Synthesis, pharmacological activity and comparative QSAR modeling of 1,5-N,N′-substituted-2-(substituted naphthalenesulphonyl) glutamamides as possible anticancer agents

Article abstract of DOI:10.1016/j.ejmech.2010.01.008

Based on our earlier QSAR study, a series of 1, 5-N,N′-substituted-2-(substituted naphthalenesulphonyl) glutamamides were synthesized as possible anticancer agents. Anticancer activities of these synthesized compounds were evaluated in vivo on Swiss Albino mice against Ehrlich Ascites Carcinoma (EAC) cells where inhibitions of tumor cell and tumor weight were considered as biological activity parameters. A comparative QSAR study was done with a set of descriptors and logarithm of tumor cell inhibition. The result shows the importance of topological parameters like ETSA and RTSA indices as well as electronic parameter like Wang-Ford charges of different atoms. Electrophilic attack at atom number 5 and increased number of chlorine atom may be favorable whereas presence of methoxy group at the atom number 8 in naphthalene ring may be detrimental to the activity.

Full text of DOI:10.1016/j.ejmech.2010.01.008

European Journal of Medicinal Chemistry 45 (2010) 1760–1771
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, pharmacological activity and comparative QSAR modeling
of 1,5-N,N0-substituted-2-(substituted naphthalenesulphonyl) glutamamides
as possible anticancer agents
1
*
Amit Kumar Halder , Nilanjan Adhikary, Milan Kumar Maity, Tarun Jha
Natural Science Laboratory, Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P.O. Box 17020, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Based on our earlier QSAR study, a series of 1, 5-N,N0-substituted-2-(substituted naphthalenesulphonyl)
glutamamides were synthesized as possible anticancer agents. Anticancer activities of these synthesized
compounds were evaluated in vivo on Swiss Albino mice against Ehrlich Ascites Carcinoma (EAC) cells
where inhibitions of tumor cell and tumor weight were considered as biological activity parameters. A
comparative QSAR study was done with a set of descriptors and logarithm of tumor cell inhibition. The
result shows the importance of topological parameters like ETSA and RTSA indices as well as electronic
parameter like Wang-Ford charges of different atoms. Electrophilic attack at atom number 5 and
increased number of chlorine atom may be favorable whereas presence of methoxy group at the atom
number 8 in naphthalene ring may be detrimental to the activity.
Article history:
Received 18 August 2009
Received in revised form
4 January 2010
Accepted 6 January 2010
Available online 21 January 2010
Keywords:
Glutamamide
EAC
Ó 2010 Elsevier Masson SAS. All rights reserved.
Anticancer activity
Comparative QSAR
Wang-Ford charge
1. Introduction
proliferation rate of tumor cells. It is indicative of the vital role of
this enzyme in tumor growth. On the other hand, glutamine
Glutamine is considered as an essential ingredient for growth of
tissues. It is an important nutrient for rapidly growing cells [1–7]. It
also plays a key role in tumor growth. It acts as one of the major
substrates [6–8] in cancer. Some cancer cells require higher gluta-
mine concentrations than normal cells. Glutamine plays a key role
in cell growth by supplying its amide nitrogen atoms in the
biosynthesis of other amino acids and purine and pyrimidine bases
and, thus, is involved in both DNA and protein syntheses, Hence, it
may may have influence to alter the genetic code of protein
syntheses and may lead to cancerous proteins which may be
slightly different from their normal counterparts [9–11]. The
balance between glutamine formation and utilization relies largely
on the activity of two enzymes namely glutaminase and glutamine
synthetase. In mitochondria, glutamine is acted upon by gluta-
minase. This enzyme requires high phosphate concentration to be
fully active. Moreover, tumor glutaminase reaches a maximum
expression and activity immediately before the maximum
synthetase is also considered as ‘dispensable enzyme’ for tumor
[11–15]. In keeping with these facts, some derivatives and analogs
of glutamamide were synthesized as a part of our composite pro-
gramme of drug design and discovery [16–23]. In the present
article, we have reported of synthesis of some glutamamide analogs
that are structural derivatives of both glutamine and glutamic acid.
Our previous QSAR study on thirty two 1,5-N,N0-disubstituted-2-
(substituted benzenesulphonyl) glutamamides [23] showed that
the increase in the number of benzene ring in the structure may be
helpful for increasing the activity of these compounds. Based on
this assumption, we have considered fused benzene ring or naph-
thalene ring in the present article we synthesized twenty eight
1,5-N,N0-disubstituted-2-(substituted naphthalenesulphonyl) glu-
tamamides. These were subsequently characterized and biologi-
cally evaluated using in vivo anticancer model. Some of these
synthesized compounds have shown considerable biological
activity. Hence, in order to further investigate the chemical struc-
tural features of these compounds, QSAR studies were performed.
For the QSAR study, in vivo anticancer activity data of inhibition of
cell count was used as the dependent parameter. Physicochemical,
topological, quantum chemical and constitutional descriptors were
calculated. These were subsequently treated as the independent
parameters. Three different statistical methods: principal compo-
nent regression analysis (PCRA), stepwise regression and factor
* Corresponding author. Tel.: þ91 33 24146666x2495 (office), þ91 33 24383814
(residencial), 09433187443 (mobile); fax: þ91 33 24146927.
E-mail address: tjupharm@yahoo.com (T. Jha).
1
Present address: Dr. B. C. Roy College of Pharmacy and Allied Health
Sciences, Dr. M. S. Sarani, Bidhannagar, Durgapur, West Bengal, India.
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.008

A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
1761
7'
8'
3. Pharmacology
6'
9'
Anticancer activity of these synthesized title compounds (18–
45) were evaluated by in vivo method. The method was standard-
ized in our laboratory [16–23]. Antitumor activities of twenty eight
synthesized glutamamides were evaluated by either dissolving
these compounds in phosphate buffered saline (PBS) or by sus-
pending in PBS with 2% Tween 80 (where and when necessary)
separately. These were used with a dose 2 mmol/Kg/day against
Ehrlich Ascites Carcinoma (EAC) cells impregnated in Swiss Albino
mice. Percentage tumor cell inhibition (% TCI) and percentage
tumor weight inhibition (% TWI) were used as biological activity
parameters. These parameters were obtained by the following
expressions:
3
O
S
5'
10'
2
4
R
N
2
1'
H
4'
O
2'
3'
O
O
1
5
R
1
NHR3 NHR3'
Fig. 1. General structure of 1,5-N,N0-disubstituted-2-(substituted naphthalenesulphonyl)
glutamamides (17–44).
analysis-multiple linear regression (FA-MLR) were used for the
development of comparative QSAR models. All QSAR models
showed significant statistical qualities. The general structure of 1,5-
N,N0-disubstituted-2-(substituted naphthalenesulphonyl) gluta-
mamides (18–45) is shown in Fig. 1.
