Possible anticancer agents: QSAR analogs of glutamamide: Synthesis and pharmacological activity of 1,5-N,N′-disubstituted-2-(substituted benzenesulphonyl) glutamamides

Article abstract of DOI:10.1016/j.ejmech.2008.03.008

Based on our earlier QSAR prediction, a series of designed QSAR analogs of 1,5-N,N′-disubstituted-2-(substituted benzenesulphonyl) glutamamides were synthesized as possible anticancer agents. Inhibitions of tumor cell proliferation of the compounds were t

Full text of DOI:10.1016/j.ejmech.2008.03.008

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 44 (2009) 70e82
http://www.elsevier.com/locate/ejmech
Original article
Possible anticancer agents: QSAR analogs of glutamamide: Synthesis
and pharmacological activity of 1,5-N,N0-disubstituted-2-
(substituted benzenesulphonyl) glutamamides
1
Soma Samanta, Sk. Mahasin Alam, Parthasarathi Panda , Tarun Jha
*
Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology,
P.O. Box 17020, Jadavpur University, Kolkata 700032, India
Received 30 January 2007; received in revised form 10 March 2008; accepted 13 March 2008
Available online 27 March 2008
Abstract
Based on our earlier QSAR prediction, a series of designed QSAR analogs of 1,5-N,N0-disubstituted-2-(substituted benzenesulphonyl) glu-
tamamides were synthesized as possible anticancer agents. Inhibitions of tumor cell proliferation of the compounds were tested in tumor cell line
IMR-32. Anticancer activities of these compounds were also evaluated on Swiss Albino mice against Ehrlich Ascites Carcinoma (EAC) cells.
Tumor weight inhibition and tumor cell inhibition were considered as anticancer activity parameters. QSAR analysis of these compounds was
performed on the basis of a set of descriptors like physicochemical, topological, quantum chemical and DRAGON whole molecular descriptors.
The study showed that the increase of length of substituent at R2 position and the increase of dipole moment of the molecule decrease the an-
ticancer activity of these compounds, presence of bromine atom at R3 position and hydrophilic substitution at R2 position are advantageous to the
activity. Nucleophilic attack at atom number 14 is advantageous and electrophilic attack at atom number 15 is detrimental to anticancer activity.
Atom number 2 is important and may be involved in dispersive interactions of the compounds with enzymes. The results offer an opportunity for
further tailoring of these analogs for an active member.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Glutamamide; Anticancer activity; IMR-32; EAC; QSAR; Cluster analysis
1. Introduction
by participating in protein, purine and pyrimidine metabolisms.
Amide nitrogen of glutamine is utilized in a number of transfer
reactions. Glutamine transports almost one third of the circulat-
ing amino acids and nitrogen; it is also the principle carrier of
nitrogen from the skeletal muscles to the visceral organs [10].
As a principle metabolic fuel for the rapidly dividing cells in-
cluding enterocytes, colonocytes, fibroblasts, lymphocytes,
macrophages, neutrophils and tumor cells, it is as efficient as
glucose. Through amidotransferase reactions, the amide nitro-
gen of glutamine serves as the precursor for the biosynthesis
of many nitrogen-containing compounds and nucleotides
such as pyridine nucleotide coenzymes, purines, pyrimidines,
glucosamines, DPN and asparagine [10e13]. Amide nitrogen
of glutamine is the precursor of nitrogen atom of carbamyl phos-
phate in many tissues [13]. It is reported that 2-(phenylacetyl)
isoglutamine, which contains 1-N-amide, deserves anticancer
Glutamine is essential for rapidly proliferating tumor tissues
as it is an important nutrient for rapidly growing cells [1e7].
Glutamine plays a key role in tumor cell growth by supplying
its amide nitrogen atom in the biosyntheses of other amino
acids, purines, pyrimidines, amino sugars and co-enzymes via
a family comprised of 16 amidotransferase enzymes [8,9].
For cellular growth, glutamine provides multiple contributions
* Corresponding author. Tel.: þ91 33 2414 6666x2495 (o), þ91 33
24383814 (r), þ91 9433187443 (m); fax: þ91 33 2414 6927.
E-mail address: tjjupharm@yahoo.com (T. Jha).
1
Present address: School of Chemical and Biomedical Engineering, Na-
nyang Technological University, 62 Nanyang Drive, Singapore 634759,
Singapore.
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.03.008

S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
71
topological, quantum chemical and DRAGON whole molecu-
lar descriptors are used to build significant models. The study
was performed on all these glutamamide analogs using per-
centage tumor weight inhibition (TWI) and tumor cell inhibi-
tion (TCI) as biological activity parameters.
2. Materials and method
2.1. Chemistry
Fig. 1. General structure of 1,5-N,N0-disustituted-2-(substituted benzenesul-
phonyl) glutamamides (26e57).
2-(Substituted benzenesulphonyl)glutamic acids (14e19)
were prepared by condensing L-glutamic acid (13) with
substituted benzenesulphonyl chlorides (7e12) [21] which
were synthesized by chlorosulphonylation of substituted ben-
zenes (1e6) [22]. 2-(Substituted benzenesulphonyl)glutamic
acid dichlorides (20e25) were obtained by treating the diacids
(14e19) with thionyl chloride and title compounds were pre-
pared by amination of acid chlorides (20e25) according to the
methods described earlier [15e19]. The structures of the syn-
thesized compounds were confirmed by IR, 1H NMR and mass
spectra as well as by elemental analyses. Melting points of all
synthesized compounds were determined in capillary tubes
with a Mel-Temp Electrothermal apparatus and are uncor-
rected. The 1H NMR spectra were determined with a BRUKER
DRX 300 MHz and referenced to the solvent. Chemical shifts
are expressed in ppm and coupling constants (J ) are in Hz, (s)
singlet, (d) doublet, (t) triplet, (m) multiplet. Position of hy-
activity [14]. As a part of the composite programme of drug
design and discovery [15e20], our aim was to develop new
compounds having possible anticancer activity. We have chosen
to synthesize molecules that are structural variants of glutamine
and/or glutamic acid as these variants may inhibit enzyme glu-
taminase and/or glutamine synthetase as well as glutamine
receptor(s). Based on our earlier QSAR studies [15e19] on
1,5-N,N0-disubstituted-2-(substituted benzenesulphonyl) gluta-
mamides, 32 new analogs of these glutamamides were designed
and selected for synthesis and biological evaluation. The
selected QSAR analogs were synthesized, characterized and
biologically evaluated using in vitro and in vivo method. As
these compounds were designed on the basis of earlier QSAR
studies, these are termed as QSAR analogs to differentiate these
analogs from the earlier synthesized non-designed analogs of
Refs. [15e19]. To further explore the chemical structural fea-
tures of these analogs, QSAR studies were performed on these
newly synthesized QSAR analogs of 1,5-N,N0-disubstituted-2-
(substituted benzenesulphonyl) glutamamides. The general
structure of 1,5-N,N0-disubstituted-2-(substituted benzenesul-
phonyl) glutamamides is shown in Fig. 1.
1
drogen described in H NMR interpretation are as per general
structure (Fig. 1) and substitution at R5 position are repre-
sented by the superscript ‘00’ (double dash) and the same for
0
R5 position are represented by the superscript ‘000’ (triple
dash). FABþ mass spectra were obtained on a JEOL JMS-
SX-102 mass spectrometer. m-Nitrobenzyl alcohol (MNBA)
was used as the matrix (Mþ) which showed the M þ 1 peak
at 154, 2M þ 1 peak at 307. Elemental analyses were per-
formed by 2400 Series-II CHN analyzer of PerkineElmer
and gave combustion values for C, H, N within 0.4% of the
theoretical values. Reactions were monitored by analytical
thin layer chromatography performed on silica gel G plates.
Pharmacological evaluation showed that some of these com-
pounds have good anticancer activities. The pharmacological
activity data has been used as a preliminary biological activity
dataset for QSAR study to find out the structural requirements
of these compounds to improve the anticancer activity. For
QSAR study, a set of descriptors like physicochemical,
Fig. 2. General structures of starting materials and intermediates.

