Synthesis and antitumor evaluation of novel cyclic arylsulfonylureas: ADME-T and pharmacophore prediction

Article abstract of DOI:10.1016/j.ejmech.2010.02.038

Novel derivatives of 5-(substituted)benzylidene-3-(4-substituted)phenylsulfonylimidazolidine-2,4-diones (3a-r), 1-(4-substituted)phenylsulfonyl-3-(4-substituted)phenylpyrimidine-2,4,6-(1H,3H,5H)-triones (6a-l), and 3-(4-substituted)phenyl-1-(4-substituted)phenylsulfonylquinazoline-2,4(1H,3H)- diones (8a-l) have been synthesized and tested for their antitumor activity against 60 tumor cell lines taken from 9 different organs. The tested compounds have showed good inhibitory effect at the ovarian cancer (IGROV1) cell line. A significant inhibition for (RXF393) renal cancer cells was observed with series 3 compounds, while in the other two series 6 and 8, there was a significant inhibition of ovarian cancer cells (OVCAR-8) and melanoma cells (SK-MEL-2). Interestingly; beside the strong inhibition of compound 3q to IGROV1 and RXF393 cells, a great inhibition (199.62%) for (M14) Melanoma cells was observed at the tested concentration (10?μM). ADME-T and pharmacophore prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.

Full text of DOI:10.1016/j.ejmech.2010.02.038

European Journal of Medicinal Chemistry 45 (2010) 2516e2530
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antitumor evaluation of novel cyclic arylsulfonylureas:
ADME-T and pharmacophore prediction
,b,
Ibrahim M. El-Deeb a, Said M. Bayoumi a, Magda A. El-Sherbeny a, Alaa A.-M. Abdel-Aziz a
*
a Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
b Department of Pharmaceutical Chemistry, College of Pharmacy, King Saudi University, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel derivatives of 5-(substituted)benzylidene-3-(4-substituted)phenylsulfonylimidazolidine-2,4-diones
(3aer), 1-(4-substituted)phenylsulfonyl-3-(4-substituted)phenylpyrimidine-2,4,6-(1H,3H,5H)-
triones (6ael), and 3-(4-substituted)phenyl-1-(4-substituted)phenylsulfonylquinazoline-2,4(1H,3H)-
diones (8ael) have been synthesized and tested for their antitumor activity against 60 tumor cell lines
taken from 9 different organs. The tested compounds have showed good inhibitory effect at the ovarian
cancer (IGROV1) cell line. A significant inhibition for (RXF393) renal cancer cells was observed with
series 3 compounds, while in the other two series 6 and 8, there was a significant inhibition of ovarian
cancer cells (OVCAR-8) and melanoma cells (SK-MEL-2). Interestingly; beside the strong inhibition of
compound 3q to IGROV1 and RXF393 cells, a great inhibition (199.62%) for (M14) Melanoma cells was
Received 8 October 2009
Received in revised form
11 February 2010
Accepted 15 February 2010
Available online 20 February 2010
Keywords:
Cancer
Molecular modeling
Imidazolidine
Pyrimidine
Quinazoline
Diarylsulfonylurea
Pharmacophore
observed at the tested concentration (10
mM). ADME-T and pharmacophore prediction methodology
were used to study the antitumor activity of the most active compounds and to identify the structural
features required for antitumor activity.
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
however, other mechanisms, such as inhibition of the mitochondrial
isozyme V of carbonic anhydrase (CAs) have also been hypothesized,
Cancer is continuing to be a major health problem in developing
as well as developed countries [1,2]. Surpassing heart diseases, it is
taking the position number one killer due to various worldwide
factors. Although major advances have been made in the chemo-
therapeutic management of some patients, the continued commit-
ment to the laborious task of discovering new anticancer agents
remains critically important. Among the wide range of compounds
tested as potential anticancer agents, derivatives comprising the
sulfonamide, diarylsulfonylurea and thiourea functionalities have
attracted reasonable attention [3e8], especially after the discovery of
sulofenur [9] (LY186641) A and its structure analogs [8] B and
(LY295501) C (Fig. 1). Sulofenur is an antineoplastic sulfonylurea that
has been clinically evaluated in lung, breast, colon, ovarian, pancre-
atic, and gastric cancer [9]. It is generally assumed that the strong
cytotoxicity and, as a consequence, the antitumor properties of the
diarylsulfonylurea is due to the uncoupling of mitochondria [4,5],
since hydrolysis of the cytotoxic agent leading to the formation of
unsubstituted sulfonamides as the principal products has been
reported both in vivo and in vitro [10]. It is well known that aromatic/
heterocyclic sulfonamides (formed after such a hydrolytic process)
act as very potent inhibitors of CAs [11,12], and that these enzymes
are involved in a multitude of crucial physiologic processes [13].
However, clinical trials of sulofenur have yielded unsatisfactory
results because of its high protein binding and limited dosing caused
by the appearance of anemia, and methemoglobinemia, a side effect
that is likely caused by its aniline-related metabolites [14]. In
contrast; LY295501 (C) is principally metabolized by hydroxylation
with negligible formation of aniline metabolites at relevant doses in
experimental animals and demonstrated impressive activity against
a broad spectrum of human tumor xenografts [15].
Trying to overcome the serious side effects of Sulofenur, several
imidazolidinone derivatives containing diarylsulfonylurea phar-
macophore, have been synthesized and screened for antitumor
activity against various human solid tumors. Among these
compounds are; 1-(4-clorophenylsulfonyl)-4-phenylimidazolidin-
2-one (D) and DW2143 (E) which have shown higher cytotoxic
activity than that of Sulofenur, in addition, there was no production
of methemoglobinemia or hypoglycemia upon administration of
* Corresponding author. Department of Pharmaceutical Chemistry, College of
Pharmacy, King Saudi University, Riyadh 11451, Saudi Arabia. Tel.: þ966 56
2947305; fax: þ966 1 4676220.
E-mail address: alaa_moenes@yahoo.com (A.A.-M. Abdel-Aziz).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.02.038

I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
2517
Fig. 1. Reported (AeE) and proposed (3, 6 and 8) diarylsulfonylureas.
these agents, which indicates a different metabolic fate from that of
2. Results and discussion
Sulofenur (Fig. 1) [16e26]. On the other hand, over the past few
years, much interest has been given to the chemotherapeutic
activity of hydantoins [27e31], quinazolinediones [32,33] and
pyrimidinetriones [34,35] as potential anticancer agents.
2.1. Chemistry
2.1.1. Synthesis of compounds 3aer (Scheme 1, Table 1)
In view of the previous rationale and in continuation of an
ongoing program aiming at finding new structure leads with
potential chemotherapeutic activities, new series of 5-(substituted)
benzylidene-3-(4-substituted)phenylsulfonylimidazolidine-2,4-
diones (3aer), 1-(4-substituted)phenylsulfonyl-3-(4-substituted)
Scheme 1 outlines the synthetic pathway used to obtain
compounds (3aer). The starting materials 5-(substituted)benzyli-
deneimidazolidine-2,4-diones (2aef) were prepared by allowing
hydantoin
1 to condense with the corresponding aromatic
aldehydes in glacial acetic acid and in the presence of fused sodium
acetate as a condensing agent [36]. Upon mixing of 2 with the
appropriate arylsulfonyl chloride and K2CO3 in acetone:
water (1:1); 5-(substituted)benzylidene-3-(4-substituted)phe-
nylsulfonylimidazolidine- 2,4-diones (3aer) were obtained in
relatively good yields. Although geometrical isomerism (E/Z
isomers) was possible because of the restricted rotation about the
exocyclic C]C bond of the arylidene hydantoins, all the derivatives
prepared in this study were obtained exclusively in the Z-form as
confirmed by the analytical data. In all the IR spectra of the prepared
arylidene hydantoins (2aef), and their subsequent arylsulfonyl
derivatives (3aer), the stretching of the C]C bond appeared in
a higher frequency region (1660e1675 cmꢀ1) compared to those
expected for the E-form (1630e1640 cmꢀ1) [37]. Furthermore, the
1H NMR spectra of the prepared arylidene hydantoins have showed
that the most diagnostic olefinic proton, H6 (eCH]) was deshiel-
phenylpyrimidine-2,4,6-(1H,3H,5H)-triones
(6ael),
and
3-(4-substituted)phenyl-1-(4-substituted)phenylsulfonylquinazo-
line-2,4(1H,3H)-diones (8ael) have been synthesized and
screened for cytotoxic activity (Fig. 1). These series comprise the
derived N1,N3-disubstituted sulfonylurea pharmacophores that are
structurally related to sulofenur A and its cyclic form D (Fig. 1). The
thrust of efforts in the derivatization of such type of compounds
focused mainly on the aryl moiety of the sulfonamide portion of
the diarylsulfonylureas. In the present study, such arylsulfonylurea
moiety was incorporated basically as a part of the cyclic structures
of hydantoin because of the reported potential anticancer activity
of this ring system hoping to induce some biological synergism. In
addition, ring replacement of the hydantoin with pyrimidinetrione
and quinazolinedione functionality was considered as an inter-
esting structure variation in order to study the influence of such
modification on the anticipated antitumor activity. The substitu-
tion pattern at the aryl part of the diarylsulfonylurea pharmaco-
phores was selected so as to confer different electronic
environment that would affect the lipophilicity, and hence the
activity of the target molecules. The objective of forming these
hybrids is an attempt to reach an active antitumor agent with
potentiated activity and selectivity toward cancerous cells. More-
over ADME-T and pharmacophore prediction methodology were
used to identify the structural features required for the antitumor
properties of these new series.
ded more (
the slightly shielded proton of the E-form (
deshielding of the olefinic proton is caused by the anisotropic effect
exerted by the nearby C4 carbonyl group in the Z-isomer [37].
d
¼ 6.4e7.0 ppm) as expected in the Z-form, relative to
d
¼ 6.2e6.3 ppm). This
2.1.2. Synthesis of compounds 6ael (Scheme 2, Table 2)
1-(4-Substituted)phenylureas (4aed); which were prepared
according to Hofmann [38,39] procedure by reacting the aromatic
amine with potassium cyanate in water and in the presence of excess
acetic acid; were treated with diethyl malonate in the presence of