Percentage inhibition of Ascites cells ¼ ð1 ꢁ T=CÞ ꢂ 100
À
Á
Percentage inhibition of Ascites fluid ¼ 1 ꢁ T0=C0 ꢂ 100
2. Chemistry
where T is the mean number of Ascitic cells/ml in test animals, C is
the mean number of Ascitic cells/ml in control animals, T0 is the
mean weight of Ascitic fluid in test animals and C0 is the mean
weight of Ascites fluid in control animals.
Substituted naphthalenesulphonyl chlorides (5–8) were
synthesized by chlorosulphonylation of naphthalene and naph-
thalene derivatives (1–4). These were first separately dissolved in
dry chloroform. The naphthalene ring is susceptible to dis-
ubstitution at higher temperature. Cold temperature (0–5 ꢀC) was
always maintained during chlorosulphonylation process. 2-
In the present study, Mitomycin C was chosen as the universal
standard drug and azaserine as well as DON as specific standards
to compare the activity of the test compounds. These were dis-
solved separately in sterile phosphate buffer (pH 7.2). Standards
were administered separately at a dose level of 1 mg/kg body
weight. These showed 100% inhibition in both cell count and
tumor weight.
(substituted naphthalenesulphonyl)-
were prepared by condensing
L
(þ) glutamic acids (10–13)
L
(þ)-glutamic acid (9) with
substituted naphthalenesulphonyl chlorides separately. In this
reaction, alkaline medium (2 N NaOH) was maintained to remove
hydrochloric acid which was continuously formed during the
condensation reaction. As chlorine and bromine are deactivating
groups, reaction temperature was maintained around 85–90 ꢀC
during the condensation. It helps to get better yield otherwise 65–
70 ꢀC temperature was maintained in Schotten–Baumann reaction
as reported earlier [23]. 2-(substituted naphthalenesulphonyl)-
4. QSAR study
A comparative QSAR study [24,25] of these twenty eight
synthesized 1,5-N,N0-substituted-2-(substituted naphthalenesul-
phonyl) glutamamides were performed using percentage tumor cell
inhibition (% TCI) as the biological activity parameters.
L
(þ) glutamic acids were subsequently refluxed separately with
thionyl chloride in order to produce corresponding dichloride
derivatives (14–17). Neucleophilic displacement of chloro-groups
of 2-(substituted naphthalenesulphonyl) glutamic acids dichloride
(14–17) with different amines yielded the corresponding diamides
(18–45) which were the title compounds. The crude compounds
were recrystallised from dilute ethanol. The general structures of
starting material and intermediates as well as synthetic scheme
are given in Fig. 2.
4.1. Dataset and parameters
A large dataset of various physicochemical, topological and
semi-empirical quantum chemical descriptors were calculated by
using different softwares. While calculating these descriptors,
arbitrary numbering of the pharmacophore was done for all atom
level calculations. This arbitrary numbering is shown in Fig. 3.
SO2Cl
R 1
R
ClSO3H
1
1. NaOH
R2
SO2NH
Chlorosulphonation
2. H2N
COOH
COOH
COOH COOH
R1
R2
5-8
R2
1-4
9
10-13
R2
SO2NH
SOCl2
COCl
COCl
SO2NH
R2
R1
CONHR3
CONHR3
Amine (R3NH2)
reflux
14-17
18-45
R1
Fig. 2. Scheme for synthesis of title compounds.

1762
A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
3
2
5. Results
4
1
12
O
Synthesized
1,5-N,N0-substituted-2-(substituted
naph-
16
6
5
14
15
11
thalenesulphonyl) glutamamides were obtained as crystalline solids
with appreciable yields. Biological activities of these compounds are
given in Table 1. Table 1 suggests that these synthesized compounds
have variable anticancer activities. For the present QSAR analysis, the
percentage EAC cell inhibition (% TCI) of these synthesized
compounds was considered as the biological activity parameter.
Thus, all % TCI values were converted to logarithmic scales. These
were subsequently used as dependent variables.
10
17
R2
S
N
7
H
O
13
8
9
19
O
O
22
18
21
R1
NHR3 NHR3
20
23
Fig. 3. General structure for QSAR with arbitrary numbering.
The results obtained by different statistical analyses are shown
below:
Apart from these, indicator parameters were also used in order
to find out the role of the specific substituent at a particular posi-
tion towards the biological activity. Parameters used to develop
QSAR equations were the standardized by using Eq. (1):
5.1. Principal component regression analysis (PCRA)
Xki ¼ ðxi ꢁ ximinimumÞ=ðximaximum ꢁ ximinimum
The standardized values of the descriptors appeared in the QSAR
models are provided in Supplementary Material.
Þ
(1)
In PCRA, ten factor scores were extracted by principle compo-
nent method. Then, it was rotated by VARIMAX rotation. These
factor scores were used as independent parameters for developing
QSAR equations. Using forward selection method, the following
equation was developed:
4.2. Statistical methods
log BA ¼ 1:448ðꢃ0:035Þ ꢁ 0:100ðꢃ0:036Þf1
þ0:063ðꢃ0:036Þf3 ꢁ 0:070ðꢃ0:036Þf4
ꢁ0:134ðꢃ0:036Þf7 ꢁ 0:160ðꢃ0:036Þf8
Three statistical methods-stepwise multiple linear regression
(sMLR), factor analysis-multiple linear regression (FA-MLR) and
principle component regression analysis (PCRA) were used sepa-
rately for development of QSAR models. These are briefly described
below in the following sections:
n ¼ 28; R ¼ 0:829; R2 ¼ 0:687; R2A ¼ 0:616; Fð5; 22Þ
¼ 9:6782; p < 0:00005; S:E:E ¼ 0:186; Rc2v
4.2.1. Principle component regression analysis (PCRA)
In PCRA [26–29], factor scores were obtained from factor anal-
ysis on the data matrix containing all the independent variables.
Factor analysis was performed after VARIMAX rotation. Regression
analysis was performed considering factor scores as predictor
variables. As factor score contains information for different
descriptors, the chance for loss of information is less.
¼ 0:492; SSY ¼ 2:442; PRESS ¼ 1:240; SDEP
¼ 0:210; SPRESS ¼ 0:237:
Where n is the number of data points. The 95% confidence intervals
of the regression coefficients are shown in parentheses.
(2)
5.2. Stepwise regression
4.2.2. Stepwise regression method
In stepwise regression, multiple linear equations were devel-
oped step by step [26]. A primary stepping criteria based on F
values was imposed on the system. Predictor variables were added
or removed according to these stepping criteria. The search was
terminated when the stepping was no longer possible.