72
S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
Table 1
Physical data for the intermediate compounds
spectral data of all substituted glutamic acids (14e19) are
given in Tables 1 and 2, respectively.
Physical data and spectral data of all final compounds are
given in Tables 3 and 4, respectively.
Cpda R1
R2 R3
R4
Mp (ꢁC)b % Yield Molecular formula
1
Cl
H
H
H
H
Br
Cl
H
Liquid
73e75
67e69
80.0
78.5
75.1
85.0
72.1
70.6
C6H3Cl3O2S
C6H4BrClO2S
C6H3Cl3O2S
C7H6Cl2O2S
C10H13ClO2S
C8H9ClO2S
2
3
H
Cl Cl
H
4
Cl
H
H
H
H
H
H
H
CH3 Liquid
2.2. Pharmacological evaluation
5
t-C4H9
CH3
H
H
H
Cl
H
H
56e58
Liquid
6
CH3
Cl
H
Synthesized title compounds are pharmacologically evalu-
ated by in vitro and in vivo method.
14
15
16
17
18
19
a
162e163 90.0
148e150 81.2
C11H11Cl2NO6S
C11H12BrNO6S
C11H11Cl2NO6S
C12H14ClNO6S
C15H21NO6S
C13H17NO6S
Br
H
Cl Cl
87e89
60.6
Cl
H
H
H
H
H
CH3 131e133 87.0
t-C4H9
CH3
H
H
162e164 44.2
109e111 68.2
2.2.1. Inhibition of tumor cell proliferation in tumor
cell line IMR-32
CH3
Compound number.
Melting point.
Anticancer activity of all final compounds was assessed
against tumor cell line IMR-32 (Human Neuroblastoma Cell
Line). Maintenance of the cell lines was carried out using
RPMI-1640 media, the subcultures of the cell lines were main-
tained for optimum (<P25) and maintained in deep freezer
(ꢀ80 ꢁC). The cell counts were performed using trypan blue
dye exclusion method on Neubaur slide (heamocytometer).
MTT method [23] was used to study the cytotoxic action of
these compounds on IMR-32 (Human Neuroblastoma Cell
Line). Medium with DMSO concentration less than 1% was
taken as the control and the cell viabilities in the test drug
treated group was expressed as % viability with respect to
b
The spots were located keeping the TLC plates in iodine
chamber. All title compounds as well as the starting material
L-glutamic acid showed optical activity when observed in
a polarimeter.
The general structure of the starting materials and interme-
diates are given in Fig. 2.
Physical data of substituted benzenesulphonyl chlorides
(1e6) and substituted glutamic acids (14e19) as well as
Table 2
Mass, IR and proton NMR spectroscopic as well as CHN analysis data of the intermediate compounds (14e19)
Cpd Mass (FAB)
IR (KBr, cmꢀ1
)
1H NMR (300 MHz, DMSO-d6)
C, H, N % calcd/found
C
H
N
ꢂ
14
15
16
17
18
19
M þ Hþ peak 2972, 2946, 2850 (ali CeH str.), 1698
d 7.95 (d, 2H, H-30, H-40), d 7.86 (d, 1H, H-60),
d 7.57 (s, 1H, SO2NH), d 3.68 (m, 1H, H-2),
2.93 (t, 2H, H-4), d 2.83 (d, 2H, H-3)
37.09/37.18 3.11/3.25 3.93/3.99
at m/z 356
(C]O str. of COOH), 1432, 1387
(S]O str. of SO2NH, asymmetric),
1160 (S]O str. of SO2NH, symmetric),
1048 (AreCl), 1582 (Ar C]C);
ꢂ
M þ Hþ peak 2980, 2862 (ali CeH str.), 1705
d 7.76 (d, 2H, H-20, H-60), d 7.54 (d, 1H, H-30, H-50), 36.08/36.00 3.30/3.39 3.83/3.81
d 7.46 (s, 1H, SO2NH), d 3.72 (m, 1H, H-2), d 2.86
(m, 2H, NeCH2-1000), d 2.53 (m, 2H, NeCH2-100),
at m/z 366
(C]O str. of COOH), 1442,1380
(S]O str. of SO2NH, asymmetric),
1158 (S]O str. of SO2NH, symmetric), d 2.33 (m, 2H, H2-4), d 1.58 (m, 2H, H2-3)
1085 (AreBr), 1590, 1510 (Ar C]C),
ꢂ
M þ Hþ peak 2981, 2888 (ali CeH str.), 1712
d 7.82 (d, 1H, H-20), d 7.65 (d, 1H, H-50), d 7.71
(d, 1H, H-60), d 7.59 (s, 1H, SO2NH), d 3.14
(m, 1H, H-2), d 3.18 (m, 2H, N-CH2-1000), d 3.64
37.09/37.15 3.11/3.21 3.93/3.84
42.93/42.99 4.20/4.25 4.17/4.32
at m/z 356
(C]O str. of COOH), 1430,1379
(S]O str. of SO2NH, asymmetric),
1162 (S]O str. of SO2NH, symmetric), (m, 2H, N-CH2-100), d 2.35 (m, 2H, H2-4), d 1.93
1048 (AreCl), 1592, 1521 (Ar C]C)
(m, 2H, H2-3)
ꢂ
M þ Hþ peak 2934, 2898 (ali CeH str.), 1721
d 7.75 (d, 2H, H-30, H-40), d 7.66 (d, 1H, H-60),
d 7.49 (s, 1H, SO2NH), d 3.83 (m, 1H, H-2),
d 2.72e1.30 (m, 4H, H2-3, H2-4)
at m/z 335
(C]O str. of COOH), 1431,1380
(S]O str. of SO2NH, asymmetric),
1188 (S]O str. of SO2NH, symmetric),
1045 (AreCl), 1498, 1532 (Ar C]C)
ꢂ
M þ Hþ peak 2946, 2890 (ali CeH str.), 1698
d 7.51 (d, 2H, H-20, H-60), d 7.62 (d, 1H, H-30, H-50), 52.46/52.44 6.16/6.28 4.08/3.99
d 7.43 (s, 1H, SO2NH), d 3.83 (m, 1H, H-2), d 2.65
(m, 2H, H2-4), d 1.38 (m, 2H, H2-3)
at m/z 343
(C]O str. of COOH), 1428, 1389
(S]O str. of SO2NH, asymmetric),
1168 (S]O str. of SO2NH, symmetric),
1492, 1526 (Ar C]C)
ꢂ
M þ Hþ peak 2952, 2892 (ali CeH str.), 1645
d 7.48 (d, 1H, H-30), d 7.29 d, 1H, H-50), d 7.37
(d, 1H, H-60), d 7.49 (s, 1H, SO2NH), d 3.77
(m, 1H, H-2), d 2.64 (m, 2H, H2-4), d 1.59
49.51/49.48 5.43/5.45 4.44/4.40
at m/z 315
(C]O str. of COOH), 1425, 1386
(S]O str. of SO2NH, asymmetric),
1158 (S]O str. of SO2NH, symmetric), (m, 2H, H2-3)
1496, 1522 (Ar C]C)

S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
73
Table 3
Physical data of final compounds and % inhibition of viable tumor cells of these synthesized compounds at the concentration of 60 mg/ml against IMR-32 cell line
Cpda
R1
R2
R3
R4
R5/R5
Mp (ꢁC)
% Yield
Molecular formula
% Inhibition
of viable cell (60 mg/ml)
0
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
a
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
C2H5
165e166
160e162
124e126
134e136
108e110
98e99
178e179
210e212
213e215
248e250
218e220
208e210
209e210
216e217
245e247
138e140
155e157
110e112
198e200
60e65
55.0
90.0
73.7
89.0
80.0
85.0
70.0
69.6
75.4
79.2
80.0
54.8
64.7
69.7
65.2
60.2
65.5
70.9
64.0
58.9
72.0
59.8
66.6
71.6
55.0
58.7
63.2
69.7
61.4
73.6
88.3
65.4
e
C15H21Cl2N3O4S
C17H25Cl2N3O4S
C19H29Cl2N3O4S
C19H29Cl2N3O4S
C21H33Cl2N3O4S
C23H37Cl2N3O4S
C23H21Cl2N3O4S
C25H25Cl2N3O4S
C19H30BrN3O4S
C23H34BrN3O4S
C23H34BrN3O4S
C25H26BrN3O4S
C21H33Cl2N3O4S
C23H33Cl2N3O4S
C25H25Cl2N3O4S
C12H16ClN3O4S
C16H24ClN3O4S
C18H28ClN3O4S
C18H28ClN3O4S
C20H32ClN3O4S
C20H32ClN3O4S
C22H36ClN3O4S
C24H40ClN3O4S
C24H36ClN3O4S
C24H24ClN3O4S
C26H28ClN3O4S
C15H23N3O4S
12.9
16.7
15.8
20.4
12.2
12.4
22.9
13.4
17.1
18.4
10.0
NDb
20.8
24.0
11.4
25.8
31.8
14.9
29.8
18.0
NDb
14.7
11.3
49.7
NDb
NDb
NDb
58.4
65.6
28.2
46.1
66.0
98.2
H
i-C3H7
n-C4H9
i-C4H9
C5H11
n-C6H13
C6H5
H
Cl
Cl
H
H
Cl
Cl
H
H
Cl
Cl
H
Br
CH2C6H5
i-C4H9
c-C6H11
C6H5
H
H
Br
Br
H
H
H
H
Br
Cl
H
CH2C6H5
C5H11
c-C6H11
CH2C6H5
H
H
H
H
Cl
Cl
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
C2H5
H
n-C3H7
i-C3H7
n-C4H9
i-C4H9
C5H11
n-C6H13
c-C6H11
C6H5
H
H
H
126e128
95e97
H
H
104e105
214e215
180e181
160e162
179e181
83e85
115e117
189e191
144e145
135e137
e
H
H
H
CH2C6H5
H
C2H5
t-C4H9
t-C4H9
t-C4H9
CH3
CH3
CH3
Cisplatin
H
H
C19H31ClO4S
C21H35N3O4S
H
H
i-C3H7
H
CH3
CH3
CH3
H
C13H17NO6S
C21H35N3O4S
H
n-C4H9
n-C6H13
H
C25H43N3O4S
e
Compound number.
Not determined due to poor solubility in appropriate solvent.
b
DMSO. Cisplatin (3 mg/ml) was used as the standard. The %
inhibition of viable cells is given in Table 3.
(26e57) were performed using percentage tumor weight inhi-
bition (%TWI) and tumor cell inhibition (%TCI) as the biolog-
ical activity parameters. All these activities are calibrated to
the logarithmic scale and are listed in Table 5.
2.2.2. Evaluation of anticancer activity by in vivo method
We faced great difficulties in dissolving these compounds
in the solvent when performing the in vitro method. We also
used in vivo method which is standardized in our laboratory
[15e19,24]. All the final compounds were screened according
to the earlier reported procedure [15e19]. In the present study,
Mitomycin C as well as Azaserin and DON (1 mg/kg body
weight) in sterile phosphate buffers (pH 7.2) were used as
standards which showed 100% inhibition. Mitomycin C was
chosen as the universal standard and azaserin, DON were
used as the specific standard drugs to compare the activity
of the test compounds. In vivo results of the final compounds
are shown in Table 5.
2.3.1. Dataset and parameters
A large set of various descriptors like physicochemical,
topological, geometrical, semi-empirical quantum chemical
descriptors, were calculated by using software like Hyper-
Chem Release 7.0 Pro Package [25], DRAGON [26], Mouse
[27] etc. The physicochemical parameters like hydrophobic
constant (p), molar refractivity (MR), steric parameter (Es),
Verloop STERIMOL parameters like L, B1, B5 were collected
from the literature [28]. Refractotopological state atom
(RTSA) indices ðRÞ [29e31] were calculated using computer
programme Mouse [27] developed in our laboratory. Before
calculation, the atoms of the molecules were numbered arbi-
trarily (shown in Fig. 3) keeping the serial number of atoms
same in all the molecules.
2.3. QSAR methodology
QSAR studies of these 32 newly synthesized 1,5-N,N0-di-
substituted-2-(substituted benzenesulphonyl) glutamamides
Semi-empirical quantum chemical descriptors were calcu-
lated by Hyperchem Release 7.0 Pro Package [25] according

