo[d][1-3]triazol-1-yl naphthalene-2-sulfonate 1
Colorless crystals in yield 80%, mp 128–129 °C, 1H NMR
(500 MHz, CDCl3) 7.43 (t, 1H, Ar–H, J = 8.4 Hz), 7.57 (t, 1H, Ar–H,
J = 7.7 Hz), 7.65 (t, 2H, Ar–H, J = 8.4 Hz), 7.75 (t, 1H, Ar–H,
J = 8.4 Hz), 7.88–8.00 (m, 4H, Ar–H), 8.07 (d, 1H, Ar–H, J = 8.4 Hz),
8.45 (s, 1H, Ar–H). 13C NMR (125 MHz, CDCl3): 109.57, 120.41,
123.16, 125.46, 128.31, 128.41, 128.85, 128.98, 129.45, 129.87,
130.41, 130.81, 131.95, 132.81, 136.46, 143.80.
2.1.2. 1H-benzo[d][1,2,3]triazol-1-yl 4-methylbenzene sulfonate 3
Colorless crystals in yield 79%, mp 80–81 °C, 1H NMR (500 MHz,
CDCl3): 2.52 (s, 3H, CH3), 7.38–7.44 (m, 3H, Ar–H), 7.57 (t, 1H, Ar–
H, J = 7.7 Hz), 7.62 (d, 1H, Ar–H, J = 8.6 Hz), 7.76 (d, 2H, Ar–H,
J = 8.6 Hz), 7.99 (d, 1H, Ar–H, J = 8.6 Hz). 13C NMR (125 MHz,
CDCl3): 22.08, 109.61, 120.35, 125.39, 127.14, 128.83, 129.16,
129.37, 129.90, 130.60, 143.01, 148.12.
2. Experimental
2.1.3. 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl naphthalene-2-sulfonate 6
colorless crystals in yield 85%, mp 141–143 °C, 1H NMR
(500 MHz, CDCl3): 7.43 (dd, 1H, Ar–H, J = 8.4, 4.6 Hz), 7.67 (t, 1H,
Ar–H, J = 8.4 Hz), 7.75 (t, 1H, Ar–H, J = 8.4 Hz), 7.96–7.99 (m, 3H,
Ar–H), 8.08 (d, 1H, Ar–H, J = 8.4 Hz), 8.36 (d, 1H, Ar–H, J = 9.2 Hz),
8.54 (s, 1H, Ar–H), 8.71 (d, 1H, Ar–H, J = 5.4 Hz). 13C NMR
(125 MHz, CDCl3): 121.36, 123.30, 128.28, 128.36, 129.52, 129.57,
129.86, 130.33, 130.75, 131.97, 132.80, 134.53, 136.44, 152.45.
Melting points were measured by Mel-Temp apparatus. NMR
spectra were recorded on a 500 MHz JEOL spectrophotometer.
Chemical shifts relative to TMS internal reference are reported in
d-units.
2.1. General method for the synthesis of sulfonate esters
Adopting a method reported earlier [9], 5 mmol suspension of
either 1-hydroxy benzotriazole or 7-aza-1-hydroxy benzotriazole
or ethyl 2-cyano-2-(hydroxyimino)acetate or 1-hydroxypyridin-
2(1H)-one in 30 mL of anhydrous CH2Cl2 was added to 5 mmol of
triethylamine with magnetic stirring. The resulting clear yellow
solution was cooled in an ice bath under N2 atmosphere and trea-
ted slowly with one equivalent of 4-tosyl chloride or 2-naphtha-
lenesulfonyl chloride. The reaction mixture was stirred at 0 °C for
2.1.4. 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 4-methylbenzene
sulfonate 8
Colorless crystals in yield 76%, mp 131–133 °C, 1H NMR
(500 MHz, CDCl3): 2.51 (s, 3H, CH3), 7.41–7.45 (m, 3H, Ar–H),
7.87 (d, 2H, Ar–H, J = 7.6 Hz), 8.38 (d, 1H, Ar–H, J = 8.4 Hz), 8.77
(dd, 1H, Ar–H, J = 4.6, 1.6 Hz). 13C NMR (125 MHz, CDCl3): 22.13,
121.37, 129.53, 129.65, 129.98, 130.85, 134.55, 140.65, 148.05,
152.50.