Using stepping criteria on the basis of F value (F ¼ 3.0 for
inclusion; F ¼ 2.9 for exclusion), the QSAR equation was derived
with six variables. The best found stepwise regression equation is
given in Eq. (3):
logBA ¼ ꢁ28:316ðꢃ5:035Þ þ 0:449ðꢃ0:173Þ f ðEÞ5
þ8:782ðꢃ1:191Þq14 ꢁ 16:474ðꢃ3:060Þq19
ꢁ4:394ðꢃ0:737ÞS15 ꢁ 8:1267ðꢃ1:526Þq12
þ2:6601ðꢃ0:577ÞR17
4.2.3. Factor analysis-multiple linear regression (FA-MLR)
In FA-MLR [29], principle component method was used to
extract these factors. Then it was rotated by VARIMAX rotation. The
goal of factor analysis was to represent the multidimensional data
matrix in low dimensional space with minimum loss of informa-
tion. The aim of VARIMAX rotation was to maximize the variance of
the new variable. This also helps to reduce the variance around the
new variable. Factor pattern suggested whether the biological
activity could be explained satisfactorily within the parameter
space or not.
n ¼ 28; R ¼ 0:906; R2 ¼ 0:821; R2A ¼ 0:770; Fð6; 21Þ
¼ 16:106; p < 0:00001; S:E:E ¼ 0:144; Rc2v
¼ 0:657; SSY ¼ 2:442; PRESS ¼ 0:837; SDEP
¼ 0:173; SPRESS ¼ 0:199:
Statistical qualities of MLR equations were judged by correlation
coefficient (R), adjusted R2 (RA2), variance ratio (F), probability factor
related to F-ratio (p) and standard error of estimate (s).
(3)
Where f(E)5 is the frontier electron density for electrophilic attack at
the atom number 5. q12, q14 and q19 are Wang-Ford charges of atom
numbers 12, 14 and 19 respectively. S15 is the ETSA index of the
atom number 15. R17 is the R-state index of the atom number 17.
4.2.4. Validation of the QSAR models
Leave-One-Out (LOO) cross-validation method was used to
validate the predictive powers of all MLR, FA-MLR, PCRA and PLS
equations. The predicted residual sum of square (PRESS), total sum
of squares (SSY), cross validated R2 (Rc2v), standard deviation error of
prediction (SDEP) and standard error of PRESS (SPRESS) were
considered for validations of QSAR models.
5.3. Factor analysis-multiple linear regression (FA-MLR)
Factor analysis was performed after VARIMAX rotation as data
preprocessing step. It helps to select descriptors for QSAR

A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
1763
Table 1
Biological activity data of synthesized compounds.
Cpda
Mean wt. of Ascitic
fluid in control (gm)
Mean wt. of Ascitic
fluid in Test (gm)
% Inhibition of
Ascitic fluid (TWI)
Mean no of cells/ml
Mean no. of cells/ml
% inhibition
of ascitic cell (TCI)
in control ꢂ 105
in Test ꢂ 105
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
Mitb
Azac
DON
1.917 (ꢃ0.325)
2.066 (ꢃ0.230)
2.166 (ꢃ0.228)
2.166 (ꢃ0.228)
2.066 (ꢃ0.230)
1.917 (ꢃ0.325)
2.066 (ꢃ0.230)
2.767 (ꢃ0.142)
1.920 (ꢃ0.228)
2.025 (ꢃ0.336)
1.920 (ꢃ0.228)
1.920 (ꢃ0.228)
2.240 (ꢃ0.420)
2.240 (ꢃ0.420)
2.235 (ꢃ0.218)
1.917 (ꢃ0.325)
2.240 (ꢃ0.420)
2.025 (ꢃ0.336)
2.025 (ꢃ0.336)
2.235 (ꢃ0.218)
2.235 (ꢃ0.218)
1.520 (ꢃ0.410)
1.520 (ꢃ0.410)
2.767 (ꢃ0.142)
1.520 (ꢃ0.410)
2.120 (ꢃ0.421)
2.120 (ꢃ0.421)
2.120 (ꢃ0.421)
2.166 (ꢃ0.228)
2.025 (ꢃ0.336)
2120 (ꢃ0.421)
1.300 (ꢃ0.198)
1.500 (ꢃ0.216)
1.633 (ꢃ0.224)
1.817 (ꢃ0.117)
1.700 (ꢃ0.156)
1.642 (ꢃ0.124)
1.820 (ꢃ0.114)
1.200 (ꢃ0.328)
1.088 (ꢃ0.428)
1.680 (ꢃ0.216)
0.86 (ꢃ0.258)
1.525 (ꢃ0.125)
1.700 (ꢃ0.208)
1.820 (ꢃ0.197)
1.683 (ꢃ0.356)
1.520 (ꢃ0.258)
1.900 (ꢃ0.129)
1.702 (ꢃ0.126)
1.675 (ꢃ0.142)
1.420 (ꢃ0.384)
1.775 (ꢃ0.310)
1.150 (ꢃ0.398)
1.475 (ꢃ0.108)
2.133 (ꢃ0.136)
1.383 (ꢃ0.198)
1.960 (ꢃ0.136)
1.833 (ꢃ0.444)
2.010 (ꢃ0.118)
0.000 (ꢃ0.020)
0.000 (ꢃ0.230)
0.000 (ꢃ0.300)
32.19
27.42
24.61
16.15
17.74
14.34
11.93
56.62
43.58
17.04
55.21
20.57
24.10
18.73
24.68
20.71
15.20
15.95
22.69
36.46
20.58
24.34
2.96
433.82 (ꢃ3.623)
299.63 (ꢃ3.150)
482.84 (ꢃ2.588)
482.84 (ꢃ2.588)
299.63 (ꢃ3.150)
433.82 (3.623)
267.49 (ꢃ2.152)
91.92 (ꢃ3.280)
348.04 (ꢃ1.942)
414.22 (ꢃ1.877)
197.3 (ꢃ1.677)
363.67 (2.635)
113.97 (ꢃ1.814)
307.83 (ꢃ2.366)
203.43 (ꢃ3.141)
272.67 (ꢃ1.540)
239.11 (ꢃ3.126)
235.29 (ꢃ3.723)
225.49 (ꢃ2.757)
266.54 (ꢃ2.097)
313.84 (ꢃ3.228)
290.22 (ꢃ3.256)
257.97 (ꢃ1.946)
205.88 (ꢃ1.566)
320.59 (ꢃ3.301)
166.91 (ꢃ4.248)
357.35 (ꢃ3.439)
379.29 (ꢃ2.049)
385.42 (ꢃ2.691)
334.82 (ꢃ1.122)
346.32 (ꢃ4.720)
346.32 (ꢃ2.740)
404.41 (ꢃ2.657)
360.26 (ꢃ2.805)
0.000 (ꢃ0.050)
0.000 (ꢃ0.045)
0.000 (ꢃ0.050)
38.34
69.32
27.92
14.21
43.96
16.17
61.96
17.64
53.76
34.46
48.52
46.52
48.67
39.33
75.17
33.10
41.28
50.51
22.94
58.25
10.62
16.22
14.86
10.42
23.50
18.78
4.34
299.63 (ꢃ3.150)
373.77 (ꢃ1.582)
439.95 (ꢃ4.073)
416.05 (ꢃ3.733)
439.95 (ꢃ4.073)
439.95 (ꢃ4.048)
439.34 (ꢃ4.048)
439.34 (ꢃ4.048)
399.81 (ꢃ3.726)
433.82 (ꢃ3.623)
439.34 (ꢃ4.048)
416.05 (ꢃ3.733)
416.05 (ꢃ3.733)
399.81 (ꢃ3.726)
399.81 (ꢃ3.726)
452.73 (ꢃ4.473)
452.73 (ꢃ4.473)
373.77 (ꢃ1.582)
452.73 (ꢃ4.473)
422.79 (ꢃ3.710)
422.79 (ꢃ3.710)
422.79 (ꢃ3.710)
482.64 (ꢃ2.588)
416.03 (ꢃ3.733)
422.79 (ꢃ3.710)
22.81
8.99
7.57
13.52
5.19
100.00
100.00
100.00
14.79
100.00
100.00
100.00
a
Compound.