Table 4
Mass, IR and proton NMR spectroscopic as well as CHN analysis data of the final compounds (26e57)
Cpd Mass (FAB)
IR (KBr, cmꢀ1
)
1H NMR (300 MHz, DMSO-d6)
C, H, N % calcd/found
C
H
N
ꢂ
26
27
M þ Hþ peak 3321, 3299 (NeH str. of CONH), 3091 (Ar CeH str.),
d 7.76 (d, 2H, H-30, H-40), d 7.86 (d, 1H, H-60), d 7.47
(s, 1H, SO2NH), d 7.35 (m, 1H, CONH-1), d 7.20
(m, 1H, CONH-5), d 3.68 (m, 1H, H-2), d 3.12 (m, 2H,
NeCH2-1000), d 2.18 (m, 2H, H2-4), d 1.78 (m, 2H, H2-3),
1.16 (3H, CH2-2000), 1.02 (m, 3H, CH3-200)
d 7.86 (d, 2H, H-30, H-40), d 7.92 (d, 1H, H-60), d 7.53
(s, 1H, SO2NH), d 7.23 (m, 1H, CONH-1), d 7.18
(m, 1H, CONH-5), d 3.78 (m, 1H, H-2), d 3.42
(m, 1H, NeCH-1000), d 3.28 (m, 1H, NeCH-100),
d 2.66 (m, 2H, H2-4), d 1.78 (m, 2H, H2-3), 1.16 (m,
2H2, H-4), 1.24e1.14 (m, 6H, CH3-20 CH3-300),
0.96e0.82 (m, 6H, CH3-2000, CH3-3000)
d 7.75 (d, 2H, H-30, H-40), d 7.90 (d, 1H, H-60),
d 7.49 (s, 1H, SO2NH), d 7.29 (m, 1H, CONH-1),
d 7.19 (m, 1H, CONH-5), d 3.70 (m, 1H, H-2), d 3.11
(m, 2H, NeCH2-1000), d 3.53 (m, 2H, N-CH2-100), d 2.17
(m, 2H, H2-4), d 1.79 (m, 2H, H2-3), 1.36e1.06 (m, 8H,
CH2-200, CH2-300, CH2-2000, CH2-3000), 0.98e0.81(m, 6H,
CH3-400, CH3-4000)
d 7.58 (d, 2H, H-30, H-40), d 7.56 (d, 1H, H-60), d 7.26
(s, 1H, SO2NH), d 7.10 (m, 1H, CONH-1), d 7.09
(m, 1H, CONH-5), d 2.62 (m, 1H, H-2), d 2.46 (m, 2H,
NeCH2-1000), d 2.44 (m, 2H, NeCH2-100), d 1.93
(m, 2H, H2-4), d 1.56 (m, 2H, H2-3), 1.37e0.41 (m, 14H,
CH-200, CH-2000, CH3-300, CH3-3000, CH3-400, CH3-4000)
d 8.03 (d, 2H, H-30, H-40), d 8.02 (d, 1H, H-60), d 7.50
(s, 1H, SO2NH), d 7.49 (m, 1H, CONH-1), d 7.30 (m, 1H,
CONH-5), d 3.16 (m, 1H, H-2), d 3.13 (m, 2H, NeCH2-1000),
d 3.86 (m, 2H, NeCH2-100), d 2.21 (m, 2H, H2-4), d 1.42
(m, 2H, H2-3), 1.4e1.25 (m, 16H, CH2-200, CH2-300, CH2-400,
CH2-500, CH2-2000, CH2-3000, CH2-4000, CH2-5000), 0.98e0.94(m,
6H, CH3-600, CH3-6000)
43.91/43.56
5.16/5.02
10.24/10.05
at m/z 410
2977, 2929 (ali CeH str.), 1649 (C]O str. of CONH),
1423,1377 (S]O str. of SO2NH, asymmetric), 1163
(S]O str. of SO2NH, symmetric), 1043 (Ar-Cl), 1452
(Ar C]C), 1564, 1548 (NeH bend of CONH)
ꢂ
M þ Hþ peak 3341, 3298 (NeH str. of CONH), 3080 (Ar CeH str.),
46.58/46.23
48.93/48.62
5.75/5.51
6.27/6.11
9.59/9.49
9.01/8.92
at m/z 438
2975, 2925 (ali CeH str.), 1429, 1375 (S]O str. of SO2NH,
asymmetric), 1166 (S]O str. of SO2NH, symmetric), 1641
(C]O str. of CONH), 1552, 1550 (NeH bend of CONH),
1452 (Ar C]C), 825 (Ar-disubstitution), 1043, 1099 (AreCl),
ꢂ
28
M þ Hþ peak 3376, 3296 (NeH str. of CONH), 3057 (Ar CeH str.),
at m/z 446
2944, 2846 (ali CeH str.), 1324 (S]O str. of SO2NH,
asymmetric), 1158 (S]O str. of SO2NH, symmetric),
1645 (C]O str. of CONH), 1553, 1548 (NeH bend of CONH)
ꢂ
29
30
M þ Hþ peak 3299 (NeH str. of CONH), 3097 (Ar CeH str.), 2958, 2927
48.93/48.71
51.01/50.88
6.27/6.13
6.73/6.69
9.01/8.96
8.50/8.46
at m/z 466
(ali CeH str.), 1649 (C]O str. of CONH), 1452, 1375
(S]O str. of SO2NH, asymmetric), 1164 (S]O str. of SO2NH,
symmetric), 1554 (NeH bend. of CONH) 1452 (Ar C]C),
823 (Ar-disubstitution), 1041 (AreCl)
ꢂ
M þ Hþ peak 3326 (NeH str. of CONH), 3045 (Ar CeH str.), 2966, 2892
at m/z 494
(ali CeH str.), 1446, 1375 (S]O str. of SO2NH, asymmetric),
1168 (S]O str. of SO2NH, symmetric), 1651
(C]O str. of CONH), 1562, 1549 (NeH bend of CONH)
ꢂ
31
32
M þ Hþ peak 3294 (NeH str. of CONH), 3280 (NeH str. of SO2NH),
d 7.73 (d, 2H, H-30, H-40), d 7.72 (d, 1H, H-60), d 7.71
(s, 1H, SO2NH), d 7.20 (m, 1H, CONH-1), d 7.10 (m, 1H,
CONH-5), d 2.91 (m, 1H, H-2), d 3.53 (m, 2H, NeCH2-1000),
d 3.74 (m, 2H, NeCH2-100), d 2.32 (m, 2H, H2-4), d 2.00
(m, 2H, H2-3), 1.72e1.03 (m, 20H, CH2-200, CH2-300, CH2-400,
CH2-500, CH2-600, CH2-2000, CH2-3000, CH2-4000, CH2-5000, CH2-6000),
0.99e0.95 (m, 6H, CH3-700, CH3-7000)
d 7.84 (d, 2H, H-30, H-40), d 7.79 (d, 1H, H-60), d 7.76
(s, 1H, SO2NH), d 7.28 (m, 1H, CONH-1), d 7.15
(m, 1H, CONH-5), d 2.95 (m, 1H, H-2), d 2.36
(m, 2H, H2-4), d 2.08 (m, 2H, H2-3, d 7.19e6.91
(m, 10H, phenyl proton)
52.87/52.77
54.55/54.49
7.14/7.00
4.18/4.12
8.04/7.97
at m/z 522
3097 (Ar CeH str.), 2986, 293 (ali CeH str.), 1643, 1560,
1491 (ali CeH def.), 1315 (S]O str. of SO2NH, asymmetric),
1153 (S]O str. of SO2NH, symmetric), 1076, 984, 897
(AreCeH def.)
ꢂ
M þ Hþ peak 3323, 3274 (NeH str. of CONH), 3062 (Ar CeH str.),
8.30/8.21.
at m/z 506
2923 2854 (ali CeH str.), 1658 (C]O str. of CONH),
1444, 1379 (S]O str. of SO2NH, asymmetric), 1150
(S]O str. of SO2NH, symmetric), 1498 (Ar C]C), 1041
(AreCl), 815 (Ar-disubstitution)