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I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
2.2.2. Structureeactivity relationship
O
H2C COOH
H+
By investigating the variation in selectivity of the tested
compounds over the full panel of cell lines, it was revealed that
nearly all of the compounds belonging to the three series
(compounds 3, 6 & 8) show significant inhibition for the ovarian
cancer cell line (IGROV1). The percentages of inhibition for (IGROV1)
ovarian cancer reached 100% in a number of the tested derivatives
(Fig. 2, Table 4). However; a distinguish in selectivity was observed
between the first series (compounds 3), and the second and third
series (compounds 6 and 8). In series 3, a significant inhibition for
(RXF393) renal cancer cells (76.2e96.5%) was observed, while in
both of the other two series 6 and 8, there was a significant inhibition
for another type of ovarian cancer cells (OVCAR-8; 33.2e58.9%) and
melanoma cells (SK-MEL-2; 61.0e79.3%). The agreement between
the three series in the inhibition of (IGROV1) ovarian cancer cells
could be correlated to a similar inhibitory mechanism related to the
common structural feature in the three series (the diarylsulfonylurea
structure), while the variation in selectivity over RXF393, OVCAR-8
and SK-MEL-2 cell lines is probably caused by the differences in
the hydrocarbon skeleton holding the cyclic urea structure in the
three series. These variations could be also correlated to the small
difference in the distance between the cores of the two aryl moieties
of the diarylsulfonylurea structure, where this distance is almost the
same in compounds 6ael and 8ael, while a little bit longer in
compounds 3aer. This variation in distance can account for the
similar inhibitory profiles for series 6 and 8, and its variation in the
compounds belonging to series 3. An odd result was observed with
compound 3q (Fig. 3, Table 5), where beside the strong inhibition of
IGROV1 cells (97.89%) and RXF393 cells (95.74%), a great inhibition
(199.62%) for M14 Melanoma cells was observed at the tested
+
KNCO
HN
NH
NH2
Glycine
O
1
CHO
Glacial acetic acid /
Sodium acetate
X
O
O
Y
1)
K2CO3
/
Acetone : Water
X
X
HN
NH
HN
N
S
2)
SO2Cl
O
O
O
O
3a-r
2a-f
Y
X= H , 4-Br , 4-Cl , 3-NO2 , 4-OCH3 , 4-N(CH3)2
Y= H , Cl , CH3
Scheme 1. Synthesis of 5-(substituted)benzylidene-3-(4-substituted)phenylsulfonyl
imidazolidine-2,4-diones 3aer.
sodium ethoxide/absolute ethanol to afford 1-(4-substituted)phe-
nylpyrimidine-2,4,6-(1H,3H,5H)-triones (5aed) [40]. As previously
mentioned under the preparation of compounds 3aer; compounds
6ael were prepared by addition of the appropriate arylsulfonyl
chloride to a stirred solution of 5aed and K2CO3 in acetone:water
(1:1).
concentration (10
mM). This great inhibition at the mentioned
concentration indicates a great potency for the compound with
a strong lethal effect over (M14) melanoma cells (99.6% lethality),
and suggests an IC50 value in the nanomolar scale.
2.3. Molecular modeling results
2.1.3. Synthesis of compounds 8ael (Scheme 3, Table 3)
3-(4-Substituted)phenylquinazoline-2,4(1H,3H)-diones (7aed)
were prepared by fusing anthranilic acid with 1-(4-substituted)
phenylureas (4aed) [41]. The synthesis of 3-(4-substituted)phenyl-
1-(4-substituted)phenylsulfonylquinazoline-2,4(1H,3H)-diones
(8ael) was performed via the reaction of 3-(4-substituted)phe-
nylquinazoline-2,4(1H,3H)-diones (7aed) with sodium tert-but-
oxide in tert-butanol to induce salt formation, then the separated
salt was refluxed with an equivalent amount of the appropriate
arylsulfonyl chloride in tert-butanol to yield the target products
8ael.
Modeling studies are required in order to construct molecular
models that incorporate all experimental evidence reported. These
models are necessary to obtain a consistent and more precise
picture of the biological active molecules at the atomic level and
furthermore, provide new insights that can be used to design novel
therapeutic agents.
2.3.1. Conformational analysis
In an attempt to gain a better insight on the molecular structures
of the active compounds 3p, 3q, 6k and 8b compared with the least
active species 3b, 6b and 8j as representative examples; conforma-
tional analysis of the target compoundshas beenperformed using the
MMFF94 force-field [42,43] (calculations in vacuo, bond dipole
option for electrostatics, PolakeRibiere algorithm, RMS gradient of
2.2. Biological activity
ꢀ
2.2.1. In vitro antitumor evaluation
0.01 kcal/A mol) implemented in MOE 2009.10 [44]. The most stable
The Thirteen compounds indicated in (Figs. 2 and 3; Tables 4
and 5) were selected by National Cancer Institute, Bethesda,
Maryland, USA on the basis of degree of the structure variation
and computer modeling techniques for evaluation of their
antineoplastic activity. The selected compounds were subjected
to in vitro anticancer assay against tumor cells in a full panel of
60-cell lines taken from 9 different organs (lung, colon, breast,
ovary, blood, kidney, skin, prostate and brain). The compounds
conformer was fully optimized by AM1 [45] semi-empirical molec-
ular orbital calculation (Fig. 4). Calculations at the AM1 level were
considered in order to determine relative energies of the E- and
Z-isomers of 5-arylidenehydantoin derivatives (3). It was found that
the Z-isomer is approximately more stable by more than 3e4 kcal/
mol and thus no double bond isomerisation is anticipated (Fig. 4)
[46]. Moreover the bond distances between N and SO2 was found to
be 1.67 A, and a twisting of c.a. 34 between the arylidene moiety and
hydantoin plane was also found [46]. As clear from the calculations;
series 3 compounds exhibit structural similarity as indicated by their
molecular parameters and are slightly different from series 6 and 8
compounds. The results showed that the lowest energy-minimized
structures of compounds belonging to the three series have exhibited
ꢁ
ꢀ
were tested at a single dose concentration of 10
mM, and the
percentages of growth inhibitions over the sixty tested cell
lines were determined. The percentages of growth inhibitions
over the most sensitive 5-cell lines are shown in Fig. 2 and
Table 4.

I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
2519
Table 1
Physical properties, yields and molecular formulae of the synthesized compounds 3aer
Comp. No.
X
Y
Yield %
68
M.P. ꢁC
Mol. Formula (Mol. Wt)
C16H12N2O4S (328.34)
Analysis
Elm.
Calc.
Found
3a
H
H
274e5
C
58.53
3.68
9.77
58.72
3.28
9.91
H
S
3b
3c
3d
3e
3f
H
Cl
76
63
41
33
37
38
41
40
52
48
45
65
71
62
22
18
18
286e8
253e4
296e7
330e1
294e5
300e2
326e9
310e1
277e9
300e2
291e3
270e2
290e2
255e6
275e7
262e4
292e3
C16H11ClN2O4S (362.79)
C17H14N2O4S (342.37)
C16H11BrN2O4S (407.24)
C16H10BrClN2O4S (441.68)
C17H13BrN2O4S (421.27)
C16H11ClN2O4S (362.79)
C16H10Cl2N2O4S (397.23)
C17H13ClN2O4S (376.81)
C16H11N3O6S (373.34)
C16H10ClN3O6S (407.79)
C17H13N3O6S (387.37)
C17H14N2O5S (358.37)
C17H13ClN2O5S (392.81)
C18H16N2O5S (372.40)
C18H17N3O4S (371.41)
C18H16ClN3O4S (405.86)
C19H19N3O4S (385.44)
C
52.97
3.06
7.72
59.64
4.12
8.18
47.19
2.72
7.87
43.51
2.28
6.34
48.47
3.11
6.65
52.97
3.06
7.72
48.38
2.54
7.05
54.19
3.48
8.51
51.47
2.97
8.59
47.13
2.47
10.3
52.71
3.38
10.85
56.98
3.94
7.82
51.98
3.34
8.16
58.05
4.33
8.61
58.21
4.61
11.31
53.27
3.97
10.35
59.21
4.97
53.33
3.26
7.42
59.82
4.06
8.23
48.31
2.55
8.03
44.02
2.57
6.11
49.14
3.02
6.79
54.17
3.32
7.48
48.22
2.64
6.99
53.74
3.38
8.74
51.68
2.72
8.71
46.88
2.61
10.47
52.44
3.61
10.93
56.49
3.70
7.66
51.66
3.19
8.41
57.78
4.50
8.54
58.61
4.87
11.06
53.88
3.52
10.60
59.09
4.68
H
N
C
H
N
C
H
S
C
H
N
C
H
N
C
H
N
C
H
N
C
H
S
C
H
S
C
H
N
C
H
N
C
H
N
C
H
S
H
CH3
H
4-Br
4-Br
Cl
4-Br
CH3
H
3g
3h
3i
4-Cl
4-Cl
Cl
4-Cl
CH3
H
3j
3-NO2
3-NO2
3-NO2
4-OCH3
4-OCH3
4-OCH3
4-(CH3)2N
4-(CH3)2N
4-(CH3)2N
3k
3l
Cl
CH3
H
3m
3n
3o
3p
3q
3r
Cl
CH3
H
C
H
S
C
H
N
C
H
N
C
Cl
CH3
H
S
8.32
8.61
the same arrangement of the arylsulfonyl groups (Figs. 4 and 5)
around the cyclic urea moiety inwhich the arylsulfonyl group was out
of the plane of cyclic urea group (:NeCOeNeSO2 torsional angle
was 177ꢁ, 155ꢁ, 133ꢁ in case of series 3, 6 and 8 compounds,
respectively).
the Lipinski's rule of five was evaluated [47]. In addition, the polar
surface area (PSA) of the compounds was also calculated (Table 6),
since it is another key property that has been linked to drug
bioavailability, where passively absorbed compounds with
a PSA > 140 A are thought to have low oral bioavailability [48]. The
results disclosed in Table 6 show that all of the synthesized
compounds comply with these rules. Hence; theoretically, all of
these compounds should present good passive oral absorption and
differences in their bioactivity cannot be attributed to this property.
2
ꢀ
2.3.2. ADME-T prediction
2.3.2.1. Lipinski's rule of five and the effect of lipophilic and steric
parameters. As a part of our study; the compliance of compounds to