b
c
Mitomycin.
Azaserine.
equations. It was observed that ten factors could explain the data
matrix to the extent of 94.5%. The factor loading of significant
variables is provided as Supplementary Material. Factor loadings
greater that 0.6 are shown in bold face. The biological activity was
highly loaded with factor 8 (loaded with S8, R8, q8, I1 and f(E)5) and
factor 7 (loaded with q18, q19, IC3, IC4 and IC5). It was intermediately
Another model obtained as:
Log BA ¼ 13:733ðꢃ1:963Þ ꢁ 1:013ðꢃ0:152ÞS12=13
ꢁ0:198ðꢃ0:053ÞR8 ꢁ 5:544ðꢃ0:988Þq17
þ0:327ðꢃ0:067ÞnCl þ 1:111ðꢃ0:202Þf ðEÞ5
n ¼ 28; R ¼ 0:890; R2 ¼ 0:793; R2A ¼ 0:746; Fð5; 22Þ
loaded with factor 1 [highly loaded with S12, S13, S14, S19, S22, R12
,
R13, R16, R17, R18, R19, R21, R22, Ms, SA(G), Vol, logP, Refr, Pol, SIC0, IC1,
SIC1, SIC2 and SIC3], factor 4 (highly loaded with R1, R2, R3, R4, R5, R6,
R9, R14 and nBr) and factor 3 (S1, S3, S4, S5, S6, S9, S10, q2, q4 and nCl),
poorly loaded with factor 6 (loaded with S15, S16, S17 and HE), factor
5 (loaded with q15, q21, f(E)18, f(E)19 and f(E)20) and factor 10 (loaded
with IC2). It was very poorly loaded with factor 2 and factor 9.
Different combinations of parameters having factor loading of more
than 0.6 (excluding very poorly loaded factors) were subjected to
multiple linear regression. Intercorrelated parameters were not
considered for the development of equations. The results evolved
Eq. (4) with five descriptors:
¼ 16:849; p < 0:00001; S:E:E ¼ 0:152; Rc2v
¼ 0:608; SSY ¼ 2:442; PRESS ¼ 0:960; SDEP
¼ 0:147; SPRESS ¼ 0:208:
(5)
S12/13 is the E-state index of the atom number 12 or 13 (as these
have same calculated values). R8 stands for the R-state index of the
atom number 8. q17 is the Wang-Ford charge of the atom number
17. nCl is one constitutional descriptor. It stands for total number of
chlorine atom of the molecule.
However, the final FA-MLR equation was developed with five
descriptors. This is shown below in Eq. (6):
Log BA ¼ ꢁ83:220ðꢃ11:031Þ
log BA ¼ ꢁ20:435ðꢃ3:692Þ ꢁ 0:109ðꢃ0:027ÞR10
þ5:711ðꢃ0:931ÞR15 þ 3:675ðꢃ0:662Þq14
þ5:481ðꢃ0:833ÞR16 ꢁ 8:075ðꢃ1:362Þq12
ꢁ17:375ðꢃ2:886Þq19 þ 34:953ðꢃ4:943ÞMe
ꢁ1:469ðꢃ0:172ÞI1
þ8:255ðꢃ1:554Þq18 þ 0:968ðꢃ0:185Þf ðEÞ5
n ¼ 28; R ¼ 0:887; R2 ¼ 0:786; R2A ¼ 0:738; Fð5; 22Þ
n ¼ 28; R ¼ 0:907; R2 ¼ 0:822; R2A ¼ 0:782; Fð5; 22Þ
¼ 16:188; p < 0:00001; S:E:E ¼ 0:154; Rc2v
¼ 0:670; SSY ¼ 2:442; PRESS ¼ 0:806; SDEP
¼ 20:337; p < 0:00001; S:E:E ¼ 0:140; Rc2v
¼ 0:697; SSY ¼ 2:442; PRESS ¼ 0:740; SDEP
¼ 0:169; SPRESS ¼ 0:191:
(4)
¼ 0:162; SPRESS ¼ 0:83:
(6)
Where, R10 and R15 are RTSA indices of atom numbers 10 and 15
respectively. q14 and q18 are Wang-Ford charges of atom number 14
and 18 respectively.
R16 is the R-state index of the atom number 16. The positive
coefficient associated with this parameter is indicative of the fact

1764
A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
Table 2
6. Discussion
t-values and p-values of Eq. (2)–(6).
The structure activity relationship of chemical structure with
biological activity values suggested that the presence of methoxy
group at R1 position of the general structure may not be favorable
for anticancer activity whereas the presence of chlorine substitu-
tion at R2 position may be conducive to the biological activity.