ꢂ
33
34
M þ Hþ peak 3321, 3264 (NeH str. of CONH), 3059 (Ar CeH str.), 2942,
d 7.55 (d, 2H, H-30, H-40), d 7.69 (d, 1H, H-60), d 7.62
(s, 1H, SO2NH), d 7.38 (m, 1H, CONH-1), d 7.25
(m, 1H, CONH-5), d 2.85 (m, 1H, H-2), d 3.66
(m, 2H, NeCH2-1000), d 3.74 (m, 2H, NeCH2-100),
d 2.46 (m, 2H, H2-4), d 2.18 (m, 2H, H2-3,
d 7.09e6.89 (m, 10H, phenyl proton)
d 7.46 (d, 2H, H-20, H-60), d 7.44 (d, 1H, H-30,
H-50), d 7.36 (s, 1H, SO2NH), d 7.34 (m, 1H,
CONH-1), d 7.26 (m, 1H, CONH-5), d 3.82
(m, 1H, H-2), d 2.76 (m, 2H, NeCH2-1000), d 2.73
(m, 2H, NeCH2-100), d 2.63 (m, 2H, H2-4), d 1.50
(m, 2H, H2-3), 1.35e0.57 (m, 14H, CH-200, CH-2000,
CH3-300, CH3-3000, CH3-400, CH3-4000)
C (calc.56.18, H (Calc.4.71, (Calc.7.86,
found 56.02)
at m/z 534
2896 (ali CeH str.), 1663 (C]O str. of CONH), 1448, 1389
(S]O str. of SO2NH, asymmetric), 1156 (S]O str. of SO2NH,
symmetric), 1494 (Ar C]C), 1045 (AreCl), 813 (Ar-disubstitution)
found 4.68)
found 7.66)
ꢂ
M þ Hþ peak 3311, 3236 (NeH str. of CONH), 3087 (Ar CeH str.), 2956, 2929
47.9/47.86
6.35/6.32
8.82/8.73
at m/z 476
(ali CeH str.), 1641 (C]O str. of CONH.), 1434, 1388 (S]O str.
of SO2NH), 1454 (Ar C]C), 1166 (S]O str. of SO2NH), 1554,
1467 (NeH bend of CONH), 649, 754 (Ar-monosubstitution),
1087 (AreBr)
ꢂ
35
36
37
M þ Hþ peak 3305, 3234 (NeH str. of CONH), 3062 (Ar CeH str.), 2925,
d 7.56 (d, 2H, H-20, H-60), d 7.64 (d, 1H, H-30, H-50),
d 7.38 (s, 1H, SO2NH), d 7.23 (m, 1H, CONH-1),
d 7.21 (m, 1H, CONH-5), d 3.72 (m, 1H, H-2),
d 1.67e1.00 (m, 22H, cyclohexyl proton),
52.27/52.21
53.49/53.31
54.95/54.86
6.48/6.39
4.29/4.22
5.16/5.11
7.95/7.92.
8.14/8.10
7.69/7.55
at m/z 528
2852 (ali CeH str.), 1652, 1641 (C]O str. of CONH), 1573,
1539 (NH bend of CONH), 1468, 1388 (S]O str. of SO2NH,
asymmetric), 1168 (S]O str. of SO2NH, symmetric), 1087
(AreBr.)
d 2.43 (m, 2H, H2-4), d 1.48 (m, 2H, H2-3)
d 7.62 (d, 2H, H-20, H-60), d 7.56 (d, 1H, H-30, H-50),
d 7.48 (s, 1H, SO2NH), d 7.33 (m, 1H, CONH-1),
d 7.28 (m, 1H, CONH-5), d 3.82 (m, 1H, H-2),
d 7.11e6.95 (m, 10H, phenyl proton), d 2.42
(m, 2H, H2-4), d 1.52 (m, 2H, H2-3)
ꢂ
M þ Hþ peak 3394 (NeH str. of CONH), 3280 (NeH str. of SO2NH), 3067
at m/z 516
(Ar CeH str.), 2956, 2832 (ali CeH str.), 1643, 1560, 1490
(ali CeH def.), 1315 (S]O str. of SO2NH, asymmetric), 1153
(S]O str. of SO2NH, symmetric), 1086, 984, 890 (AreCeH def.)
ꢂ
M þ Hþ peak 3319, 3252 (NeH str. of CONH), 3092 (Ar CeH str.), 2961, 2893
d 7.56 (d, 2H, H-20, H-60), d 7.64 (d, 1H, H-30, H-50),
at m/z 544
(ali CeH str.), 1646 (C]O str. of CONH.), 1454, 1398
d 7.38 (s, 1H, SO2NH), d 7.43 (m, 1H, CONH-1),
(S]O str. of SO2NH), 1456 (Ar C]C), 1172 (S]O str. of SO2NH), d 7.22 (m, 1H, CONH-5), d 3.72 (m, 1H, H-2),
1576, 1487 (NeH bend of CONH), 650, 761 (Ar-monosubstitution),
1091 (AreBr)
d 2.66 (m, 2H, NeCH2-1000), d 2.83 (m, 2H, NeCH2-100),
d 2.53 (m, 2H, H2-4), d 1.48 (m, 2H, H2-3), 7.17e6.86
(m, 10H, phenyl proton)
ꢂ
38
M þ Hþ peak 3312, 3233 (NeH str. of CONH), 3089 (Ar CeH str.), 2978, 2932
d 7.85 (d, 1H, H-20), d 7.55 (d, 1H, H-50), d 7.70
(d, 1H, H-60), d 7.58 (s, 1H, SO2NH), d 7.31
(m, 1H, CONH-1), d 7.14 (m, 1H, CONH-5),
d 3.17 (m, 1H, H-2), d 3.14 (m, 2H, NeCH2-1000),
d 3.74 (m, 2H, NeCH2-100), d 2.25 (m, 2H, H2-4),
d 1.89 (m, 2H, H2-3), 1.49e1.28 (m, 16H, CH2-200,
CH2-300, CH2-400, CH2-500, CH2-2000, CH2-3000, CH2-4000,
CH2-5000), 0.92e0.86 (m, 6H, CH3-600, CH3-6000)
d 7.92 (d, 1H, H-20), d 7.65 (d, 1H, H-50),
d 7.74 (d, 1H, H-60), d 7.58 (s, 1H, SO2NH),
d 7.36 (m, 1H, CONH-1), d 7.24 (m, 1H, CONH-5),
d 3.27 (m, 1H, H-2), d 1.87e1.02 (m, 22H, cyclohexyl
proton), d 2.27 (m, 2H, H2-4), d 1.92 (m, 2H, H2-3)
d 7.96 (d, 1H, H-20), d 7.56 (d, 1H, H-50), d 7.26
(d, 1H, H-60), d 7.21 (s, 1H, SO2NH), d 7.18 (m, 1H,
CONH-1), d 7.07 (m, 1H, CONH-5), d 4.28 (m, 1H, H-2),
d 4.07 (m, 2H, NeCH2-1000), d 3.58 (m, 2H, NeCH2-100),
d 2.53 (m, 2H, H2-4), d 2.07 (m, 2H, H2-3), 7.07e6.76
(m, 10H, phenyl proton)
51.01/50.92
6.73/6.68
8.5/8.48
at m/z 494
(ali CeH str.), 1657 (C]O str. of CONH), 1553, 1542 (NeH bend
of CONH), 1423, 1378 (S]O str. of SO2NH, asymmetric), 1169
(S]O str. of SO2NH, symmetric), 1456 (AreC]C), 1041 (AreCl)
ꢂ
39
40
M þ Hþ peak 3309, 3242 (NeH str. of CONH), 3090 (Ar CeH str.), 2931
53.28/53.18
56.18/56.11
6.42/6.32
4.71/4.68
8.10/7.92
7.86/7.75
at m/z 518
(ali CeH str.), 1643 (C]O str. of CONH.), 1541 (NeH bend of
CONH), 1438, 1371 (S]O str. of SO2NH, asymmetric), 1168
(S]O str. of SO2NH, symmetric), 1454 (AreC]C.), 817
(Ar-disubstitution), 1031 (AreCl)
ꢂ
M þ Hþ peak 3318, 3238 (NeH str. of CONH), 3088 (Ar CeH str.), 2932
at m/z 534
(ali CeH str.), 1652 (C]O str. of CONH.), 1543 (NeH bend of
CONH), 1448, 1381 (S]O str. of SO2NH, asymmetric), 1159
(S]O str. of SO2NH, symmetric), 1464 (AreC]C.), 815
(Aredisubstitution), 1032 (AreCl)
(continued on next page)