2520
I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
H2N
HN
O
O
O
OC2H5
OC2H5
H2N
HN
NH
NaOEt /
X
O
O
O
+
Absolute Ethanol
N
COOH
NH2
N
Fusion at
O
O
+
N
H
O
190o
C
Diethyl malonate
X
4a-d
X
7a-d
X
4a-d
5a-d
Na-tert-
butoxide /
tert-butanol
O
Y
O
S
O
K2CO3
/
Acetone : Water
O
N
N
N
N
S
SO2Cl
Y
SO2Cl
Y
O
O
O
O
O
X
X
Y
6a-
l
8a-l
X = H , Cl , CH3 , OCH3
Y = H , Cl , CH3
X = H , Cl , CH3 , OCH3
Y = H , Cl , CH3
Scheme 2. Synthesis of 1-(4-substituted)phenylsulfonyl-3-(4-substituted)phenyl-
pyrimidine-2,4,6-(1H,3H,5H)-triones 6ael.
Scheme 3. Synthesis of 3-(4-substituted)phenyl-1-(4-substituted)phenylsulfonyl
quinazoline-2,4(1H,3H)-diones 8ael.
Table 3
Physical properties, yields and molecular formulae of the synthesized compounds
Table 2
8ael
Physical properties, yields and molecular formulae of the synthesized compounds
6ael
Comp.
No.
X
Y
Yield M.P. ꢁC Mol. Formula
Analysis
Comp.
No.
X
Y
Yield M.P. ꢁ
%
C
Mol. Formula
(Mol. Wt)
Analysis
%
(Mol. Wt)
Elm. Calc. Found
Elm. Calc.
Found
6a
6b
6c
6d
6e
6f
H
H
59
255e7
C16H12N2O5S
(344.34)
C
55.81 55.61
8a
8b
8c
8d
8e
8f
H
H
49
195e6 C20H14N2O4S
C
63.48 63.62
H
N
C
H
S
3.51
8.14
3.82
8.36
(378.40)
H
N
C
H
S
3.73
7.40
3.51
7.64
H
Cl
51
218e20 C16H11ClN2O5S
50.73 50.41
H
Cl
27
220e2 C20H13ClN2O4S
58.18 58.26
(378.79)
2.93
8.47
2.68
8.90
(412.85)
3.17
7.77
3.28
7.42
H
CH3 54
248e50 C17H14N2O5S
C
56.98 57.22
H
CH3 47
170e1 C21H16N2O4S
C
64.27 64.39
(358.37)
H
N
C
H
N
C
H
S
C
H
S
C
H
S
C
H
N
C
H
N
C
H
N
C
H
S
3.94
7.82
3.70
7.96
(392.43)
H
N
C
H
N
C
H
N
C
H
S
4.11
7.14
4.33
7.01
Cl
H
47
44
230e2
232e4
243e5
242e3
247e8
252e4
C16H11ClN2O5S
(378.79)
50.73 50.42
Cl
H
26
19
180e1 C20H13ClN2O4S
58.18 57.82
2.93
7.40
3.06
7.28
(412.85)
3.17
6.79
3.35
6.64
Cl
Cl
C16H10Cl2N2O5S
(413.23)
46.50 46.33
Cl
Cl
213e5 C20H12Cl2N2O4S
53.70 53.89
2.44
7.76
2.61
7.60
(447.29)
2.70
6.26
2.45
6.29
Cl
CH3 42
C17H13ClN2O5S
(392.81)
51.98 52.26
Cl
CH3 24
192e3 C21H15ClN2O4S
59.09 59.11
3.34
8.16
3.39
7.97
(426.87)
3.54
7.51
3.41
7.39
6g
6h
6i
CH3
CH3
CH3
OCH3
H
33
38
C17H14N2O5S
(358.37)
56.98 56.62
8g
8h
8i
CH3
CH3
CH3
OCH3
H
29
22
194e6 C21H16N2O4S
C
H
S
64.27 64.02
3.94
8.95
3.75
9.16
(392.43)
4.11
8.17
4.37
7.86
Cl
C17H13ClN2O5S
(392.81)
51.98 51.62
Cl
202e4 C21H15ClN2O4S
C
59.09 59.31
3.34
7.13
3.59
7.33
(426.87)
H
N
C
H
N
C
H
N
C
H
S
3.54
6.56
3.62
6.44
CH3 39
C18H16N2O5S
(372.40)
58.05 58.33
CH3 33
216e7 C22H18N2O4S
65.01 65.26
4.33
7.52
4.09
7.68
(406.45)
4.46
6.89
4.29
6.92
6j
H
52
46
228e30 C17H14N2O6S
54.54 54.23
8j
H
32
21
190e2 C21H16N2O5S
61.76 62.03
(374.37)
3.77
7.48
3.91
7.52
(408.43)
3.95
6.86
3.77
6.92
6k
6l
OCH3 Cl
246e8
224e5
C17H13ClN2O6S
(408.81)
49.95 50.16
8k
8l
OCH3 Cl
167e8 C21H15ClN2O5S
56.95 56.66
3.21
7.84
3.42
7.62
(442.87)
3.41
7.24
3.62
7.52
OCH3 CH3 50
C18H16N2O6S
(388.39)
C
H
N
55.66 55.41
OCH3 CH3 30
178e9 C22H18N2O5S
C
H
S
62.55 62.21
4.15
7.21
4.31
7.06
(422.45)
4.29
7.59
4.44
7.34

I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
2521
200
150
100
50
IGROV1
OVCAR-8
RXF393
M14
SK-MEL-2
0
Tested compound
-50
3b
3g
3h
3m
3n
3p
3q
6b
6f
6k
8a
8b
8j
Fig. 2. The percentages of growth inhibition of the 13 selected compounds over the most sensitive tumor cell lines.
The introduction of cyclic ring fragments incorporating the aryl-
sulfonylurea core and the variation of ring size and the substituents
on these fragments have allowed us to evaluate the influence of
lipophilicity and steric parameters at the pharmacophoric part of the
molecules. Table 6 gathers cytotoxic activity against ovarian human
cell line (IGROV1) as a representative example as well as values of
ClogP (lipophilic factors), molar refractometry and polar surface area
(steric factors) for each compound, determined by using MOE
program. Within the series of compounds 3aed we have observed
sharp increase in the antitumor activity with the increase in molar
refractometry from 88.7 cm3/mol (3b and 3g) to 99.3e103.9 cm3/mol
(3p and 3q). This effect of molar refractometry was observed within
the other two series too, such as in compounds 6b, 6k, 8a and 8bwith
molar refractometris of 86.4 cm3/mol, 93.7 cm3/mol, 98.1 cm3/mol
and 102.7 cm3/mol respectively. Although lipophilicity does not exert
a significant effect on activity in compounds 3 and 6, an increase in
200
150
100
50
0
-50
Lung
Colon
Breast
Ovarian
Leukemia
Renal
Melanoma Prostate CNS
Cell line type
Fig. 3. The percentages of growth inhibition of compound 3q over the full panel of tumor cell lines.