Eq. (2) explains 61.6% and predicts 49.2% variances of the bio-
logical activity. The regression coefficients of variables f3 and f4 are
significant at 91.0% and 94.0% levels respectively. These were sup-
ported by t- and p-values shown in Table 2. Eq. (2) shows impor-
tance of factor 1, 3, 4, 7 and 8. Factor loadings of different factors are
included in Supplementary Material. Factor 1 was highly loaded
Eq. No
(2)
Intercept/Parameters
t-value
p-value
Intercept
41.129
ꢁ2.794
1.765
ꢁ1.956
ꢁ3.733
ꢁ4.439
0.000
0.010
0.091
0.063
0.001
0.000
f1
f3
f4
f7
f8
(4)
(6)
Intercept
R10
R15
q14
q18
ꢁ5.534
ꢁ4.085
6.132
5.553
5.313
0.000
0.000
0.000
0.000
0.000
f
(E)5
5.226
ꢁ7.544
6.579
ꢁ5.927
ꢁ6.021
7.072
0.000
0.000
0.000
0.000
0.000
0.000
0.000
with variables like S12, S13, S14, S19, S22, R12, R13, R16, R17, R18, R19, R21
,
Intercept
R16
q12
q19
Me
R22, Ms, SA(G), Vol, logP, Refr, Pol, SIC0, IC1, SIC1, SIC2 and SIC3. It
showed importance of these parameters. Factor 3 was highly
loaded with S1, S3, S4, S5, S6, S9, S10, q2, q4 and nCl. Factor 4 showed
importance of parameters like R1, R2, R3, R4, R5, R6, R9, R14 and nBr.
Factor 7 was highly loaded with q18, q19, IC3, IC4 and IC5. Factor 8
was highly loaded with S8, R8, q8, I1 and f(E)5. These factors showed
the significance of these parameters.
I1
ꢁ8.534
(3)
(5)
Intercept
S15
R17
q12
q14
ꢁ5.624
ꢁ5.964
4.610
0.000
0.000
0.000
0.000
0.000
0.000
0.016
Eq. (3) explains 77.0% and predicts 65.0% of variances of the
biological activity. All regression coefficients involved in Eq. (3) are
significant at 95% confidence level as suggested by t- and p-values
shown in Table 2. The positive coefficient associated with the
parameter f(E)5 suggests that higher probability of electrophilic
attack at the atom number 5 may be favorable to the biological
activity. Negative coefficients of q12 and q19 indicate that increases
in the negative charge or electron density at atom number 12 and
18 may be detrimental to the biological activity. The positive
coefficient of q14 indicates that the increase in the negative charge
or electron density at the atom number 14 may be favorable to
higher antitumor activity. ETSA index is related with the electro-
static interaction. The negative coefficient associated with this
parameter at the atom number 15 (S15) indicates that the increase
in the ETSA index of the atom number 15 may be detrimental to
biological activity of these compounds. Refractotopological state
atom index is assumed to be involved through the dispersive/van
der Walls interactions. The positive coefficient of R17 in Eq. (3)
indicates that the increase of the value of R-state index of the atom
number 17 may improve antitumor activities of these molecules.
All regression coefficient of Eq. (4)–(6) are significant more than
95% confidence level. In Eq. (4), the negative coefficient of R10
suggests that the increase in the R-state index of the atom number
10 may be unfavorable for higher antitumor activity. The positive
ꢁ5.327
7.371
q19
ꢁ5.383
2.595
f
(E)5
Intercept
S12/13
R8
6.995
ꢁ6.665
ꢁ3.709
ꢁ5.610
4.847
0.000
0.000
0.001
0.000
0.000
0.000
q17
nCL
f
(E)5
5.498
that the increase in the R-state index of this atom may be
conducive to biological activity. Me is one constitutional
descriptor. It stands for the mean atomic Sanderson electroneg-
ativity (scaled on carbon atom). Indicator parameter I1 represents
the presence or absence of methoxy group at R1 position of the
general structure.
The t-values and p-values of Eq. (3)–(6) are shown in Table 2.
The correlation matrix of different descriptors used in the QSAR
models is shown in Table 3. All models were validated by leave-
one-out (LOO) cross-validation method. The observed (Obs),
calculated (Calc.), residual (Res), predicted residual (PRES), and
LOO-predicted activities of Eq. (2)–(6) are shown in Table 4a and b.
Table 3
Correlation matrix of dependent and independent variables.
BA
S12/13
S15
R8
0.33
R10
R15
0.22
ꢁ0.22
ꢁ0.55
ꢁ0.28
0.44
R16
R17
q12
0.19
0.09
ꢁ0.40
0.32
ꢁ0.37
ꢁ0.02
0.21
q14
0.45
q17
0.02
ꢁ0.57
ꢁ0.24
0.12
q18
0.04
0.40
0.42
q19
Me
0.31
ꢁ0.69
ꢁ0.56
0.38
nCL
0.44
ꢁ0.06
ꢁ0.15
0.33
I1
f(E)
5
BA
1.00
ꢁ0.45
ꢁ0.19
0.14
1.00
ꢁ0.07
0.18
0.15
ꢁ0.20
0.89
ꢁ0.06
ꢁ0.59
0.37
ꢁ0.19
0.90
0.00
ꢁ0.55
0.33
0.07
0.99
1.00
ꢁ0.32
ꢁ0.11
0.18
ꢁ0.49
0.60
ꢁ0.18
ꢁ0.77
0.41
0.47
ꢁ0.17
ꢁ0.07
0.36
S12/13
S15
R8
1.00
ꢁ0.53
ꢁ0.60
0.03
0.31
1.00
ꢁ0.42
0.68
ꢁ0.25
0.04
R10
R15
R16
R17
q12
q14
q17
q18
q19
Me
nCL
I1
1.00
ꢁ0.32
ꢁ0.26
ꢁ0.58
ꢁ0.53
0.29
ꢁ0.24
0.45
ꢁ0.15
ꢁ0.08
ꢁ0.18
ꢁ0.17
ꢁ0.21
0.23
ꢁ0.47
ꢁ0.49
0.05
1.00
0.15
1.00
0.15
ꢁ0.16
0.35
0.35
ꢁ0.42
ꢁ0.36
ꢁ0.53
1.00
0.42
0.02
0.41
0.60
0.54
ꢁ0.10
ꢁ0.11
ꢁ0.10
0.11
0.19
0.31
ꢁ0.11
ꢁ0.10
ꢁ0.06
0.21
ꢁ0.59
ꢁ0.62
ꢁ0.28
0.05
ꢁ0.59
ꢁ0.63
0.21
0.30
0.49
ꢁ0.03
ꢁ0.03
0.25
0.22
0.13
ꢁ0.11
ꢁ0.10
0.31
0.24
1.00
ꢁ0.30
ꢁ0.85
ꢁ0.18
0.28
ꢁ0.14
ꢁ0.20
ꢁ0.24
1.00
1.00
1.00
0.28
ꢁ0.57
ꢁ0.64
1.00
0.11
1.00
1.00
ꢁ0.39
f
(E)5
1.00

A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
1765
Table 4a
Observed (Obs), calculated (Calc), residual (Res), predicted residual (Pres) and LOO-predicted (Pred) activities of Eq. (2)–(4).