M. Ghazzali et al. / Journal of Molecular Structure 1046 (2013) 147–152
149
2.1.5. Ethyl 2-cyano-2-(naphthalen-2-ylsulfonyloxyimino) acetate 11
Colorless crystals, 1.53 g (92%), mp 94–95 °C; 1H NMR
(500 MHz, CDCl3): 1.35 (t, 3H, CH3, J = 7.7 Hz), 4.38 (quart, 2H,
CH2, J = 7.7 Hz), 7.69, 7.75 (2t, 2H, Ar–H, J = 7.7 Hz), 7.95–7.97 (m,
2H, Ar–H), 8.03 (d, 1H, Ar–H, J = 2.3 Hz), 8.05 (d, 1H, Ar–H,
J = 3.8 Hz), 8.68 (s, 1H, Ar–H). 13C NMR (125 MHz, CDCl3): 13.98,
64.69, 106.19, 123.14, 128.22, 128.37, 129.84, 130.00, 130.09,
130.58, 131.46, 131.96, 132.35, 155.94.
DIAMOND package [12]. Crystallogrpahic data are summarized in
Table 1.
4. Theoretical calculations
The ab initio DFT quantum calculations for 1, 6 and 13 were cal-
culated with SPARTAN08 package [13]. The starting z-matrices
were truncated from X-ray derived coordinates and used without
geometrical constraints. The geometry optimizations were per-
formed at ground state by Hartree–Fock 6-31GÃ theory. The Hes-
sians analysis shows only non-imaginary frequencies. The density
was calculated using the B3LYLP functional as a perturbation on
self consistent density with 6-31+GÃ basis set. The PESs were calcu-
lated with BSSE-corrected MP2 6-31+GÃ level of theory. Basically,
MP2 is known to consistently provide a good description of inter-
molecular interactions [14]. These calculations have been carried
out with a high accuracy large integration grid, so that sensitivity
is minimized.
2.1.6. Ethyl 2-cyano-2-(tosyloxyimino) acetate 12
Colorless crystals in yield 85%, mp 64–65 °C. 1H NMR (500 MHz,
CDCl3): 1.37 (t, 3H, CH3, J = 6.9 Hz), 2.48 (s, 3H, CH3), 4.40 (quart,
2H, CH2, J = 6.9 Hz), 7.40 (d, 2H, Ar–H, J = 7.6 Hz), 7.92 (d, 2H, Ar–
H, J = 7.6 Hz). 13C NMR (125 MHz, CDCl3): 14.00, 22.00, 64.66,
106.20, 129.64, 130.18, 130.36, 131.26, 147.39, 156.02.
2.1.7. 2-Oxopyridin-1(2H)-yl 4-methylbenzene sulfonate 13
Colorless crystals in yield 78%, mp 92–94 °C, 1H NMR (500 MHz,
CDCl3): 2.47 (s, 3H, CH3), 6.15 (dt, 1H, Ar–H, J = 6.4, 1.6 Hz), 6.51
(dd, 1H, Ar–H, J = 9.2, 1.6 Hz), 7.29 (m, 1H, Ar–H), 7.37 (d, 2H,
Ar–H, J = 8.0 Hz), 7.59 (dd, 1H, Ar–H, J = 7.2, 2.0 Hz), 7.89 (d, 2H,
Ar–H, J = 8.4 Hz). 13C NMR (125 MHz, CDCl3): 22.19, 105.32,
123.41, 130.01, 130.07, 130.09, 130.14, 130.19, 130.67, 137.16,
139.60, 147.44, 157.04.
5. Biological activity
5.1. Cell culture
Cell lines were obtained from the American Type Culture Collec-
tion (ATCC) and the German Collection of Microorganisms and Cell
Cultures (DSMZ). All cell lines were cultured under the conditions
recommended by their respective depositors. Media were pur-
chased from Sigma and Fetal Bovine Serum (FBS) was supplied
by Invitrogen.
3. X-ray single crystal diffraction
Suitable single crystals of compounds 1, 6 and 13 were selected,
glued and mounted onto thin glass capillary. Diffraction data were
collected using a Rigaku R-axis SPIDER diffractometer equipped
5.2. Cell proliferation assay
with imaging plate area detector utilizing Mo
(k = 0.71075 Å) with graphite monochromator. The data were col-
lected using -scans at a temperature of 294 2 K to a maximum
Ka radiation
Growth inhibition was measured in 96-well plates. Aliquots of
120
60
l
L of the suspended cells (5 Â 104 Cells/mL) were given to
x
l
L of compound solutions. After 5 days, growth was determined
2h of 55.0°. Preliminary orientation matrices, unit cell determina-
tion, data reduction and absorption correction were performed
using CrystalClear package [10]. The data were empirically cor-
rected for Lorentz and polarization effects. Structures were solved
by direct methods and refined by full-matrix least squares on all
|F2| data using SHELX package [11]. Hydrogen atoms were isotrop-
ically refined and constrained to ideal geometry, using their appro-
priate riding model and non-hydrogen atoms were anisotropically
refined. The crystallographic descriptive figures were created using
using MTT assay [15].