2522
I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
Table 4
2.3.2.2. ADME-Tox evaluation [49,50]. To estimate the prospect of
series 3, 6 and 8 compounds as antitumor agents compared with the
reported antitumor agents A, D and E; their drug-likeliness were
calculated according to absorption, distribution, metabolism,
elimination, and toxicity (ADME-T) program, and defined human
intestinal absorption (HIA) model [49]. It was predicted that the
examined compounds could be transported across the intestinal
epithelium, they probably have high affinity to the plasma proteins,
and they can cross the bloodebrain barrier and are of medium
aqueous solubility. The values of HIA, protein binding, BBB crossing
and solubility prediction for all compounds are presented in Table 7.
In general, all compounds presented some advantages and disad-
vantages when compared to each other. No marked differences in
health effects and in rodent toxicity profiles were observed among
the compounds. However, the absorption related parameters call for
attention, since the promising compounds 3 and 6 were calculated
to be at least as soluble as the reported compounds, and are pre-
dicted to have oral bioavailability and absorption significantly
higher than that of the reported antitumor agents A, D and E. These
values are also comparable (marginally inferior or superior) to those
obtained from series 8 compounds. The present results suggest an
optimal pharmacokinetic profile. Accordingly; it can be deduced
from these results that the pharmacokinetic profile of diary-
lsulfonylureas is affected and modified by the presence of arylsul-
fonyl moiety connected to heterocyclic ring systems.
The percentages of growth inhibition of the thirteen selected compounds over the
most sensitive tumor cell lines.a
Comp. No. IGROV1 (%) OVCAR-8 (%) RXF393 (%) M14 (%) SK-MEL-2 (%)
3b
3g
3h
3m
3n
3p
3q
6b
6f
6k
8a
8b
8j
ꢀ9.05
1.13
3.88
6.79
4.01
0.92
7.42
76.2
96.49
84.12
80.28
95.74
e
e
11.71
19.95
17.63
11.57
8.98
3.98
1.29
65.1
e
80.99
114.67
ꢀ1.97
106.89
97.89
34.14
65.6
76.55
86.78
91.42
63.16
ꢀ20.14
e
5.23
ꢀ1.23
e
1.17
ꢀ2.88
199.62
8.19
ꢀ7.35
ꢀ3.04
1.02
17.36
ꢀ8.63
58.86
54.13
42.41
33.24
40.85
26.02
e
73.93
61.07
70.4
e
e
e
79.27
42.95
56.53 ꢀ43.25
a
The showed inhibition percentages are measured at a single concentration of
10 mM. % inhibition is calculated by simple abstraction of the % activity from 100.
100% activity is the activity of cells in presence of test solvent only (DMSO).
% Inhibition between 100 and 200% means that the compound has a lethal effect at
cancer cells.
potency was observed in compounds 8a, 8b & 8k with log P values
higher than 2.7. Regarding steric parameters; from the data gathered
in Table 6 there is a clear influence of refractometry on antitumor
activity compared with lipophilicity and polar surface area for either
series of all compounds. The optimal refractometry for the most
active compounds was found to lie in the range of 91.4e103.9 cm3/
mol (Table 6).
2.3.3. Pharmacophore modeling [51,52]
A molecular modeling experiment was carried out to develop
a hypothetical pharmacophore model for the antitumor activity
aiming to study the fitting of the designed compounds to this
pharmacophore. A ligand-based pharmacophore model was devel-
oped using a training set of nine diarylsulfonylureas of diverse
chemical structures including compounds AeE (Fig. 6), in addition to
compounds 3h, 3n, 6b and 8a. The generated hypothetical pharma-
cophore (Fig. 6) showed nine overlapping points with similar
chemical properties in the training set; F1: a hydrogen bond acceptor
center; F2: an aromatic or hydrophobic center with two parallel
places “F3 and F5” for Pi orbital accommodation; F4: an aromatic
center with a H-bond donor group; F6: a hydrophobic center; and F7:
a second H-bond acceptor center. Fitting of the designed active
compounds 3p, 3q, 6k and 8b to the pharmacophore revealed the
presence of the appropriate chemical groups superimposed on the
pharmacophoric elements (Figs. 6 and 7). The diaryl tail represents
the aromatic ring with its Pi orbitals properly oriented to fit to F2, F3
and F5. Also, NeCOeN and CeCOeC of the ring fragment are H-bond
acceptors corresponding to F1. The hydrogen bond acceptor sulfonyl
group was found to be fit into F6; it is worthy to mention that this
moiety was perfect in adjusting the distance between the other
groups in the molecule. This pharmacophoric assumption was in
consistence with the reported results for the antitumor arylsylfony-
lureas [26,53,54].
Table 5
The percentages of growth inhibition of compound 3q over the full panel of tumor
cell lines.a
Cell line
type
Cell line
name
Inhibition Cell line
Cell line
name
Inhibition
(%)
(%)
type
Non-small A549/ATCC
cell lung EKVX
cancer
ꢀ8.84
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
786e0
A498
ACHN
CAKI-1
RXF393
SN12C
TK-10
2.95
4.85
8.89
14.7
11.19
ꢀ9.94
ꢀ1.8
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
BT-549
HS 578T
MCF7
11.54
ꢀ6.72
34.66
ꢀ0.44
ꢀ8.94
ꢀ5.38
ꢀ5.71
95.74
0.04
ꢀ16.53
ꢀ15.77
9.78
Renal
Cancer
Colon
cancer
ꢀ14.66
ꢀ54.05
ꢀ3.55
1.55
ꢀ2.64
ꢀ11.59
ꢀ1.96
4.63
ꢀ33.42
UO-31
5.5
Melanoma LOX IMVI
M14
6.44
199.62
Breast
cancer
14.08
ꢀ6.37
ꢀ2.18
MALME-3M ꢀ49.66
SK-MEL-2
1.29
ꢀ4.69
MDA-MB-231/
ATCC
SK-MEL-28
MDA-MB-435
NCI/ADR-RES
T-47D
ꢀ4.89
ꢀ6.33
ꢀ9.29
97.89
ꢀ13.88
7.93
ꢀ4.44
ꢀ8.63
ꢀ8.45
ꢀ4.25
ꢀ6.65
SK-MEL-5
UACC-257
UACC-62
ꢀ3.11
ꢀ1.01
3.93
3. Conclusion
Ovarian
cancer
IGROV1
CNS cancer SF-268
SF-295
ꢀ21.61
ꢀ8.92
ꢀ0.9
The present work has lead to the development of novel
antitumor molecules and some of which have shown promising
antitumor activities. As evident from the experimental and calcu-
lated data, the structural features (pharmacophores) essential for
the antitumor activity of this series are as follows; (1) a cyclic urea
that is an essential backbone that carries the recognition feature for
biological activity, (2) the presence of arylsulfonyl moiety at the
position 1 in case of series 8 and position 3 in case of series 3 and 6
of cyclic urea core, (3) the two aryl groups of the diarylsulfonylurea
skeleton should reside in a certain distance, ranging between 8.7
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
DU-145
SF-539
SNB-19
SNB-75
U251
ꢀ6.78
ꢀ5.55
ꢀ0.69
Prostate
cancer
PC-3
a
The showed inhibition percentages are measured at a single concentration of
mM. % inhibition is calculated by simple abstraction of the % activity from 100.
100% activity is the activity of cells in presence of test solvent only (DMSO).
% Inhibition between 100 and 200% means that the compound has a lethal effect at
cancer cells.
10
ꢀ
and 9.5 A. The new cyclic arylsulfonylureas prepared in this work

I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
2523
Fig. 4. Lowest energy conformers of the most active compounds 3p, 3q, 6k and 8b as representative examples.
have good physical properties that qualify them to have good
pharmacokinetics and drug bioavailability. They are fully compat-
ible with Lipinski's rule of five (low molecular weight, favourable
Clog P, favourable hydrogen bond-donating and accepting
capabilities). They have a simple synthetic access and thus low
production costs. Further optimization and pharmacokinetic
profiling of these series are currently ongoing.
was further stirred for 24 h at room temperature. The separated solid
was then filtered, washed with cold water, dried and crystallized
from ethanol. The yield percentages, melting points, molecular
formulae and micro-analytical data for (compounds 3aer) are
shown in Table 1.
4.1.1.1. 5-Benzylidene-3-phenylsulfonylimidazolidine-2,4-dione
(3a). 1H NMR (DMSO-d6);
d 6.61 (s, 1H, ]CHe), 7.33e7.39 (m, 3H,
Ar-H), 7.60 (d, 2H, J ¼ 6.9 Hz, 2H, Ar-H), 7.68e7.85 (m, 3H, Ar-H),
4. Experimental
8.07 (d, 2H, J ¼ 7.6 Hz, Ar-H), 11.33 (s, 1H, NH, exchangeable with
D2O); 13C NMR (DMSO-d6):
d 112.61, 124.92, 128.38, 129.24, 129.63,
4.1. Chemistry
130.12, 130.24, 132.60, 135.66, 138.04, 149.85, 160.28.
All melting points (ꢁC) were measured by fisherejohns appa-
ratus and are uncorrected, 1H NMR and 13C NMR spectra (TMS as
internal standard, chemical shifts in ppm) were recorded on a var-
ian EM 360 (200 MHz) and a Bruker Avance 300 spectrometers
(300 MHz). Thin-layer chromatography (TLC) was conducted on
silica gel 60F254 plates (Merck KgaA). Elemental analysis (C, H, N, S)
was performed at the micro-analytical center, Cairo University, all
the compounds were within 0.4% of the theoretical values.
Compounds 2aef [36], 4aed [38,39], 5aed [40], and 7aed [41]
have been synthesized according to the reported procedures.
4.1.1.2. 5-Benzylidene-3-(4-chlorophenylsulfonyl)imidazolidine-2,4-
dione (3b). IR (KBr, cmꢀ1
) n: 3222 (NH), 1783, 1745 (C]O), 1318,
4.1.1. General procedure for the synthesis of compounds 3aer
A mixture of compounds 2aef (0.01 mol) and K2CO3 (0.69 g,
0.005 mol) was stirred in acetone/water solvent system (1:1; 30 mL)
at room temperature for 20 min. The reaction mixture was then
filtered and to the clear filtrate, a solution of the appropriate aryl-
sulfonyl chloride (0.012 mol) in acetone/water system (1:1; 5 mL)
was added dropwise over a period of 20 min. The resulted mixture
Fig. 5. Deduced 2D-cyclic arylsulfonylurea pharmacophore.