Cpd
Obs
Eq. (2)
Calc
Eq. (3)
Calc
Eq. (4)
Calc
Res
Pres
Pred
Res
Pres
Pred
Res
0.000
0.203
ꢁ0.001
ꢁ0.082
0.012
0.000
0.180
0.000
0.230
Pres
0.000
0.223
ꢁ0.001
ꢁ0.092
0.015
0.000
0.233
0.000
0.306
Pred
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
1.584
1.841
1.446
1.153
1.209
1.643
1.792
1.246
1.730
1.537
1.686
1.668
1.687
1.595
1.876
1.616
1.703
1.361
1.520
1.765
1.026
1.210
1.172
1.018
1.371
1.274
0.637
1.170
1.737
1.839
1.404
1.296
1.558
1.312
1.982
1.357
1.593
1.627
1.766
1.757
1.488
1.397
1.665
1.463
1.675
1.576
1.423
1.567
0.983
1.211
1.093
1.261
1.286
1.314
0.765
1.143
ꢁ0.153
0.002
0.042
ꢁ0.209
0.002
0.047
1.793
1.838
1.399
1.308
1.541
1.322
2.084
1.370
1.555
1.654
1.809
1.775
1.472
1.383
1.638
1.457
1.703
1.557
1.475
1.471
0.672
1.212
1.076
1.292
1.222
1.361
0.861
1.125
1.619
1.862
1.575
1.370
1.669
1.212
1.683
1.209
1.332
1.502
1.681
1.869
1.639
1.570
1.844
1.425
1.582
1.742
1.469
1.527
1.028
1.365
1.219
1.121
1.221
1.076
0.859
1.266
ꢁ0.035
ꢁ0.021
ꢁ0.129
ꢁ0.218
ꢁ0.026
ꢁ0.003
0.109
0.037
0.399
0.036
0.005
ꢁ0.045
ꢁ0.030
ꢁ0.147
ꢁ0.242
ꢁ0.033
ꢁ0.004
0.159
0.048
0.444
0.039
0.006
1.629
1.871
1.593
1.394
1.676
1.213
1.634
1.198
1.287
1.498
1.680
1.931
1.635
1.568
1.828
1.418
1.578
1.753
1.481
1.479
1.038
1.384
1.228
1.163
1.193
0.984
0.981
1.314
1.584
1.638
1.446
1.234
1.631
1.209
1.612
1.246
1.500
1.657
1.808
1.436
1.743
1.532
1.906
1.520
1.695
1.910
1.408
1.632
1.325
1.159
1.265
1.018
1.343
1.133
0.777
1.171
1.584
1.618
1.446
1.245
1.628
1.209
1.559
1.246
1.424
1.696
1.844
1.409
1.755
1.527
1.913
1.520
1.728
1.986
1.447
1.592
1.370
1.150
1.275
1.018
1.324
0.986
0.881
1.172
ꢁ0.143
ꢁ0.155
0.085
0.102
ꢁ0.104
ꢁ0.190
ꢁ0.110
0.138
ꢁ0.090
ꢁ0.080
ꢁ0.089
0.200
ꢁ0.113
ꢁ0.292
ꢁ0.124
0.176
ꢁ0.116
ꢁ0.123
ꢁ0.108
0.215
ꢁ0.120
ꢁ0.122
0.232
ꢁ0.158
ꢁ0.158
0.259
ꢁ0.201
ꢁ0.264
0.048
0.053
ꢁ0.056
ꢁ0.068
0.198
0.211
0.057
0.212
0.239
0.063
0.025
0.032
0.095
0.034
ꢁ0.039
ꢁ0.108
0.239
ꢁ0.002
ꢁ0.155
ꢁ0.047
ꢁ0.103
0.150
0.027
0.048
0.102
0.037
ꢁ0.050
ꢁ0.120
0.287
ꢁ0.012
ꢁ0.174
ꢁ0.056
ꢁ0.145
0.179
0.063
0.068
ꢁ0.030
0.000
ꢁ0.079
ꢁ0.207
ꢁ0.047
0.134
ꢁ0.036
0.000
ꢁ0.113
ꢁ0.282
ꢁ0.087
0.173
ꢁ0.059
ꢁ0.087
0.127
0.147
ꢁ0.062
0.198
0.043
ꢁ0.114
0.294
0.354
ꢁ0.299
ꢁ0.344
ꢁ0.001
ꢁ0.001
0.051
0.060
0.079
0.096
ꢁ0.093
0.000
0.028
ꢁ0.103
0.000
0.047
ꢁ0.243
0.085
ꢁ0.040
ꢁ0.127
0.027
ꢁ0.274
0.149
ꢁ0.087
ꢁ0.224
0.045
0.198
0.290
0.141
0.287
ꢁ0.221
ꢁ0.344
ꢁ0.140
ꢁ0.244
ꢁ0.096
ꢁ0.144
ꢁ0.001
ꢁ0.002
coefficient of R15 indicates that the increase in the R-state index of
the atom number 15 may be favorable for the biological activity.
The positive coefficient associated with q18 suggested that with the
increase in the positive charge of the atom number 18 may be
conducive to the biological activity of these glutamamide
compounds. This means that electron density of this atom may be
needed to be decreased for higher biological activity. Eq. (4)
explains 73.8% and predicts 67.0% of variances of the biological
activity.
Eq. (5) explains 74.6% and predicts 60.7% of variances of the
biological activity. The negative coefficient associated with S12/13
indicates that the increase in the E-state index of the atom number
12 as well as that of 13 may be detrimental to the biological activity.
The negative coefficient of R8 suggests that the increase in the R-state
Table 4b
Observed (Obs), calculated (Calc), residual (Res), predicted residual (Pres) and LOO-predicted (Pred) activities of Eq. (5)–(6).