5.3. Mosquito culture
Cx. pipiens larvae were obtained from an in-house maintained
colony and reared indoor at 27 2 °C of 50 5% relative humidity
with 14:10 h/day of light:dark period. The emergent adults were
fed with a 10% glucose solution in a jar with cotton wick. The
Table 1
Crystallographic data and refinement details for compounds 1, 6 and 13.
1
6
13
Formula
C
16H11N3O3S
C15H10N4O3S
326.34
Triclinic
C12H11NO4S
265.29
Monoclinic
P21/a
15.2735(16)
5.5502(6)
16.0039(16)
90
114.376(3)
90
Formula weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
325.35
Monoclinic
P21/a
8.0778(9)
14.5640(14)
12.8205(12)
90
99.879(3)
90
P-1
7.3199(7)
7.8798(7)
13.3033(12)
72.163(2)
86.170(2)
89.228(3)
728.79(12)
2
a
(°)
b (°)
c
(°)
V (Å3)
1485.9(3)
4
1235.7(2)
4
Z
D (calc) (g/cm3)
h Min–Max (°)
Dataset (h;k;l)
Tot., Uniq. Data, R(int)
Observed data (I > 2.0 d(I))
Nref, Npar
1.454
3.1, 27.5
1.487
3.1, 27.5
1.426
3.1, 27.5
À10:10; À18:17; À16:16
17102, 3407, 0.048
2144
3407, 209
0.0420, 0.1588, 1.00
À0.40, 0.22
À9:9; À10:10; À16:17
7304, 3203, 0.027
2027
3203, 209
0.0426, 0.1703, 1.06
À0.31, 0.24
À19:19; À7:7; À20:20
12776, 2789, 0.052
1973
2789, 164
0.0527, 0.1545, 1.05
À0.30, 0.20
R, wR2, S
Min. and Max. Resd. Dens.

150
M. Ghazzali et al. / Journal of Molecular Structure 1046 (2013) 147–152
adults were given mouse blood meals overnight. Glass Petri dish
lined with filter paper and 100 mL tap water was kept inside the
cage for ovi-position.
5.4. Larvicidal test
c. pipiens 4th instar larvae were tested with different concentra-
tions of compound solutions. Each test solution was placed in 12
multi-well test plates along with the 4th instar larvae. Each exper-
iment was conducted in triplicates and a concurrent control group
was maintained. Dead larvae were counted after 24 h.
Fig. 2. The O- and N- forms of sulphonate active ester.
6. Results and discussion
The sulfonate esters were prepared by reaction of HOBt, HOAt,
ethyl cyanoglyoxylate-2-oxime or 1-hydroxy-2-pryridinone with
the sulfonyl chloride (toluene or naphthalene derivatives) using
two phase DCM-H2O method in presence of Na2SO4 to afford the
corresponding sulfonate ester 1, 3, 6, 8, 11, 12 and 13 (Fig. 1). All
prepared esters were characterized by 1H and 13C NMR spectra,
giving similar data to those earlier reported [9,16]. As hypothesized
from solution characterization, and derived from X-ray single crys-
tal diffraction, the structures of the benzotriazole sulfonate esters
showed that both esters are exist in O-form not N-form (Fig. 2).
In the molecular structures of 1, 6 and 13, the sulfur atoms
adopt a variable distortion degree of tetrahedral geometry. In 1,
the dihedral angle between the best-fit least-square two planes
of HOBt with naphthalene is 33.89(4)°. The same dihedral angle
definition at 6 in-between HOAt and naphthalene is 49.79(5)°.
The bridging C10-S1-O3-N1 sulfonate torsion angle is À67.63(1)°
in 1, 66.36(2)° in 6 and 102.13(2)° in 13.
Table 2
Selected bond distances (Å) and angles (°) for compounds 1, 6 and 13.