Table 4 (continued)
Cpd Mass (FAB)
IR (KBr, cmꢀ1
)
1H NMR (300 MHz, DMSO-d6)
C, H, N % calcd/found
C
H
N
ꢂ
41
42
M þ Hþ peak 3380, 3292 (NeH str. of CONH), 3091 (Ar CeH str.), 2978,
d 7.95 (d, 2H, H-30, H-40), d 7.46 (d, 1H, H-60), d 7.40
(s, 1H, SO2NH), d 7.30 (m, 2H, CONH2-1), d 6.78
(m, 2H, CONH2-5), d 3.81 (m, 1H, H-2), d 2.69e1.29
(m, 4H, H2-3, H2-4), d 2.5 (s, 3H, AreCH3)
43.18/43.02
4.83/4.83
12.59/12.48
at m/z 333
2932 (ali CeH str.), 1668 (C]O str. of CONH.), 1429, 1387
(S]O str. of SO2NH, asymmetric), 1154 (S]O str. of SO2NH,
symmetric), 1043 (AreCl.)
ꢂ
M þ Hþ peak 3305, 3251 (NeH str. of CONH), 3093 (Ar CeH str.), 2979,
d 7.91 (d, 2H, H-30, H-40), d 7.90 (d, 1H, H-60),
49.29/49.12
51.73/51.70
6.20/6.11
6.75/6.68
10.78/10.56
10.05/9.99
at m/z 389
2933 (ali CeH str.), 1645 (C]O str. of CONH), 1556 (NeH bend of d 7.42 (s, 1H, SO2NH), d 7.30 (m, 1H, CONH-1),
CONH), 1440, 1380 (S]O str. of SO2NH, asymmetric), 1161
(S]O str. of SO2NH, symmetric), 1460 (AreC]C), 819
(Aredisubstitution), 1041 (AreCl)
d 7.25 (m, 1H, CONH-5), d 3.15 (m, 1H, H-2),
d 3.14 (m, 2H, NeCH2-1000), d 2.68 (m, 2H, H2-4),
d 2.41 (m, 2H, H2-3), 1.26 (3H, CH2-2000), 1.03
(m, 3H, CH3-200), d 2.44 (s, 3H, AreCH3)
d 7.87 (d, 2H, H-30, H-40), d 7.41 (d, 1H, H-60), d 7.39
(s, 1H, SO2NH), d 7.27 (m, 1H, CONH-1), d 6.97
(m, 1H, CONH-5), d 3.65 (m, 1H, H-2), d 3.24 (m, 2H,
NeCH2-1000), d 3.63 (m, 2H, NeCH2-100), d 2.65
(m, 2H, H2-4), d 2.28 (m, 2H, H2-3), 1.95e1.35
(m, 4H, CH2-200, CH2-2000, 0.97e0.80 (t, 6H, CH3-300,
CH3-3000), d 2.35 (s, 3H, AreCH3)
d 7.67 (d, 2H, H-30, H-40), d 7.50 (d, 1H, H-60), d 7.24
(s, 1H, SO2NH), d 7.21 (m, 1H, CONH-1), d 7.06
(m, 1H, CONH-5), d 3.55 (m, 1H, H-2), d 2.41
(m, 1H, NeCH-1000), d 2.45 (m, 1H, NeCH-100), d 2.06
(m, 2H, H2-4), d 1.98 (m, 2H, H2-3), 1.72 (m, 2H2, H-4),
1.70e1.69 (m, 6H, CH3-200, CH3-300), 0.97e0.72
(m, 6H, CH3-2000, CH3-3000), d 2.57 (s, 3H, AreCH3)
d 7.90 (d, 2H, H-30, H-40), d 7.89 (d, 1H, H-60), d 7.30
(s, 1H, SO2NH), d 7.28 (m, 1H, CONH-1), d 6.45
(m, 1H, CONH-5), d 3.71 (m, 1H, H-2), d 3.30
(m, 2H, NeCH2-1000), d 3.14 (m, 2H, NeCH2-100),
d 2.67 (m, 2H, H2-4), d 1.40 (m, 2H, H2-3),
ꢂ
43
44
45
M þ Hþ peak 3316, 3276 (NeH str. of CONH), 3089 (Ar CeH str.), 2972, 2923
at m/z 417
(ali CeH str.), 1649 (C]O str. of CONH), 1562 (NeH bend of
CONH), 1442, 1389 (S]O str. of SO2NH, asymmetric), 1172
(S]O str. of SO2NH, symmetric), 1465 (AreC]C), 812
(Aredisubstitution), 1038 (AreCl)
ꢂ
M þ Hþ peak 3316, 3278 (NeH str. of CONH), 3068 (Ar CeH str.), 2980, 2911
51.73/51.66
53.86/53.78
6.75/6.59
7.23/7.11
10.05/9.98
at m/z 417
(ali CeH str.), 1652 (C]O str. of CONH), 1554 (NeH bend of
CONH), 1435, 1399 (S]O str. of SO2NH, asymmetric), 1171
(S]O str. of SO2NH, symmetric), 1458 (AreC]C), 822
(Ar-disubstitution), 1033 (AreCl)
ꢂ
M þ Hþ peak 3325, 3295 (NeH str. of CONH), 3085 (Ar CeH str.), 2962, 2895
9.42/9.39
at m/z 446
(ali CeH str.), 1630 (C]O str. of CONH), 1549 (NeH bend
of CONH), 1433, 1397 (S]O str. of SO2NH, asymmetric), 1170
(S]O str. of SO2NH, symmetric), 1459 (AreC]C), 829
(Ar-disubstitution), 1037 (AreCl)
1.32e1.00 (m, 8H, CH2-200, CH2-300, CH2-2000,
CH2-3000), 0.96e0.88 (m, 6H, CH3-400, CH3-4000),
d 2.62 (s, 3H, AreCH3)
ꢂ
46
47
M þ Hþ peak 3312, 3286 (NeH str. of CONH), 3078 (Ar CeH str.), 2999, 2912
d 7.91 (d, 2H, H-30, H-40), d 7.90 (d, 1H, H-60),
d 7.30 (s, 1H, SO2NH), d 7.28 (m, 1H, CONH-1),
d 7.19 (m, 1H, CONH-5), d 3.15 (m, 1H, H-2), d 2.98
(m, 2H, NeCH2-1000), d 2.68 (m, 2H, NeCH2-100),
d 2.40 (m, 2H, H2-4), d 0.99 (m, 2H, H2-3),
53.86/53.66
55.74/55.69
7.23/7.18
7.65/7.57
9.42/9.34
8.86/8.73
at m/z 446
(ali CeH str.), 1628(C]O str. of CONH), 1542 (NeH bend of
CONH), 1429, 1393 (S]O str. of SO2NH, asymmetric), 1167
(S]O str. of SO2NH, symmetric), 1492 (AreC]C), 832
(Ar-disubstitution), 1023 (AreCl)
0.98e0.82 (m, 14H, CH-200, CH-2000, CH3-300,
CH3-3000, CH3-400, CH3-4000), d 2.51 (s, 3H, AreCH3)
d 7.715 (d, 2H, H-30, H-40), d 7.409 (d, 1H, H-60), d 7.20
(s, 1H, SO2NH), d 7.08 (m, 1H, CONH-1), d 7.06
(m, 1H, CONH-5), d 2.98 (m, 1H, H-2), d 2.96 (m, 2H,
NeCH2-1000), d 2.63 (m, 2H, NeCH2-100), d 2.47 (m, 2H, H2-4),
d 2.21 (m, 2H, H2-3), 1.32e1.15 (m, 16H, CH2-200, CH2-300,
CH2-400, CH2-500, CH2-2000, CH2-3000, CH2-4000, CH2-5000),
1.14e0.70 (m, 6H, CH3-600, CH3-6000), d 2.49 (s, 3H, AreCH3)
ꢂ
M þ Hþ peak 3354, 3276 (NeH str. of CONH), 3083 (Ar CeH str.),
at m/z 474
2992, 2903 (ali CeH str.), 1665(C]O str. of CONH), 1565
(NeH bend of CONH), 1454, 1374 (S]O str. of SO2NH,
asymmetric), 1164 (S]O str. of SO2NH, symmetric), 1464
(AreC]C), 814 (Ar-disubstitution), 1044 (AreCl)