Cpd
Obs
Eq. (5)
Calc
Eq. (6)
Calc
Res
Pres
Pred
Res
Pres
Pred
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
1.584
1.841
1.446
1.153
1.209
1.643
1.792
1.246
1.730
1.537
1.686
1.668
1.687
1.595
1.876
1.616
1.703
1.361
1.520
1.765
1.026
1.210
1.172
1.018
1.371
1.274
0.637
1.170
1.651
1.733
1.595
1.335
1.267
1.658
1.856
1.287
1.631
1.278
1.744
1.809
1.668
1.639
1.839
1.491
1.415
1.600
1.507
1.459
0.963
1.283
1.208
1.117
1.282
1.216
0.836
1.169
ꢁ0.067
0.108
ꢁ0.088
0.128
1.671
1.713
1.612
1.349
1.272
1.660
1.911
1.292
1.528
1.229
1.765
1.835
1.665
1.645
1.832
1.472
1.348
1.660
1.505
1.372
0.401
1.291
1.213
1.137
1.265
1.195
0.945
1.169
1.718
1.675
1.591
1.444
1.391
1.732
1.703
1.337
1.283
1.447
1.717
1.596
1.578
1.542
1.886
1.722
1.639
1.554
1.473
1.445
1.225
1.210
1.155
1.074
1.256
1.046
0.876
1.221
ꢁ0.134
0.166
ꢁ0.176
0.209
1.759
1.632
1.613
1.473
1.411
1.755
1.675
1.372
1.195
1.429
1.732
1.582
1.561
1.535
1.891
1.752
1.626
1.602
1.465
1.352
1.294
1.210
1.152
1.095
1.218
0.920
1.004
1.249
ꢁ0.149
ꢁ0.182
ꢁ0.058
ꢁ0.015
ꢁ0.064
ꢁ0.040
0.099
ꢁ0.166
ꢁ0.197
ꢁ0.063
ꢁ0.017
ꢁ0.119
ꢁ0.046
0.203
ꢁ0.145
ꢁ0.292
ꢁ0.182
ꢁ0.089
0.089
ꢁ0.167
ꢁ0.320
ꢁ0.202
ꢁ0.112
0.117
ꢁ0.090
ꢁ0.125
0.448
0.536
0.259
0.308
0.090
0.108
ꢁ0.058
ꢁ0.142
0.020
ꢁ0.079
ꢁ0.168
0.022
ꢁ0.031
ꢁ0.046
0.071
0.086
0.109
0.052
ꢁ0.010
ꢁ0.107
0.065
0.126
0.059
ꢁ0.015
ꢁ0.137
0.077
ꢁ0.045
ꢁ0.050
0.037
0.045
0.125
0.288
0.144
0.356
ꢁ0.239
ꢁ0.299
ꢁ0.193
ꢁ0.242
0.013
0.015
0.047
0.055
0.306
0.063
ꢁ0.073
ꢁ0.036
ꢁ0.099
0.089
0.394
0.625
ꢁ0.081
ꢁ0.041
ꢁ0.119
0.106
0.320
0.414
ꢁ0.199
ꢁ0.268
0.000
0.000
0.017
0.020
ꢁ0.056
ꢁ0.077
0.115
0.153
0.058
0.078
0.228
0.353
ꢁ0.198
ꢁ0.308
ꢁ0.238
ꢁ0.367
0.001
0.001
ꢁ0.051
ꢁ0.079

1766
A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
Electrostatic interaction important
Electron density of this atom should be increased
Increase in the van der Walls
interaction increases activity
3
2
4
1
O
5
O
13
6
12
15
16
17
R
S
11
N
2
14
7
H
10
Electron density of these atoms
should be decreased
8
9
18
21
19
O
22
O
R
1
NHR3
NHR3
20
Decrease in van der Walls interaction
favors activity
23
Presence of methoxy group inhibits activity
Fig. 4. Important atoms and substitution of 1, 5-N,N0-substituted-2-(substituted naphthalenesulphonyl) glutamamides.
index of the atom number 8 may not be favorable for anticancer
activity of these compounds. The negative coefficient of q17 indicates
that higher biological activity may correspond to decrease in the
negative charge or electron density of the atom number 17. nCl is one
constitutional descriptor. It stands for total number of chlorine atom
of the molecule. The positive coefficient associated with this
descriptor indicates that increase in the total number of chlorine
atom of these molecules may be favorable to the biological activity.
Eq. (6) explains 78.2% and predicts 69.7% of variances of the
biological activity. R16 is the R-state index of the atom number 16.
The positive coefficient associated with this parameter is indicative
of the fact that with the increase in the R-state index of this atom
may be conducive to the biological activity. The positive coefficient
of Me indicates that the increase in the mean atomic electronega-
tivity of these compounds may correspond to higher biological
activity. Indicator parameter I1 stands for presence or absence of
methoxy group at R1 position of the general structure. The negative
coefficient of this parameter suggests that the presence of this
group at R1 position may be unfavorable for biological activity.
synthesized glutamamide compounds. It may help in further
tailoring of these analogs to get an active member.
8. Experimental
8.1. Chemistry
All reactions were monitored by analytical thin layer chroma-
tography performed on silica gel G plates. Spots were located
keeping these TLC plates in iodine chamber. Final compounds were
obtained as solid crystalline forms. Structures of these synthesized
compounds were confirmed by IR, 1H NMR, mass spectra and
elemental analyses. Melting points of all synthesized compounds
were first measured on Mel-Temp, a capillary melting point appa-
ratus. These were verified in CTRONICS, a digital melting point
apparatus. Infrared spectra were recorded on SASCO FTIR-410
Model Fourier Transformed Infrared spectrophotometer of SHI-
MADZU using KBr pellets. Running the spectrum of 0.05 mm
polystyrene film did the finer calibration of the machine.
Frequencies were expressed in cmꢁ1. Proton Nuclear Magnetic
Resonance (1H NMR) spectra were collected at 25 ꢀC in the pulsed
Fourier Transformation mode on Bruker DPX 300 MHz spectro-
7. Conclusion
photometers. Chemical shifts are reported in
d ppm (parts per
From the study, it is evident that these twenty eight synthesized
glutamamideanalogshavevaryinganticanceractivities.Comparative
QSAR study showed that the decrease in the electrostatic interactions
of atom number 12/13 and 15 may be conducive to antitumor activity
of these compounds. Decreases in the R-state indices of atom
numbers 8 and 10 and increase in the R-state indices of the atom
numbers 15,16 and 17 may be favorable to the biological activity. The
increase in the charges of atom numbers 14 and 18 as well as the
decrease in the charges of atom numbers 12, 17 and 19 may be
conducive to higher biological activity. From the calculated charges of
these atoms, it is obvious that electron density may be decreased in
atom numbers 12, 17, 18 and 19 whereas electron density may be
increased in the atom number 14. QSAR study also revealed the fact
thatthe presenceofmethoxygroupatR1 positionmaybeunfavorable
for higher antitumor activity of these glutamamides. The increase in
the number of chlorine atom in the molecule as well as mean atomic
electronegativity of these compounds may lead to higher anticancer
activity. QSAR study emphasizes that higher probability of electro-
philic attack at the atom number 5 may be favorable to the biological
activity. QSAR results are shown diagramically in Fig. 4. The current
study allows us to investigate the structural features of these
million) relative to Tetramethyl Silane (Me4Si) as an internal stan-
dard for solutions in deuteriorated chloroform (CDCl3). Splitting
patterns have been designated as s (singlet), d (doublet), t (triplet),
dd (doublet of doublet) and m (multiplet). Positions of the
hydrogen atoms described in 1H NMR interpretation are as per
general structure (Fig. 1). Substitutions at the R3 position has taken
the superscript ‘00’ (double dash) and the substitution at R30 position
has taken the superscript ‘%’ (triple dash). The mass spectra (FAB/
Table 5
Physical data of the intermediate compounds.