1
S1–O1
S1–O2
S1–O3
S1–C10
O3–N1
N1–N2
N1–C11
N2–N3
1.4238(2)
1.4108(2)
1.6803(2)
1.743(2)
1.380(2)
1.351(3)
1.360(3)
1.300(3)
1.388(3)
122.12(11)
105.74(9)
111.19(10)
99.94(11)
111.75(10)
103.52(9)
113.22(12)
118.51(16)
128.15(16)
12.66(17)
107.18(18)
108.43(19)
N2–N3
1.306(4)
O1–S1–O2
O1–S1–O3
O1–S1–C10
O2–S1–O3
O2–S1–C10
O3–S1–C10
S1–O3–N1
O3–N1–N2
O3–N1–C11
N2–N1–C11
N1–N2–N3
13
S1–O1
S1–O2
S1–O3
S1–C7
O3–N1
O4–C12
N1–C8
O1–S1–O2
122.31(15)
100.19(13)
110.87(13)
106.76(12)
110.75(13)
103.65(10)
113.35(13)
120.2(2)
N3–C16
O1–S1–O2
O1–S1–O3
O1–S1–C10
O2–S1–O3
O2–S1–C10
O3–S1–C10
S1–O3–N1
O3–N1–N2
O3–N1–C11
N2–N1–C11
N1–N2–N3
N2–N3–C16
126.9(2)
111.5(2)
107.6(2)
1.416(2)
1.4201(19)
1.6611(19)
1.744(3)
1.399(2)
1.219(3)
Selected bond distances with angles are presented in Table 2
and the molecular structures with thermal ellipsoidal numbering
schemes for 1, 6 and 13 are shown in Fig. 3.
1.366(4)
122.45(12)
In 1,
p–p interactions exist in between the naphthalene rings
6
O1–S1–O3
O1–S1–C7
O2–S1–O3
O2–S1–C7
O3-S1-C7
S1–O3–N1
O3–N1–C8
O3–N1–C12
C8–N1–C12
102.06(11)
109.80(12)
108.28(10)
109.87(12)
102.22(11)
114.55(15)
117.0(2)
and HOBt part, with C–HÁ Á ÁN hydrogen bonding of C(8) first level
chain pattern along the ac-crystallographic plane. Fig. 4 and Table 3
presenting some highlights on the hydrogen bonding geometry
featured in 1, 6 and 13, while for graph set descriptors, the readers
are referred to [17].
S1–O1
S1–O2
S1–O3
S1–C10
O3–N1
N1–N2
N1–C11
1.411(3)
1.418(2)
1.6671(18)
1.741(3)
1.370(3)
1.353(3)
1.367(3)
In 6, having a lower symmetry than 1 beside a clockwise rota-
115.83(19)
127.0(2)
tion of the C10–S1–O3–N1 angle, the
p–p interactions are no long-
er exist and only dimeric molecules are arranged with respect to
Fig. 3. Atomic numbering scheme of 1, 6 and 13 displacement ellipsoids shown at 50% probability level.
Fig. 4. Perspective drawing of the structures in 1, 6 and 13 showing the intermolecular C–HÁÁÁN and C–HÁÁÁO hydrogen bonding. The C–HÁÁÁN in 1 and the C–HÁÁÁO hydrogen
bonding in 6 with 13 are represented as blue and red dotted lines, respectively. For symmetry codes, see Table 3.

M. Ghazzali et al. / Journal of Molecular Structure 1046 (2013) 147–152
151
Table 3
C–HÁ Á ÁO hydrogen bond. In 13, the ketonic (O4) is incorporated in
dimeric C–HÁ Á ÁO interactions.
Hydrogen bonding geometries for compounds 1, 6 and 13.
In order to evaluate the energetic differences and similarities
between hydrogen bonding in 1, 6 and 13, we carried out geometry
optimizations, molecular electronic density and electrostatic den-
sity potentials calculations. The difference in molecular geome-
tries, excluding hydrogen atoms, between the two z-matrices of
single-crystal and geometry-optimized atomic coordinates in 1, 6
and 13 was examined by structural overlay analyses using sulfo-
nate SO2 center. The overlay presented in Fig. 5 showed the
r.m.s. deviation of 0.171, 0.099 and 0.074 Å in 1, 6 and 13 respec-
tively, with a clear effect of replacing HOBt with HOAt in 1 and 6.