2524
I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
Table 6
Molar refractometry and calculated Lipinski's rule of five for the tested compounds.
Comp No
IGROV1a (% inhibition)
MRb
Parameter
Log Pc
Nviolationsh
TPSAd
MWe
nONf
nOHNHg
3b
3g
3h
3m
3n
3p
3q
6b
6f
6k
8a
8b
8j
ꢀ9.05
1.13
88.7
2.5
2.5
3.3
1.8
2.5
2.0
2.7
2.8
3.3
2.7
3.8
4.5
3.7
83.6
83.6
83.6
92.8
92.8
86.8
86.8
91.8
91.8
101.1
74.8
74.8
84.0
362.8
362.8
397.2
358.4
392.8
371.4
405.9
378.8
392.8
408.8
378.4
412.9
408.4
6
6
6
7
7
7
7
7
7
8
6
6
7
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
88.7
93.3
91.4
96.0
99.3
103.9
86.4
92.3
93.7
98.1
102.7
105.4
80.99
114.67
ꢀ1.97
106.89
97.89
34.14
65.6
76.55
86.78
91.42
63.16
a
Data taken from Table 1.
Molar refractometry.
Calculated lipophilicity.
Total polar surface area.
b
c
d
e
f
Molecular weigh.
Number of hydrogen bond acceptor.
Number of hydrogen bond donor.
Number of violation from Lipinski's rule of five.
g
h
1189 (O]S]O); 1H NMR (DMSO-d6)
d
: 6.60 (s, 1H, ]CHe),
7.46 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.63 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.78
(d, 2H, J ¼ 8.7 Hz, Ar-H), 8.05 (d, 2H, J ¼ 8.5 Hz, Ar-H), 11.38(s, 1H,
7.32e7.41 (m, 3H, Ar-H), 7.59 (d, 2H, J ¼ 6.9 Hz, Ar-H), 7.74 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 8.06 (d, 2H, J ¼ 8.4 Hz, Ar-H), 11.35 (s, 1H, NH
NH, exchangeable with D2O); 13C NMR (DMSO-d6)
d: 110.97, 125.65,
exchangeable with D2O); 13C NMR (DMSO-d6);
d
112.60, 124.97,
129.27, 130.21, 130.52, 131.61, 131.86, 134.11, 136.66, 140.70, 149.80,
160.13.
129.22, 129.60, 130.17, 130.21, 130.49, 132.59, 136.67, 140.71, 149.79,
160.20.
4.1.1.9. 5-(4-Chlorobenzylidene)-3-(4-methylphenylsulfonyl)imida-
4.1.1.3. 5-Benzylidene-3-(4-methylphenylsulfonyl)imidazolidine-2,4-
zolidine-2,4-dione (3i). 1H NMR (DMSO-d6)
d: 2.43 (s, 3H, CH3), 6.60
(s, 1H, ]CHe), 7.46 (d, 2H, J ¼ 8.6 Hz, Ar-H), 7.52 (d, 2H, J ¼ 8.4 Hz,
Ar-H), 7.65 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.94 (d, 2H, J ¼ 8.1 Hz, Ar-H),
11.32 (s, 1H, NH, exchangeable with D2O).
dione (3c). IR (KBr, cmꢀ1
)
n
: 3221 (NH), 1784, 1752 (C]O), 1318,
1184 (O]S]O); 1H NMR (DMSO-d6)
d
2.48 (s, 3H, CH3), 6.62 (s, 1H,
]CHe), 6.62 (s, 1H, ]CHe), 7.40e7.65 (m, 7H, Ar-H), 7.96 (d, 2H,
J ¼ 7.8 Hz, Ar-H), 11.30 (s, 1H, NH exchangeable with D2O).
4.1.1.10. 5-(3-Nitrobenzylidene)-3-phenylsulfonylimidazolidine-2,4-
4.1.1.4. 5-(4-Bromobenzylidene)-3-phenylsulfonylimidazolidine-2,4-
dione (3j). 1H NMR (DMSO-d6)
d: 6.76 (s, 1H, ]CHe), 7.55e8.06 (m,
dione (3d). IR (KBr, cmꢀ1
)
n
: 3226 (NH), 1792, 1736 (C]O), 1383,
7H, Ar-H), 8.18 (d, 1H, J ¼ 3.3 Hz, Ar-H), 8.40 (s, 1H, Ar-H), 11.60 (br s,
1190 (O]S]O); 1H NMR (DMSO-d6)
d: 6.60 (s, 1H, ]CHe),
1H, NH, exchangeable with D2O).
7.32e7.42 (m, 3H, Ar-H), 7.60 (d, 2H, J ¼ 7.2 Hz, Ar-H), 7.77 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 8.05 (d, 2H, J ¼ 8.7 Hz, Ar-H), 11.33 (s, 1H, NH,
4.1.1.11. 5-(3-Nitrobenzylidene)-3-(4-chlorophenylsulfonyl)imidazo-
exchangeable with D2O); 13C NMR (DMSO-d6);
d
112.53, 125.04,
lidine-2,4-dione (3k). IR (KBr, cmꢀ1
)
n: 3429 (NH), 1740, 1693 (C]O),
129.26, 129.63, 130.21, 130.51, 132.61, 136.68, 140.69, 149.79, 160.22.
1390, 1166 (O]S]O); 1H NMR (DMSO-d6)
d: 6.05 (s, 1H, ]CHe),
7.52 (dd, 1H, J ¼ 3.9, 7.5 Hz, Ar-H), 7.72 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.92
(d, 1H, J ¼ 4.1 Hz, Ar-H), 7.98 (d, 2H, J ¼ 7.8 Hz, Ar-H), 8.15 (d, 1H,
J ¼ 3.3 Hz, Ar-H), 8.43 (s, 1H, Ar-H), 11.42 (br s, 1H, NH, exchangeable
with D2O).
4.1.1.5. 5-(4-Bromobenzylidene)-3-(4-chlorophenylsulfonyl)imidazo-
lidine-2,4-dione (3e). 1H NMR (DMSO-d6)
d: 6.60 (s, 1H, ]CHe),
7.80 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.90 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.98 (d,
2H, J ¼ 8.1 Hz, Ar-H), 8.15 (d, 2H, J ¼ 8.0 Hz, Ar-H), 11.36 (s, 1H, NH,
exchangeable with D2O).
4.1.1.12. 5-(3-Nitrobenzylidene)-3-(4-methylphenylsulfonyl)imidazo-
lidine-2,4-dione (3l). 1H NMR (DMSO-d6)
d: 2.47 (s, 3H, CH3), 6.77
4.1.1.6. 5-(4-Bromobenzylidene)-3-(4-methylphenylsulfonyl)imida-
(s, 1H, ]CHe), 7.51 (dd, 1H, J ¼ 3.1, 7.7 Hz, Ar-H), 7.61 (d, 2H,
J ¼ 8.1 Hz, Ar-H), 7.89 (d, 1H, J ¼ 3.2 Hz, Ar-H), 7.96 (d, 2H, J ¼ 7.9 Hz,
Ar-H), 8.16 (d, 1H, J ¼ 4.1 Hz, Ar-H), 8.44 (s, 1H, Ar-H), 11.61 (br s, 1H,
NH exchangeable with D2O).
zolidine-2,4-dione (3f). IR (KBr, cmꢀ1
)
n
: 3228 (NH),1793,1736 (C]
O), 1383, 1189 (O]S]O); 1H NMR (DMSO-d6)
d: 2.45 (s, 3H, CH3),
6.59 (s, 1H, ]CHe), 7.51 (d, 2H, J ¼ 8.5 Hz, Ar-H), 7.74 (d, 2H,
J ¼ 7.7 Hz, Ar-H), 7.94 (d, 2H, J ¼ 8.5 Hz, Ar-H), 8.01 (d, 2H, J ¼ 7.9 Hz,
Ar-H), 11.34 (s, 1H, NH, exchangeable with D2O).
4.1.1.13. 5-(4-Methoxybenzylidene)-3-phenylsulfonylimidazolidine-
2,4-dione (3m). 1H NMR (DMSO-d6)
d: 3.78 (s, 3H, OCH3), 6.59
4.1.1.7. 5-(4-Chlorobenzylidene)-3-phenylsulfonylimidazolidine-2,4-
(s, 1H, ]CHe), 6.96 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.59 (d, 2H, J ¼ 8.4 Hz,
dione (3g). IR (KBr, cmꢀ1);
n
: 3224 (NH), 1794, 1736 (C]O), 1384,
Ar-H), 7.67e7.84 (m, 3H, Ar-H), 8.06 (d, 2H, J ¼ 7.5 Hz, Ar-H), 11.22
1190 (O]S]O); 1H NMR (DMSO-d6)
d
: 6.63 (s, 1H, ]CHe), 7.48 (d,
(s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6)
d: 55.78,
2H, J ¼ 7.7 Hz, Ar-H), 7.64 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.70e7.94 (m, 5H,
113.23, 114.82, 122.80, 125.08, 128.30, 130.12, 132.19, 135.61, 138.12,
149.79, 160.34, 160.59.
Ar-H), 11.33 (s, 1H, NH, exchangeable with D2O).
4.1.1.8. 5-(4-Chlorobenzylidene)-3-(4-chlorophenylsulfonyl)imidazo-
4.1.1.14. 5-(4-Methoxybenzylidene)-3-(4-chlorophenylsulfonyl)imi-
lidine-2,4-dione (3h). 1H NMR (DMSO-d6)
d: 6.60 (s, 1H, ]CHe),
dazolidine-2,4-dione (3n). IR (KBr, cmꢀ1
) n: 3231 (NH), 1778, 1740