ꢂ
48
M þ Hþ peak 3355, 3282 (NeH str. of CONH), 3094 (Ar CeH str.), 2969,
d 7.91 (d, 2H, H-30, H-40), d 7.89 (d, 1H, H-60), d 7.41
(s, 1H, SO2NH), d 7.39 (m, 1H, CONH-1), d 7.28 (m, 1H,
CONH-5), d 3.28 (m, 1H, H-2), d 3.11 (m, 2H, NeCH2-1000),
d 3.07 (m, 2H, NeCH2-100), d 2.67 (m, 2H, H2-4), d 2.21
(m, 2H, H2-3), 1.96e1.26 (m, 20H, CH2-200, CH2-300, CH2-400,
CH2-500, CH2-600, CH2-2000, CH2-3000, CH2-4000, CH2-5000, CH2-6000),
0.92e0.87 (m, 6H, CH3-700, CH3-7000), d 2.38 (s, 3H, AreCH3)
d 7.77 (d, 2H, H-30, H-40), d 7.76 (d, 1H, H-60), d 7.37
(s, 1H, SO2NH), d 7.36 (m, 1H, CONH-1), d 7.26
(m, 1H, CONH-5), d 3.53 (m, 1H, H-2), d 2.56
57.41/57.39
8.03/7.97
8.37/8.28
at m/z 502
2912 (ali CeH str.), 1642 (C]O str. of CONH), 1552 (NeH bend
of CONH), 1438, 1382 (S]O str. of SO2NH, asymmetric), 1162
(S]O str. of SO2NH, symmetric),
ꢂ
49
50
51
M þ Hþ peak 3487, 3284 (NeH str. of CONH), 3093 (Ar CeH str.), 2929
57.87/57.79
59.31/59.22
60.75/60.67
7.29/7.24
4.98/4.85
5.49/5.45
8.44/8.33
8.65/8.58
8.17/8.08
at m/z 498
(ali CeH str.), 1639 (C]O str. of CONH), 1556 (NeH bend
of CONH), 1380 (S]O str. of SO2NH, asymmetric), 1159
(S]O str. of SO2NH, symmetric), 1444 (AreC]C.), 833
(Aredisubstitution), 1043 (AreCl)
(m, 2H, H2-4), d 2.34 (m, 2H, H2-3), 1.77e1.08
(m, 22H, cyclohexyl proton), d 2.26 (s, 3H, AreCH3)
d 7.87 (d, 2H, H-30, H-40), d 7.65 (d, 1H, H-60), d 7.39
(s, 1H, SO2NH), d 7.28 (m, 1H, CONH-1), d 7.16
(m, 1H, CONH-5), d 3.43 (m, 1H, H-2), d 2.55
ꢂ
M þ Hþ peak 3325, 3255 (NeH str. of CONH), 3088 (Ar CeH str.), 2999,
at m/z 485
2900(ali CeH str.), 1650 (C]O str. of CONH), 1561 (NeH bend
of CONH), 1441, 1389 (S]O str. of SO2NH, asymmetric), 1171
(S]O str. of SO2NH, symmetric), 1472 (AreC]C), 832
(Ar-disubstitution), 1045 (AreCl)
(m, 2H, H2-4), d 2.24 (m, 2H, H2-3), 7.01e6.89
(m, 10H, phenyl proton), d 2.46 (s, 3H, AreCH3)
ꢂ
M þ Hþ peak 3282 (NeH str. of CONH), 3089 (Ar CeH str.), 2939 (ali CeH str.), d 7.67 (d, 2H, H-30, H-40), d 7.56 (d, 1H, H-60), d 7.47
at m/z 514
1643 (C]O str. of CONH), 1544, 1512 (NeH bend of CONH),
1433,1382 (S]O str. of SO2NH, asymmetric), 1161 (S]O str.
of SO2NH, symmetric), 1454 (AreC]C.), 825 (Ar-disubstitution),
1029(AreCl)
(s, 1H, SO2NH), d 7.26 (m, 1H, CONH-1), d 7.29
(m, 1H, CONH-5), d 3.51 (m, 1H, H-2), d 2.45
(m, 2H, H2-4), d 2.14 (m, 2H, H2-3), 7.05e6.96
(m, 10H, phenyl proton), d 3.97 (m, 2H, NeCH2-1000),
d 3.48 (m, 2H, NeCH2-100), d 2.54 (s, 3H, AreCH3)
d 7.48 (d, 2H, H-20, H-60), d 7.41 (d, 1H, H-30, H-50),
d 7.33 (s, 1H, SO2NH), d 7.23 (m, 2H, CONH2-1),
d 7.20 (m, 2H, CONH2-5), d 3.71 (m, 1H, H-2),
d 2.53 (m, 2H, H2-4), d 1.48 (m, 2H, H2-3)
d 7.42 (d, 2H, H-20, H-60), d 7.49 (d, 1H, H-30, H-50),
d 7.35 (s, 1H, SO2NH), d 7.27 (m, 1H, CONH-1),
d 7.21 (m, 1H, CONH-5), d 3.72 (m, 1H, H-2),
d 2.66 (m, 2H, NeCH2-1000), d 2.73 (m, 2H, NeCH2-100),
d 2.63 (m, 2H, H2-4), d 1.50 (m, 2H, H2-3), 1.35e0.57
(m, 6H, CH3-200, CH3-2000)
d 7.36 (d, 2H, H-20, H-60), d 7.39 (d, 1H, H-30, H-50),
d 7.30 (s, 1H, SO2NH), d 7.24 (m, 1H, CONH-1),
d 7.16 (m, 1H, CONH-5), d 3.42 (m, 1H, H-2),
d 2.66 (m, 2H, NeCH-1000), d 2.53 (m, 2H, NeCH-100),
d 2.33 (m, 2H, H2-4), d 1.55 (m, 2H, H2-3),
1.25e0.67 (m, 6H, CH3-200, CH3-2000)
d 7.38 (d, 1H, H-30), d 7.28 d, 1H, H-50), d 7.31
(d, 1H, H-60), d 7.43 (s, 1H, SO2NH), d 7.27
(m, 2H, CONH2-1), d 7.20 (m, 2H, CONH2-5),
d 3.77 (m, 1H, H-2), d 2.54 (m, 2H, H2-4), d 1.49
(m, 2H, H2-3)
d 7.56 (d, 1H, H-30), d 7.48 d, 1H, H-50), d 7.32
(d, 1H, H-60), d 7.63 (s, 1H, SO2NH), d 7.29
(m, 1H, CONH-1), d 7.19 (m, 1H, CONH-5), d 3.67
(m, 1H, H-2), d 2.51 (m, 2H, H2-4), d 1.42
(m, 2H, H2-3), d 3.37 (m, 2H, NeCH2-1000),
d 3.24 (m, 2H, NeCH2-100), 1.36e1.09 (m, 8H, CH2-200,
CH2-300, CH2-2000, CH2-3000), 0.98e0.82 (m, 6H,
CH3-400, CH3-4000)
ꢂ
52
53
M þ Hþ peak 3379 (NeH str. of CONH), 3149(Ar CeH str.), 2964 (ali CeH str.),
52.77/52.76
57.40/57.38
6.79/6.77
7.86/7.78
12.31/12.29
10.57/10.48
at m/z 341
1663 (C]O str. of CONH), 1431, 1342 (S]O str. of SO2NH,
asymmetric), 1161 (S]O str. of SO2NH, symmetric), 1460
(AreC]C)
ꢂ
M þ Hþ peak 3352, 3238 (NeH str. of CONH), 3088 (Ar CeH str.), 2948
at m/z 397
(ali CeH str.), 1645, 1565, 1472 (ali CeH def.), 1354 (S]O str.
of SO2NH, asymmetric), 1155 (S]O str. of SO2NH, symmetric),
1024, 976, 894 (AreCeH def.)
ꢂ
54
M þ Hþ peak 3307, 3261 (NeH str. of CONH), 3075 (Ar CeH str.), 2970, 2933,
59.27/59.22
8.29/8.15
9.87/9.77
at m/z 425
2873 (ali CeH str.), 1645 (C]O str. of CONH), 1596, 1546
(NH bend of CONH), 1458 (AreC]C), 1323 (S]O str. of SO2NH,
asymmetric), 1155 (S]O str. of SO2NH, symmetric)
ꢂ
55
56
M þ Hþ peak 3357, 3249 (NeH str. of CONH), 3191(Ar CeH str.), 2945
49.83/49.77
59.27/59.19
6.11/6.02
8.29/8.27
13.41/13.35
9.87/9.79
at m/z 313
(ali CeH str.), 1654 (C]O str. of CONH), 1596 (NeH bend of
CONH), 1421, 1323 (S]O str. of SO2NH, asymmetric), 1155
(S]O str. of SO2NH, symmetric), 1458 (AreC]C def.), 819
(Ar-disubstitution)
ꢂ
M þ Hþ peak 3307, 3240 (NeH str. of CONH), 3083 (Ar CeH str.), 2956, 2931
at m/z 425
(ali CeH str.), 1660 (C]O str. of CONH), 1552 (NeH bend of
CONH), 1436, 1380 (S]O str. of SO2NH, asymmetric), 1155
(S]O str. of SO2NH, symmetric), 1454 (AreC]C), 819
(Ar-disubstitution)
(continued on next page)

78
S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
to AM1 method using Polok Ribiere (conjugate gradient) algo-
˚
rithm with RMS gradient of 0.1 kcal/A mol. The Molecular
Mechanics (MMþ) force field was applied for the preliminary
structure optimization to shorten the total time required for the
energy minimization by AM1 method.
Various descriptors such as geometrical descriptors, consti-
tutional descriptors, functional groups, properties and empirical
descriptors were calculated by DRAGON [26] software e
version 3, 2003.
Besides these, indicator parameters were also used in order
to find out the role of the specific substituent at the specific
position towards the biological activity. Parameters used to de-
velop QSAR equation were standardized first by the following
equation (1).
À
ÁꢀÀ
Á
Xki ¼ xi ꢀ xiðminimumÞ
x
iðmaximumÞ ꢀ xiðminimumÞ
ð1Þ
The standardized values of these variables are provided as
supplementary material.
2.4. Computational procedure
2.4.1. Correlation analysis
All descriptors were subjected to correlation analysis. Inter-
correleted parameters were eliminated stepwise. All possible
combinations of parameters were considered for the multiple
linear regression analysis.
2.4.2. Multiple linear regression analysis
Multiple linear regression analysis [32e35] was carried out
by ‘‘Multi Regress’’ [36] a computer programme developed in
our laboratory. The statistical qualities of the regression equa-
tions were justified by parameters like correlation coefficient
R, percentage of explained variance (% EV), adjusted R2
(R2A), variance ratio (F ), standard error of estimate (s).
2.4.3. Validation of the QSAR model
The predictive power of the equations was validated by
Leave-One-Out (LOO) [37] cross-validation method. Pre-
dicted residual sum of square (PRESS), total sum of
squares (SSY), cross-validated R2 (Rc2v), standard error
of PRESS (SPRESS) and predictive standard error of pre-
diction (SDEP) were considered for the validation of
QSAR models.
2.4.4. k-Means cluster analysis
Designing of a test set and the training set was done with
the help of k-means cluster analysis (k-MCA). A k-MCA splits
all the synthesized compounds in four clusters with 1, 18, 3
and 9 members. Selection of the training and test set was car-
ried out in a random way using compounds belonging to each
cluster.
2.4.5. Prediction of the test set
On the basis of these models built using the training set,
predicted values of the test set compounds were calculated.