D-HÁ Á ÁA
d(HÁ Á ÁA)
d(DÁ Á ÁA)
<(DHA)
165
1
C1–H1Á Á ÁN3i
2.48
3.387(3)
i: À1/2 + x, 3/2 À y, z
6
C14–H14Á Á ÁO2i
i: 1 – x, Ày, Àz
13
2.60
3.345(4)
138
C8–H8Á Á ÁO2i
2.43
2.38
3.342(3)
3.307(3)
166
173
C11–H11Á Á ÁO4ii
i: x, À1 + y, z, ii: Àx, 1 À y, 1 À z
Fig. 5. Structural overlays of single crystal vs. HF-geometry optimized atomic coordinates in 1 (left), 6 (middle) and 13 (right).
Fig. 6. electronic density isosurfaces (mesh in grey) and isoelectrostatic potentials (solid in red) for 1, 6 and 13 calculated by DFTMP2. Isoelectrostatic surfaces are in the range
+10 eV to À10 eV. Scales for electrostatic potentials are given in kJ/mol.
Fig. 7. Effect on the growth of colon human cancer cell line SW756.

152
M. Ghazzali et al. / Journal of Molecular Structure 1046 (2013) 147–152
Table 4
Larvicidal activities of tested compounds against 4th instar larvae of cx. pipiens. Mortality is given as mean e.s.d.%, and control with Nil mortality.
Compound
Concentration (
l
g/mL)
250
500
125
62.5
31.25
15.63
7.81
1
11
12
100
100 + 0
100
0
40.33 3.33
40.33 3.33
16.67 3.33
16.67 3.33
0
0
100
0
0
0
0
10
0
0
0
0
100
0
100
0
0
40.33 3.33
0
The Møller–Plesset second level perturbation theory (MP2) is
computationally – affordable ab-initio quantum calculation with
s- and p-closed shell orbital of reasonable size organic molecules
[18]. The restricted MP2 correlation-corrected density matrix con-
verges at energy slightly higher than SCF gradient. Fig. 6 depicts
the isosurfaces of electronic density and electrostatic density po-
tential. In 1 and 6, the highest negative electronic density or the
lowest delocalization parameter is defined around the triazole N-
atom (N3) with less contribution from the sulfonyl O-atoms (O1
ger. This derivative fully inhibits the development of the larvae at
62.5 g/mL. Further investigations are currently carried out in
order to define the mechanism of larvae growth inhibition by these
l
compounds.
To summarize, we present here the molecular structures X-ray
single-crystal elucidation for three new sulfonate ester derivatives.
We studied the intermolecular interactions in DFT geometry-opti-
mized structures and evaluated the synthesized compounds
against human cancer cells as well as mosquito. One of the tested
compound was able to effectively inhibits the growth at relatively
low concentration.
and O2). An evidence for the p–p interactions can be seen at PESs
of 1. In 13, the negative electronic density is located mainly at the
ketonic O-atom (O4). The electrostatic density potential is inten-
sively localized at the C–HÁÁÁN hydrogen-bonding acceptor atoms
in 1. In 6, the energy associated with the C–HÁÁÁN is greater than
those of C–HÁÁÁO hydrogen bond, while in 13 it is defined only at
the C–HÁÁÁO acceptor, as no C–HÁÁÁN exists, with the greater contri-
Acknowledgment
Authors are thankful for Mr. Almohannad Baabbad and the bio-
products research chair at zoology department KSU for technical
assistance.
bution is at the ketone oxygen atom. Moreover, energy of the p–p
interactions 1 can be seen as almost negligible, compared to those
associated with the C–HÁÁÁN hydrogen bonding.
Appendix A. Supplementary material
To test possible anti-proliferation effects of the compounds,
MTT-assay was performed according to a reported method [15].
Three cell lines were tested: the mouse fibroblast L929, the human
cervices carcinoma cell line KB-3.1, and the human colon cancer
cell line SW756. A constant number of cells were incubated with
a serial dilution of each substance for 5 days under cultivation con-
ditions as described in the method section. Methanol was used as a
negative reference. The viability of the treated cells was calculated
as a percent of the control cells. Fig. 7 shows the effect of the eight
selected compounds on the growth of the SW756 cancer cell line.
Only compounds 3 and 13 showed moderate anti-proliferative
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2013.
04.025.
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500
tion of 250
l
g/mL. The inhibitory effect became around 40% at concentra-
lg/mL. In contrast, the larvicidal effect of 12 was stron-