Table 7
The predicted ADME-Tox of the proposed and reported antitumor agents.
ADME-Tox
3h
3m
3p
3q
6b
6f
6k
8a
8b
8j
A
D
E
Solubility (Log S)
ꢀ6.11
(ꢂ0.5)
97.38
(ꢂ15)
95.17
(ꢂ13)
0.32
ꢀ4.76
(ꢂ0.5)
98.27
(ꢂ15)
95.17
(ꢂ13)
ꢀ0.32
(73.54)
ꢀ4.96 (ꢂ0.5) ꢀ5.83 (ꢂ0.5) ꢀ4.48 (ꢂ0.5)
ꢀ4.92 (ꢂ0.5)
ꢀ4.87 (ꢂ0.5)
ꢀ5.56 (ꢂ0.5)
ꢀ6.44 (ꢂ0.5)
ꢀ5.95
(ꢂ0.5)
57.08
(ꢂ15)
110.98
(ꢂ13)
ꢀ5.47 (ꢂ0.5)
ꢀ4.99 (ꢂ0.5) ꢀ6.28
(ꢂ0.5)
F (%)a
83.78 (ꢂ15)
99.02 (ꢂ13)
0.34 (87.38)
84.27 (ꢂ15)
99.23 (ꢂ13)
0.43 (96.07)
290/460
710/1100
100
107.62 (ꢂ15)
99.71 (ꢂ13)
107.25 (ꢂ15)
94.66 (ꢂ13)
110.04 (ꢂ15) 56.88 (ꢂ15)
56.18 (ꢂ15)
81.41 (ꢂ15)
90.32 (ꢂ13)
69.04 (ꢂ15)
51.15
(ꢂ15)
HIA (%)b
100.09 (ꢂ13) 110.61 (ꢂ13) 110.80 (ꢂ13)
79.02 (ꢂ13)
76.31
(ꢂ13)
ꢀ0.10
(91.16)
470/790
LogBBBc (PPB%)d
ꢀ0.57 (98.65) ꢀ0.90 (98.87) ꢀ1.03 (98.96) ꢀ0.16 (88.70) ꢀ0.06 (95.03) ꢀ0.62
ꢀ0.06 (99.21) 0.25 (87.66)
(96.63)
(88.57)
290/530 640/530
LD50 rat/mouse
(mg kgꢀ1, oral)
LD50 rat/mouse
560/860 500/690 280/420
400/730
1000/2000
170
390/720
980/1400
150
380/700
940/2100
150
310/570
1100/1700
120
310/620
980/1800
110
620/960
1900/1900
170
1500/
1500/
1700
150
770/1100
110
1000/
1900
100
1100/1600
110
1900/
2300
100
(mg kgꢀ1, intraperitoneal) 2200
LD50 mouse
(mg kgꢀ1, intravenous)
LD50 mouse
130
1300
850
570
610
660
620
570
660
700
580
550
1300
730
(mg kgꢀ1, subcutaneous)
Ames test (genotoxicity, %)
Prob. of blood effect
Prob. of cardiovascular
system
0.007
0.53
0.84
0.008
0.38
0.78
0.015
0.56
0.75
0.011
0.61
0.76
0.001
0.36
0.27
0.002
0.34
0.22
0.001
0.31
0.28
0.012
0.31
0.77
0.009
0.36
0.80
0.013
0.26
0.79
0.002
0.37
0.48
0.006
0.42
0.80
0.399
0.37
0.94
Prob. of gastrointestinal
system
0.88
0.82
0.93
0.99
0.74
0.74
0.71
0.70
0.73
0.67
0.84
0.47
0.89
Prob. of kidney effect
Prob. of liver effect
Prob. of lung effect
0.25
0.34
0.31
0.15
0.60
0.26
0.20
0.53
0.58
0.22
0.57
0.57
0.10
0.12
0.20
0.14
0.13
0.20
0.13
0.36
0.18
0.12
0.12
0.18
0.14
0.13
0.19
0.10
0.35
0.22
0.24
0.18
0.50
0.21
0.25
0.29
0.20
0.65
0.17
a
Human oral bioavailability.
Human intestinal absorption.
Bloodebrain barrier.
Plasma protein binding.
b
c
d

2526
I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
Fig. 6. Alignment of a training set (Left panel) and the hypothetical 3D-pharmacophore geometry developed for the proposed cyclic arylsulfonylurea (Right panel). F1: Hydrogen
bond acceptor center; F2: Aromatic or hydrophobic center; F3 and F5: Aromatic or Pi orbital place at the receptor site; F4: Aromatic center carrying a H-bond donor;
F6: Hydrophobic center; F7: H-bond acceptor place at the receptor site.
(C]O), 1319, 1186 (O]S]O); 1H NMR (DMSO-d6)
OCH3), 6.60 (s, 1H, ]CHe), 6.98 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.62 (d, 2H,
J ¼ 8.5 Hz, Ar-H), 7.80 (d, 2H, J ¼ 7.9 Hz, Ar-H), 8.06 (d, 2H, J ¼ 8.2
Ar-H), 11.23 (s, 1H, NH, exchangeable with D2O).
d
: 3.80 (s, 3H,
4.1.1.16. 5-(4-(N,N-Dimethylamino)benzylidene)-3-phenylsulfonylimi-
dazolidine-2,4-dione (3p). 1H NMR (DMSO-d6)
: 2.97 (s, 6H, N
(CH3)2), 6.55 (s, 1H, ]CHe), 6.68 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.49 (d, 2H,
J ¼ 8.7 Hz, Ar-H), 7.67e7.84 (m, 3H, Ar-H), 8.04 (d, 2H, J ¼ 8.0 Hz,
Ar-H),11.04 (s,1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6)
d
4.1.1.15. 5-(4-Methoxybenzylidene)-3-(4-methylphenylsulfonyl)imi-
d: 112.25, 115.27, 119.66, 119.92, 128.19, 130.13, 132.24, 135.55, 138.29,
149.60, 151.29.
dazolidine-2,4-dione (3o). 1H NMR (DMSO-d6)
d: 2.43 (s, 3H, CH3),
3.80 (s, 3H, OCH3), 6.60 (s, 1H, ]CHe), 6.98 (d, 2H, J ¼ 7.8 Hz, Ar-H),
7.52 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.61 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.94
(d, 2H, J ¼ 8.0 Hz, Ar-H), 11.20 (s, 1H, NH, exchangeable with D2O).
4.1.1.17. 5-(4-(N,N-Dimethylamino)benzylidene)-3-(4-chlorophenyl-
sulfonyl)imidazolidine-2,4-dione (3q). IR (KBr, cmꢀ1);
n: 3211 (NH),
Fig. 7. Superimposition of the energy-minimized structures of compounds 3p (Upper left panel), 3q (Upper right panel), 6k (Lower left panel) and 8b (Lower right panel) on the
hypothetical 3D-pharmacophore geometry developed for the proposed cyclic arylsulfonylurea.