S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
79
Table 5
Pharmacological activities of glutamamide analogs (26e57) against EAC cells
Cpda
Avg. wt. of Ascitic
fluid in controlb
Avg wt. of Ascitic
fluid in Testb
% Inhibition of
Ascitic fluid (TWI)
Avg. no of cells/ml
in controlb ꢃ 105
Avg. no. of cells/ml
in Testb ꢃ 105
% Inhibition
of ascetic cell (TCI)
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58d
59e
60f
a
3.2 (ꢄ0.3)
2.8 (ꢄ0.7)
3.2 (ꢄ0.3)
3.2 (ꢄ0.3)
4.2 (ꢄ0.5)
4.2 (ꢄ0.5)
4.2 (ꢄ0.5)
2.8 (ꢄ0.7)
3.7 (ꢄ0.7)
3.7 (ꢄ0.7)
2.8 (ꢄ0.7)
3.2 (ꢄ0.4)
3.5 (ꢄ0.5)
3.5 (ꢄ0.5)
3.5 (ꢄ0.5)
2.8 (ꢄ0.7)
3.9 (ꢄ0.2)
1.3 (ꢄ0.3)
1.7 (ꢄ0.4)
2.1 (ꢄ0.2)
1.9 (ꢄ0.3)
2.5 (ꢄ0.3)
2.9 (ꢄ0.2)
2.7 (ꢄ0.3)
1.4 (ꢄ0.2)
1.7 (ꢄ0.1)
2.1 (ꢄ0.5)
1.0 (ꢄ0.2)
1.0 (ꢄ0.2)
2.5 (ꢄ0.5)
2.9 (ꢄ0.3)
2.1 (ꢄ0.3)
1.8 (ꢄ0.3)
2.8 (ꢄ0.3)
60.5
38.5
34.0
42.5
41.2
31.9
35.2
49.9
54.0
43.0
63.4
70.0
28.1
16.8
40.0
36.5
28.1
N.P.Dc
81.5
25.2
27.9
33.3
24.2
40.2
41.2
36.5
27.5
30.8
44.7
31.2
46.1
38.4
100.0
100.0
100.0
345.6 (ꢄ6.3)
298.2 (ꢄ5.5)
345.6 (ꢄ6.3)
345.6 (ꢄ6.3)
507.4 (ꢄ6.7)
507.4 (ꢄ6.7)
507.4 (ꢄ6.7)
298.2 (ꢄ5.5)
449.2 (ꢄ3.1)
449.2 (ꢄ3.1)
298.2 (ꢄ5.5)
350.1 (ꢄ8.9)
397.1 (ꢄ3.5)
397.1 (ꢄ3.5)
397.1 (ꢄ3.5)
298.2 (ꢄ5.5)
463.2 (ꢄ8.4)
112.3 (ꢄ5.4)
92.4 (ꢄ3.8)
145.4 (ꢄ4.6)
71.8 (ꢄ4.5)
197.3 (ꢄ4.8)
239.1(ꢄ3.6)
146.5 (ꢄ3.8)
238.0 (ꢄ3.1)
220.9 (ꢄ4.0)
238.2 (ꢄ5.4)
150.3 (ꢄ4.2)
229.6 (ꢄ4.8)
357.4 (ꢄ7.8)
328.1 (ꢄ4.7)
217.1 (ꢄ5.6)
283.7 (ꢄ3.1)
313.8 (ꢄ4.2)
67.5
73.3
57.9
79.3
61.1
52.9
71.1
53.1
50.8
47.0
66.5
48.9
10.0
17.4
45.3
28.6
32.3
N.P.Dc
53.0
43.5
40.0
47.1
33.4
35.0
45.5
50.5
42.15
21.6
34.1
35.2
35.6
52.1
100.0
100.0
100.0
3.2 (ꢄ0.4)
3.2 (ꢄ0.4)
3.2 (ꢄ0.3)
4.2 (ꢄ0.5)
3.9 (ꢄ0.3)
3.9 (ꢄ0.3)
3.2 (ꢄ0.3)
3.7 (ꢄ0.3)
3.7 (ꢄ0.3)
3.7 (ꢄ0.3)
3.7 (ꢄ0.3)
3.2 (ꢄ0.4)
3.9 (ꢄ0.3)
3.9 (ꢄ0.3)
3.9 (ꢄ0.2)
3.7 (ꢄ0.7)
3.5 (ꢄ0.5)
0.6 (ꢄ0.3)
2.4 (ꢄ0.4)
2.3 (ꢄ0.3)
2.8 (ꢄ0.2)
3.0 (ꢄ0.2)
2.4 (ꢄ0.3)
1.9 (ꢄ0.2)
2.3 (ꢄ0.3)
2.7 (ꢄ0.2)
2.5 (ꢄ0.2)
2.0 (ꢄ0.4)
2.2 (ꢄ0.3)
2.1 (ꢄ0.3)
2.4 (ꢄ0.3)
0.0 (ꢄ0.0)
0.0 (ꢄ0.0)
0.0 (ꢄ0.0)
350.1 (ꢄ8.9)
350.1 (ꢄ8.9)
345.6 (ꢄ6.3)
507.4 (ꢄ6.7)
477.9 (ꢄ3.5)
477.9 (ꢄ3.5)
345.6 (ꢄ6.3)
437.5 (ꢄ5.0)
437.5 (ꢄ5.0)
437.5 (ꢄ5.0)
437.5 (ꢄ5.0)
350.1 (ꢄ8.9)
477.9 (ꢄ3.5)
477.9 (ꢄ3.5)
463.2 (ꢄ8.4)
449.2 (ꢄ3.1)
397.1 (ꢄ3.5)
217.6 (ꢄ4.6)
261.7 (ꢄ3.2)
278.0 (ꢄ2.6)
252.7 (ꢄ2.1)
318.5 (ꢄ2.8)
310.7 (ꢄ3.3)
260.6 (ꢄ4.4)
216.7 (ꢄ5.0)
253.5 (ꢄ3.1)
342.9 (ꢄ6.0)
288.4 (ꢄ6.7)
204.8 (ꢄ2.3)
203.7 (ꢄ2.3)
151.6 (ꢄ5.0)
0.0 (ꢄ0.0)
0.0 (ꢄ0.1)
0.0 (ꢄ0.0)
Compound number.
Results represent mean of 6 data points and figure in parenthesis represent standard error of mean.
b
c
d
e
f
Not possible to determine.
Mitomycin C as the standard.
Azaserin as the standard.
DON as the standard.
3. Results and discussion
all these analogs against Ehrlich Ascites Carcinoma in Swiss
Albino mice was done using percentage inhibition of tumor
weight and percentage inhibition of ascites cells as activity
Synthesis of 1,5-N,N0-disubstituted-2-(substituted benzene-
sulphonyl) glutamamides was carried out according to the
method starting with chlorosulphonylation of the substituted
benzenes. Final compounds were obtained as the crystalline
solids with appreciable yields.
In order to get the action of these synthesized analogs (26e
57) as anticancer agents, compounds were tested against IMR-
32 cell line and Ehrlich Ascites Carcinoma cells in Swiss
Albino mice. All samples were dissolved in 100% DMSO
but for MTT assay, 1% DMSO is allowed as it is highly toxic
to the cell. It is found that some of these compounds are not
soluble in 1% DMSO. Thus, inhibition of tumor cell prolifera-
tion in IMR-32 cell line cannot be observed for all these com-
pounds. In vivo method of evaluation of anticancer activity for
Fig. 3. Arbitrary numbering of 1,5-N,N0-disustituted-2-(substituted benzene-
sulphonyl) glutamamides (26e57).