I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
2527
1729, 1711 (C]O), 1380, 1172 (O]S]O); 1H NMR (DMSO-d6)
d
2.99
4.1.2.8. 1-(4-Methylphenyl)-3-(4-chlorophenylsulfonyl)pyrimidine-
2,4,6-(1H,3H,5H)-trione (6h). IR (KBr, cmꢀ1
: 1730, 1662 (C]O),
1381, 1168 (O]S]O); 1H NMR (DMSO-d6)
: 2.35 (s, 3H, CH3),
5.43 (s, 2H, CH2), 7.11 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.25 (d, 2H,
J ¼ 8.0 Hz, Ar-H), 7.90 (d, 2H, J ¼ 7.8 Hz, Ar-H), 8.15 (d, 2H,
J ¼ 8.0 Hz, Ar-H).
(s, 6H, N(CH3)2), 6.57 (s, 1H, ]CHe), 6.71 (d, 2H, J ¼ 8.5 Hz, Ar-H),
7.52 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.79 (d, 2H, J ¼ 8.2 Hz, Ar-H), 8.06
(d, 2H, J ¼ 8.4 Hz, Ar-H), 11.06 (s, 1H, NH exchangeable, with D2O).
) n
d
4.1.1.18. 5-(4-(N,N-Dimethylamino)benzylidene)-3-(4-methylphe-
nylsulfonyl)imidazolidine-2,4-dione (3r). 1H NMR (DMSO-d6)
d: 2.43
(s, 3H, Ar-CH3), 2.99 (s, 6H, N(CH3)2), 6.56 (s, 1H, ]CHe), 6.70 (d,
2H, J ¼ 7.9 Hz, Ar-H), 7.51 (d, 4H, J ¼ 7.5 Hz, Ar-H), 7.94 (d, 2H,
J ¼ 7.8 Hz, Ar-H), 11.03 (s, 1H, NH, exchangeable with D2O).
4.1.2.9. 1-(4-Methylphenyl)-3-(4-methylphenylsulfonyl)pyrimidine-
2,4,6-(1H,3H,5H)-trione (6i). 1H NMR (DMSO-d6)
d: 2.35 (s, 3H,
CH3), 2.52 (s, 3H, CH3), 5.40 (s, 2H, CH2), 7.11 (d, 2H, J ¼ 7.6 Hz, Ar-H),
7.26 (d, 2H, J ¼ 7.6 Hz, Ar-H), 7.60 (d, 2H, J ¼ 8.3 Hz, Ar-H), 7.97
4.1.2. General procedure for the synthesis of compounds 6ael
A mixture of compounds 5aed (0.01 mol) and K2CO3 (0.69 g,
0.005 mol) was stirred in acetone/water mixture (1:1; 30 mL) at
room temperature for 10 min. To the resulted solution; the appro-
priate arylsulfonyl chloride (0.012 mol) in acetone/water system
(1:1; 5 mL) was added dropwise over a period of 20 min. The reac-
tion mixture was further stirred at room temperature for 24 h. The
separated solid was then filtered, washed with cold water, dried and
crystallized from the appropriate solvent. The yield percentages,
melting points, molecular formulae and micro-analytical data for
compounds 6ael are shown in Table 2.
(d, 2H, J ¼ 8.0 Hz, Ar-H); 13C NMR (DMSO-d6)
d: 21.67, 55.82, 113.15,
114.85, 122.79, 125.09, 128.34, 130.54, 132.18, 135.28, 146.56, 149.80,
160.33, 160.61.
4.1.2.10. 1-(4-Methoxyphenyl)-3-phenylsulfonylpyrimidine-2,4,6-
(1H,3H,5H)-trione (6j). 1H NMR (DMSO-d6)
d: 3.79 (s, 3H, OCH3),
5.34 (s, 2H, CH2), 7.00 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.15 (d, 2H, J ¼ 7.8 Hz,
Ar-H), 7.68e8.04 (m, 5H, Ar-H).
4.1.2.11. 1-(4-Methoxyphenyl)-3-(4-chlorophenylsulfonyl)pyrim-
idine-2,4,6-(1H,3H,5H)-trione (6k). 1H NMR (DMSO-d6)
d: 3.79
(s, 3H, OCH3), 5.32 (s, 2H, CH2), 6.96 (d, 2H, J ¼ 8.7 Hz, Ar-H), 7.61
4.1.2.1. 1-Phenyl-3-phenylsulfonylpyrimidine-2,4,6-(1H,3H,5H)-trione
(d, 2H, J ¼ 8.4 Hz, Ar-H), 7.78 (d, 2H, J ¼ 8.4 Hz, Ar-H), 8.04 (d, 2H,
(6a). IR (KBr, cmꢀ1
)
n
: 1728, 1655 (C]O), 1374, 1165 (O]S]O); 1H
J ¼ 8.4 Hz, Ar-H); 13C NMR (DMSO-d6)
d: 55.82, 113.20, 114.86,
122.90, 125.10, 130.23, 130.42, 132.17, 136.81, 140.64, 149.70, 160.26,
160.61.
NMR (DMSO-d6);
d
5.36 (s, 2H, CH2), 7.32e7.86 (m, 8H, Ar-H), 8.06
(d, 2H, J ¼ 7.9 Hz, Ar-H); 13C NMR (DMSO-d6)
d: 112.55, 124.97,
128.37, 129.26, 129.65, 130.13, 130.24, 132.61, 135.67, 138.02, 149.86,
160.30.
4.1.2.12. 1-(4-Methoxyphenyl)-3-(4-methylphenylsulfonyl)pyrim-
idine-2,4,6-(1H,3H,5H)-trione (6l). IR (KBr, cmꢀ1
)
n
: 1729, 1660 (C]
4.1.2.2. 1-Phenyl-3-(4-chlorophenylsulfonyl)pyrimidine-2,4,6-
O), 1370, 1181 (O]S]O); 1H NMR (DMSO-d6)
d: 2.42 (s, 3H, CH3),
(1H,3H,5H)-trione (6b). 1H NMR (DMSO-d6)
d: 5.41 (s, 2H, CH2),
3.79 (s, 3H, OCH3), 5.32 (s, 2H, CH2), 6.96 (d, 2H, J ¼ 8.7 Hz, Ar-H),
7.50 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.60 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.92
(d, 2H, J ¼ 8.1 Hz, Ar-H).
7.13e7.55 (m, 5H, Ar-H), 7.92 (d, 2H, J ¼ 8.1 Hz, Ar-H), 8.15 (d, 2H,
J ¼ 7.9 Hz, Ar-H); MS m/z (%): 380 (5.15, Mþ þ 2), 378 (13.25, Mþ),
204 (14.76), 175 (89.07), 119 (100), 111 (62.28), 77 (25.94).
4.1.3. General procedure for the synthesis of compounds 8ael
The appropriate compounds 4aed (0.01 mol) was added in
one portion to a solution of metallic sodium (0.345 g, 0.015 mol)
in tert-butanol (30 mL). The reaction mixture was heated under
reflux for 6 h. The precipitated salt was filtered while hot, washed
with hot tert-butanol (50 mL) and dried. To a suspension of the
separated salt (0.005 mol) in tert-butanol (20 mL); the appro-
priate arylsulfonyl chloride (0.006 mol) in tert-butanol (5 mL) was
added dropwise while heating and stirring. The reaction mixture
was heated under reflux for 12 h. The solvent was evaporated
under reduced pressure, and the obtained solid was stirred with
aqueous NaOH solution (5%, 100 mL) for 30 min. The insoluble
material was filtered, washed with water, dried and crystallized
from ethanol. The yield percentages, melting points, molecular
formulae and micro-analytical data (for compounds 8ael are
shown in Table 3).
4.1.2.3. 1-Phenyl-3-(4-methylphenylsulfonyl)pyrimidine-2,4,6-
(1H,3H,5H)-trione (6c). 1H NMR (DMSO-d6)
d: 2.51 (s, 3H, CH3), 5.35
(s, 2H, CH2), 7.10e7.50 (m, 5H, Ar-H), 7.61 (d, 2H, J ¼ 7.6 Hz, Ar-H),
8.01 (d, 2H, J ¼ 8.2 Hz, Ar-H); MS m/z (%): 359 (3.22, Mþ þ 1), 358
(5.23, Mþ), 204 (7.94), 155 (37.09), 119 (45.08), 91 (100), 77 (26.53).
4.1.2.4. 1-(4-Chlorophenyl)-3-phenylsulfonylpyrimidine-2,4,6-
(1H,3H,5H)-trione (6d). 1H NMR (DMSO-d6)
d: 5.35 (s, 2H, CH2),
7.32 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.54 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.65e8.10
(m, 5H, Ar-H).
4.1.2.5. 1-(4-Chlorophenyl)-3-(4-chlorophenylsulfonyl)pyrimidine-
2,4,6-(1H,3H,5H)-trione (6e). 1H NMR (DMSO-d6)
d: 5.39 (s, 2H,
CH2), 7.30 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.53 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.90
(d, 2H, J ¼ 7.7 Hz, Ar-H), 8.15 (d, 2H, J ¼ 8.0 Ar-H); 13C NMR (DMSO-
d6) d: 114.77, 115.69, 122.96, 128.04, 128.57, 129.28, 129.57, 135.64,
136.23, 140.28, 150.68, 162.69.
4.1.3.1. 3-Phenyl-1-phenylsulfonylquinazoline-2,4(1H,3H)-dione
(8a). IR (KBr, cmꢀ1 : 1727, 1679 (C]O), 1378, 1165 (O]S]O); 1H
) n
4.1.2.6. 1-(4-Chlorophenyl)-3-(4-methylphenylsulfonyl)pyrimidine-
NMR (CDCl3) d d:
: 7.25e8.23 (m, 14H, Ar-H); 13C NMR (DMSO-d6)
118.43, 120.12, 126.13, 128.55, 128.74, 129.20, 129.49, 130.02, 134.97,
135.27, 135.32, 136.89, 139.03, 149.00, 161.36.
2,4,6-(1H,3H,5H)-trione (6f). IR (KBr, cmꢀ1);
n
: 1736, 1650 (C]O),
2.49 (s, 3H, CH3),
1381, 1170 (O]S]O); 1H NMR (DMSO-d6);
d
5.35 (s, 2H, CH2), 7.30 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.52 (d, 2H,
J ¼ 7.9 Hz, Ar-H), 7.61 (d, 2H, J ¼ 8.3 Hz, Ar-H), 8.02 (d, 2H,
J ¼ 8.5 Hz, Ar-H).
4.1.3.2. 3-Phenyl-1-(4-chlorophenylsulfonyl)quinazoline-2,4(1H,3H)-
dione (8b). IR (KBr, cmꢀ1
)
n: 1729, 1681 (C]O), 1377, 1169 (O]S]O);
1H NMR (CDCl3)
d: 7.24e8.22 (m, 13H, Ar-H).
4.1.2.7. 1-(4-Methylphenyl)-3-phenylsulfonylpyrimidine-2,4,6-
(1H,3H,5H)-trione (6g). 1H NMR (DMSO-d6)
d
: 2.34 (s, 3H, CH3), 5.41
4.1.3.3. 3-Phenyl-1-(4-methylphenylsulfonyl)quinazoline-2,4(1H,3H)-
dione (8c). IR (KBr, cmꢀ1
: 1729, 1679 (C]O), 1377, 1168 (O]S]O);
1H NMR (CDCl3)
: 2.47 (s, 3H, CH3), 7.09e8.25 (m, 13H, Ar-H).
(s, 2H, CH2), 7.12 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.25 (d, 2H, J ¼ 7.8 Hz, Ar-
) n
H), 7.63e8.01 (m, 5H, Ar-H).
d