80
S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
parameters. QSAR studies of these 1,5-N,N0-disubstituted-2-
(substituted benzenesulphonyl) glutamamides were performed.
All parameters were subjected to correlation analysis. Intercor-
related parameters were eliminated depending on their individ-
ual correlation with the biological activity. All possible
combinations of these parameters were considered and sub-
jected to the multiple linear regression analysis. The correlation
matrix is presented and provided as supplementary material.
k-Means cluster analysis (k-MCA) was used in designing
the training set and the test set. From the total dataset, six
compounds (compound nos. 28, 32, 34, 36, 46, 55) were cho-
sen as the test set and the remaining 25 compounds were
treated as the training set for QSAR study. The results of re-
gressions of the antitumor activities are presented in Table 6.
Eqs. (2)e(5) resulted for the inhibition of tumor weight and
Eqs. (6) and (7) were obtained for the inhibition of tumor cells
(Table 8). The statistical parameters shown in Table 8 are cor-
relation coefficient (R), explained variance (% EV), variance
ratio (F ), standard error of estimate (s) and cross-validated
R2 (R2cv). Eq. (2) explains 70.34% of variances in biological ac-
tivity data. This equation suggests the importance of LR2
(STERIMOL length parameter for R2 substituent), dipole mo-
ment (m), number of benzene like ring (NBZ) and the indicator
parameter (I1 for the presence of bromine at R3 position of
benzene ring) for tumor weight inhibition of these glutama-
mide analogs. The negative coefficient of LR2 suggests that
with the increase of the length of substituent at R2 position
the activity decreases. With the increase of dipole moment
the activity decreases as evidenced by the negative coefficient
of m. The positive coefficient of NBZ implies that benzene like
ring is important for the activity. The positive coefficient of I1
suggests that the presence of bromine atom at R3 position is
conducive to the activity. Deletion of outliers (Compounds
49 and 56), which might act through a different mechanism
of action, improved the statistical qualities of Eq. (2) as shown
in Eq. (3). This equation explains 81.90% of variances in the
biological activity data. The significant value of R2cv (0.705)
confirms the validity of the model and good predictivity.
In our efforts to further explore the relationship, another
model was developed using pR2 (hydrophobic constant for
substituent at R2 position), m (dipole moment) and f(E)15 (fron-
tier electron density for electrophilic attack at atom number
15) as shown in Eq. (4). This equation explains 73.66% vari-
ances of the anticancer activity data .The negative contribution
of pR2 reveals that the hydrophobic interaction at this position
of benzene ring is detrimental to the activity or hydrophilic
substitution may be advantageous to the activity. Like previous
model, this model also suggests that the increase of dipole
moment is detrimental to the activity. The positive coefficient
of I1 suggests that the presence of bromine atom at R3 position
is favorable to the activity. The negative coefficient of f(E)15
suggests that the higher probability of electrophilic attack at
atom number 15 is detrimental to the activity. Stepwise dele-
tion of compounds 27 and 48 improves statistical qualities
of the equation as shown by Eq. (5) which explains 81.56%
variances of the anticancer activity data. Here, this equation
is also significantly predictive (R2cv ¼ 0.661) in nature.

S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
81
Another model was developed using the inhibition of tumor
cells as the dependent parameter. For this case, we have also
tried all possible combinations of descriptors to get significant
models. The best equation obtained in combination of R2;sR4,
qC3 and f(N)14 was as shown in Eq. (6) which explains 76.53%
of variances of activity data. The positive coefficient of R2
(RTSA index of atom number 2) indicates that the higher
value of this index is advantageous to the activity. The positive
coefficient of sR4 indicates that electron-withdrawing groups
in this position of the benzene ring may help to the activity.
The negative coefficient of qC3 (charge at atom number 3) in-
dicates that the higher value of charge at 3 position reduces the
activity. The positive coefficient of f(N)14 (frontier electron
density for nucleophilic attack at atom number 14) demon-
strates that the higher probability of the nucleophilic attack
at this position is favorable for the activity. On deletion of
compound 40, statistical qualities of the previous equation
are increased as shown by Eq. (7) which explains 81.68% var-
iances of the anticancer activity data. Here, this equation is
also significantly predictive (R2cv ¼ 0.667) in nature. The stu-
dent t-values and probability values of all equations are given
in Table 7.
In deriving the above equations, some compounds were de-
leted, viz, compounds 49 and 56 for Eq. (3), compounds 27
and 48 for Eq. (5), compound 40 for Eq. (7). All these com-
pounds exhibited aberrant behaviors. However, further study
is necessary to find out convincing reasons behind such aber-
ration of the excluded compounds.
Useful informations are obtained from QSAR study of the
1,5-N,N0-disubstituted-2-(substituted benzenesulphonyl) gluta-
mamides for anticancer activity from the above three
equations (Eqs. (3), (5) and (7)). The predictive powers of
the equations were confirmed by Leave-One-Out (LOO)
cross-validation method and details are avoided.
On the basis of these three models, the predicted values of
the test set compounds were calculated. The observed and the
predicted values of the test set compounds are given in Table 8.
It shows significant R2pred for the test set as shown below:
R2pred ¼ 0.672 for Eq. (3)
R2pred ¼ 0.655 for Eq. (5)
R2pred ¼ 0.625 for Eq. (7).
4. Conclusion
From the study, it is found that these 32 newly synthesized
QSAR analogs of glutamamide have prominent anticancer ac-
tivity. Amongst all these analogs, compound 44 showed good
anticancer activity compared to the standard drugs against
Ehrlich Ascites Carcinoma (EAC) cells. QSAR study showed
that with the increase of the length of substituents at R2 posi-
tion and that of dipole moment the anticancer activity decrease
when inhibition of tumor weight was considered as the depen-
dent parameter. The presence of bromine atom at R3 position
is conducive to the activity. The presence of benzene like ring
is also important for the activity. Hydrophobic interaction at
R2 position of benzene ring is detrimental to the activity or
hydrophilic substitution may be advantageous to the activity.
Even the higher probability of electrophilic attack at atom
number 15 is detrimental to the activity.
Considering the inhibition of tumor cell as the biological
activity parameter, it is found that the higher value of RTSA
index of atom number 2 is advantageous to the activity.
Atom number 2 may be involved in dispersive interactions
of these compounds with enzymes. Electron-withdrawing
groups at R4 position of the benzene ring may help to increase
the said activity. The higher value of charge at atom number 3
reduces the activity. Frontier electron density for nucleophilic
attack at atom number 14 demonstrates that the higher proba-
bility of nucleophilic attack at this position is favorable for the
activity.
Table 7
t-Statistics and p-values for all the equations
Eq. Intercept/ t-Value p-Value Equation Intercept/ t-Value p-Value
no. parameter
parameter
(2) Intercept
35.539 0.000
ꢀ2.961 0.008
ꢀ5.092 0.000
2.080 0.051
2.374 0.028
(6)
Intercept
R2
16.442 0.000
2.414 0.026
3.748 0.001
ꢀ3.164 0.005
3.022 0.007
LR2
m
sR4
qC3
NBZ
I1
f(N)14
This QSAR study gives some important information about
the structural requirements of the glutamamide moiety for the
increased antitumor activity. As the selected QSAR analogs of
(3) Intercept
42.975 0.000
ꢀ3.187 0.005
ꢀ6.968 0.000
2.869 0.010
3.285 0.004
(7)
Intercept
R2
16.012 0.000
3.537 0.002
4.155 0.001
ꢀ3.635 0.002
3.087 0.006
LR2
m
sR4
qC3
NBZ
I1
f(N)14
Table 8
Observed and predicted values of test set compounds
Cpda
Observed
Predicted value
(4) Intercept
38.530 0.000
ꢀ2.740 0.013
ꢀ4.938 0.000
3.273 0.0038
ꢀ2.720 0.013
pR2
m
Log (TWI)
Log (TCI)
Eq. (3)
Eq. (5)
Eq. (7)
I1
f(E)15
28
32
34
36
46
55
1.531
1.546
1.732
1.802
1.446
1.494
1.763
1.852
1.706
1.823
1.602
1.547
1.520
1.681
1.777
1.905
1.490
1.500
1.576
1.631
1.833
1.852
1.558
1.482
1.889
1.769
1.673
1.721
1.639
1.586
(5) Intercept
43.395 0.000
ꢀ3.559 0.002
ꢀ5.890 0.000
3.583 0.002
pR2
m
I1
f(E)15
R2pred ¼ 0.672 for Eq. (3); Rp2red ¼ 0.655 for Eq. (5); R2pred ¼ 0.625 for Eq. (7).
ꢀ3.571 0.000
a
Compound number.

82
S. Samanta et al. / European Journal of Medicinal Chemistry 44 (2009) 70e82
1,5-N,N0-disubstituted-2-(substituted benzenesulphonyl)gluta-
mamide have shown good anticancer activity, the present
QSAR study may help in further tailoring of these analogs
to find an active member.
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Des. 1 (2002) 488e502.<http://www.biochempress.com>.
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Acknowledgements
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Med. Chem. 41 (2006) 1190e1195.
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The authors are thankful to the University Grants Commis-
sion (UGC), New Delhi and All India Council for Technical
Education (AICTE), New Delhi for providing financial sup-
port. One of the authors SS is grateful to University Grants
Commission (UGC), New Delhi for awarding Junior Research
Fellowship (JRF). Two of the authors PP and MA are grateful
to UGC, New Delhi for awarding Post Graduate Fellowships.
Authors also thank D.R. Krishna of Kakatiya University, War-
angel for help in performing in vitro test.
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