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I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
4.1.3.4. 3-(4-Chlorophenyl)-1-phenylsulfonylquinazoline-2,4(1H,3H)-
dione (8d). IR (KBr, cmꢀ1
: 1727, 1683 (C]O), 1377, 1170 (O]S]O);
1H NMR (CDCl3)
at the time of drug addition (Tz). Experimental drugs are solubi-
lized in dimethyl sulfoxide at 400-fold the desired final maximum
test concentration and stored frozen prior to use. At the time of
drug addition, an aliquot of frozen concentrate is thawed and
diluted to twice the desired final maximum test concentration with
)
n
d
: 7.06 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.30 (d, 2H, J ¼ 8.2 Hz,
Ar-H), 7.44e8.28 (m, 9H, Ar-H).
4.1.3.5. 3-(4-Chlorophenyl)-1-(4-chlorophenylsulfonyl)quinazoline-
complete medium containing 50
mg/mL gentamicin. Aliquot of
2,4(1H,3H)-dione (8e). IR (KBr, cmꢀ1
)
n
: 1729, 1681 (C]O), 1377,
100 L of this drug dilutions was added to the appropriate micro-
m
1168 (O]S]O); 1H NMR (CDCl3)
d
: 7.06 (d, 2H, J ¼ 8.4 Hz, Ar-H),
titer wells already containing 100 mL of medium, resulting in the
required final drug concentrations.
Following drug addition, the plates are incubated for an addi-
tional 48 h at 37 ꢁC, 5% CO2, 95% air, and 100% relative humidity.
For adherent cells, the assay is terminated by the addition of cold
7.30 (d, 2H, J ¼ 8.5 Hz, Ar-H), 7.40e8.28 (m, 8H, Ar-H).
4.1.3.6. 3-(4-Chlorophenyl)-1-(4-methylphenylsulfonyl)quinazoline-
2,4(1H,3H)-dione (8f). IR (KBr, cmꢀ1
)
n
: 1729, 1681 (C]O), 1376,
1170 (O]S]O); 1H NMR (CDCl3)
d
: 2.47 (s, 3H, CH3), 7.07 (d, 2H,
TCA. Cells are fixed in situ by the gentle addition of 50 mL of cold
J ¼ 8.1 Hz, Ar-H), 7.31 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.44e8.25 (m, 8H,
50% (w/v) TCA (final concentration, 10% TCA) and incubated for
60 min at 4 ꢁC. The supernatant is discarded, and the plates are
washed five times with tap water and air dried. Sulforhodamine B
Ar-H).
4.1.3.7. 3-(4-Methylphenyl)-1-phenylsulfonylquinazoline-2,4(1H,3H)-
(SRB) solution (100 mL) at 0.4% (w/v) in 1% acetic acid is added to
dione (8g). IR (KBr, cmꢀ1
)
n
: 1729, 1681 (C]O), 1381, 1174 (O]S]O);
each well, and plates are incubated for 10 min at room
temperature. After staining, unbound dye is removed by washing
five times with 1% acetic acid and the plates are air dried. Bound
stain is subsequently solubilized with 10 mM trizma base, and the
absorbance is read on an automated plate reader at a wavelength
of 515 nm. For suspension cells, the methodology is the same
except that the assay is terminated by fixing settled cells at the
1H NMR (CDCl3)
d
: 2.40 (s, 3H, CH3), 6.99 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.28
(d, 2H, J ¼ 8.0 Hz, Ar-H), 7.44e8.26 (m, 9H, Ar-H).
4.1.3.8. 3-(4-Methylphenyl)-1-(4-chlorophenylsulfonyl)quinazoline-
2,4(1H,3H)-dione (8h). IR (KBr, cmꢀ1
)
n
: 1730, 1684 (C]O), 1381,
1175 (O]S]O); 1H NMR (CDCl3)
d: 2.41 (s, 3H, CH3), 7.02 (d, 2H,
J ¼ 7.5 Hz, Ar-H), 7.30 (d, 2H, J ¼ 7.7 Hz, Ar-H), 7.44e8.28 (m, 8H,
bottom of the wells by gently adding 50 mL of 80% TCA (final
concentration, 16% TCA) [55e57].
Ar-H).
4.1.3.9. 3-(4-Methylphenyl)-1-(4-methylphenylsulfonyl)quinazoline-
4.3. Molecular modeling methods
2,4(1H,3H)-dione (8i). IR (KBr, cmꢀ1
)
n
: 1730, 1683 (C]O), 1380,
1175 (O]S]O); 1H NMR (CDCl3)
d: 2.42 (s, 3H, CH3), 2.48 (s, 3H,
4.3.1. General methodology
CH3), 7.01 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.28 (d, 2H, J ¼ 7.8 Hz, Ar-H),
All molecular modeling calculations were performed using
“Molecular Operating Environment (MOE) version 2008.10”,
Chemical Computing Group Inc., running on “Windows Vista”
operating system installed on an Intel core 2du PC with a 1.8 MHz
processor and 1000 Mb RAM.
7.40e8.24 (m, 8H, Ar-H).
4.1.3.10. 3-(4-Methoxyphenyl)-1-phenylsulfonylquinazoline-2,4
(1H,3H)-dione (8j). IR (KBr, cmꢀ1
)
n
: 1730, 1684 (C]O), 1384, 1182
: 3.77 (s, 3H, OCH3), 6.97 (d, 2H,
J ¼ 8.9 Hz, Ar-H), 7.09 (d, 2H, J ¼ 9.0 Hz, Ar-H), 7.51 (t, 1H, J ¼ 7.5 Hz,
Ar-H), 7.67e8.18 (m, 8H, Ar-H); 13C NMR (DMSO-d6)
: 55.83,
(O]S]O); 1H NMR (CDCl3)
d
4.3.2. Alignment of the training set compounds
d
The training set compounds, consisting of nine diary-
lsulfonylureas of diverse chemical structures including compounds
AeE, in addition to, compounds 3h, 3n, 6b and 8a, were built using
the builder interface of the MOE software. The compounds were
aligned using the flexible alignment tool of the program adjusting the
energy cut off to 10 kcal/mol and root mean square deviation (RMSD)
tolerance to 0.5. The stochastic conformation search option was used
as the method of alignment.
114.65, 118.42, 120.09, 126.11, 127.69, 128.51, 128.73, 130.00, 130.16,
134.88, 135.24, 136.77, 139.01, 149.08, 159.63, 161.47.
4.1.3.11. 3-(4-Methoxyphenyl)-1-(4-chlorophenylsulfonyl)quinazo-
line-2,4(1H,3H)-dione (8k). IR (KBr, cmꢀ1
)
n
: 1732, 1685 (C]O),
1385, 1182 (O]S]O); 1H NMR (CDCl3)
d: 3.85 (s, 3H, OCH3), 6.98
(d, 2H, J ¼ 8.3 Hz, Ar-H), 7.14 (d, 2H, J ¼ 8.5 Hz, Ar-H), 7.40e8.29 (m,
8H, Ar-H).
4.3.3. Target compounds optimization
4.1.3.12. 3-(4-Methoxyphenyl)-1-(4-methylphenylsulfonyl)quinazo-
Conformational analyses of the built molecules were performed in
a two-step procedure. First, the target compounds were subjected to
energy minimization tool using the included MOPAC 7.0. The
geometry of the compounds was optimized with the semiemperical
AM1 Hamiltonian using Restricted Hartree-Fock (RHF) and RMS
gradient of 0.05 Kcal/mol. Then, the produced model wassubjected to
the ‘Systematic Conformational Search’ of the MOE. All items were set
as default with
line-2,4(1H,3H)-dione (8l). IR (KBr, cmꢀ1
)
n
: 1730, 1684 (C]O),
1384, 1182 (O]S]O); 1H NMR (CDCl3)
d: 2.49 (s, 3H, CH3), 3.85
(s, 3H, OCH3), 6.99 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.14 (d, 2H, J ¼ 7.6 Hz,
Ar-H), 7.44e8.29 (m, 8H, Ar-H).
4.2. Biological evaluation
ꢀ
The human tumor cell lines of the cancer screening panel are
grown in RPMI 1640 medium containing 5% fetal bovine serum and
RMS gradient of 0.01 Kcal/mol and RMS distance of 0.1 A. The
obtained data were then saved into a MDB file to be used in the
pharmacophore fitting calculations.
2 mM
L-glutamine. For a typical screening experiment, cells are
inoculated into 96 well microtiter plates in 100
mL at plating densities
ranging from 5000 to 40,000 cells/well depending on the doubling
time of individual cell lines. After cell inoculation, the microtiter
plates are incubated at 37 ꢁC, 5% CO2, 95% air and 100% relative
humidity for 24 h prior to addition of experimental drugs.
After 24 h, two plates of each cell line are fixed in situ with TCA,
to represent a measurement of the cell population for each cell line
4.3.4. Pharmacophore building
A pharmacophore model was created using the ‘Pharmacophore
Query Editor’. The aligned training set compounds were used as the
template for building the model. The settings of the software
parameters were adjusted to: ‘Unified’ as the scheme of annotation
ꢀ
‘Consensus method’ for model building. Tolerance was set to 1.2 A

I.M. El-Deeb et al. / European Journal of Medicinal Chemistry 45 (2010) 2516e2530
2529
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Using the generated pharmacophore model and the saved
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Acknowledgments
The authors would like to express their gratitude and thanks to
the National Cancer Institute (NCI), Bethesda Maryland, USA, http://
dtp.cancer.gov/ for doing the antitumor testing of the new
compounds. Our sincere acknowledgments to Chemical Computing
Group Inc, 1010 Sherbrooke Street West, Suite 910, Montreal, H3A
2R7, Canada., for its valuable agreement to use the package of MOE
2008.10 software.
Appendix. Supplementary data
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