Cpd
R1
R2
mp (ꢀC)
% Yield
Molecular formula
Mw
5
6
7
8
10
11
12
13
H
H
H
OCH3
H
H
H
OCH3
H
63–65
78–80
82–84
110–112
96–98
180–182
154–156
170–172
72.92
96.13
74.53
11.13
78.69
78.38
69.45
42.31
C10H7ClO2S
C10H6Cl2O2S
C10H6ClBrO2S
C11H9ClO3S
226.67
261.12
305.57
256.70
337.38
371.82
416.28
367.41
Cl
Br
H
H
C15H15NO6S
Cl
Br
H
C15H14ClNO6S
C15H14BrNO6S
C16H17NO7S

A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
1767
Table 6
Physical data of synthesized 1,5-N,N0-disustituted-2-(substituted naphthalenesulphonyl) glutamamides (18–45).
Cpd.a No.
R1
R2
R3/R3
Mw
% Yield
Structural formula
15H17N3O4S
mp (ꢀC)
0
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
H
H
H
335.39
363.48
391.54
419.60
419.60
447.66
447.66
474.84
499.39
515.68
369.86
397.92
425.96
454.04
454.04
482.10
482.10
537.62
549.36
414.31
442.37
470.43
498.44
554.56
594.57
545.71
529.70
533.73
19.43
74.52
80.23
59.36
60.25
53.44
77.23
68.66
60.80
73.55
69.36
42.63
48.96
50.20
36.24
62.99
33.62
51.90
64.28
67.84
55.56
60.52
71.23
57.73
55.25
27.56
33.65
42.43
C
165–167
184–186
120–122
153–154
170–172
152–154
158–160
114–116
226–228
156–158
227–229
235–237
201–203
183–185
167–167
148–150
192–194
156–158
181–183
217–219
241–243
211–213
186–188
158–160
180–182
160–162
169–171
178–180
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
C2H5
C17H21N3O4S
C19H25N3O4S
C21H29N3O4S
C21H29N3O4S
C23H33N3O4S
C23H33N3O4S
C25H37N3O4S
C27H37N3O4S
C29H29N3O4S
C15H16N3O4SCl
C17H20N3O4SCl
C19H24N3O4SCl
C21H28N3O4SCl
C21H28N3O4SCl
C23H32N3O4SCl
C23H32N3O4SCl
C27H40N3O4SCl
C29H28N3O4SCl
C15H16N3O4SBr
C17H20N3O4SBr
C19H24N3O4SBr
C21H28N3O4SBr
C25H36N3O4SBr
C29H28N3O4SBr
C30H31N3O5S
C28H39N3O5S
C28H43N3O5S
n-C3H7
i-C3H7
n-C4H9
i-C4H9
n-C5H11
C6H11
C6H5CH2
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
H
CH3
C2H5
n-C3H7
i-C3H7
n-C4H9
i-C4H9
C6H13
C6H5CH2
H
CH3
C2H5
n-C3H7
n-C5H11
C6H5CH2
C6H5CH2
C6H11
C6H13
OCH3
OCH3
OCH3
H
H
a
Cpd ¼ Compound.
EI) were recorded on API 200 mass spectrophotometer. Elemental
analyses or microanalyses (C, H, N) of these compounds were
performed on 2400 Series-II CHN analyzer of Perkin–Elmer. The
general structures of starting materials, intermediates as well as the
synthetic scheme are given in Fig. 2. Physical data of intermediate
compounds are shown in Table 5. Physical data and spectral data of
all final compounds are given in Tables 6 and 7 respectively.
only the vehicle. On the ninth day, food and water was withheld 6 h
before sacrificing these animals. Weights of all the animals were
recorded before these were sacrificed. The peritoneal cavity was
dissected. The ascitic fluid was withdrawn by a syringe to a suitable
volume. It was collected in sterile ice cold saline. This was preserved
in ice bath. The number of living cells/ml in the peritoneal fluid of
each mouse in a group were counted using trypan blue as an indi-
cator. These were done under a microscope with the help of a hae-
mocytometer. After removing the fluid from the peritoneal cavity
for cell count, ascitic fluid was wiped off with absorbent cotton. The
weight of the six mice after sacrifice was recorded. The difference in
weight was considered as the tumor weight.
8.2. Anticancer activity
Swiss albino mice of either sex (female in this case) of 10 weeks
old with an average body weight of 18–20 g were used for in vivo
method. All mice were kept on basal metabolic diet with water ad
libitum. The ambient room temperature (25–27 ꢀC) was maintained
during these experiments. Two groups of Swiss Albino mice were
made. Each group was containing six healthy female mice. These
were having approximately of the same age and body weight (18–
20 g). Animals were selected at random. One of these two groups
was served as the control while the other was served as the test.
Ehrlich Ascites Carcinoma (EAC) cells were collected from the donor
mouse. These were suspended in sterile isotonic solution (0.9% w/v
NaCl). Numbers of tumor cells per ml of this suspension were
counted under microscope with the help of a haemocytometer
manufactured by Marienfeld, Germany. About 2 ꢂ 106 cells/0.2 mL
of these living viable cells were injected into the peritoneal cavity of
each mouse. In this instance, tumor cells multiplied relatively freely
within the peritoneal cavity. Ascites were developed in the cavity. A
day of incubation was allowed to establish the disease in the body
before starting the administration of the drug. From the second day
of transplantation up to the eighth day, a suitable challenge dose
(0.2 m mol/kg body weight) of the drug solution/suspension in
sterile phosphate buffer (pH 7.2) were injected intraperitoneally to
each mouse in the test group at 24 h interval. Thus, seven doses of
the compound and standard drug were administered intraperito-
neally from the first day of injection up to the seventh day with 24 h
intervals to each mouse in the test group. Control animals received
The mean of Ascites cells/ml was taken for evaluation of anti-
neoplastic activity. The evaluation of the test drug was made by
comparing the cell count and tumor weight of the test with that of
the control.
8.3. QSAR study
Topological descriptors like electrotopological state atom index
(ETSA) [30–35] and refractotopological state atom index (RTSA)
[36–39] were calculated by using the computer program ‘Mouse’
[40] developed in our laboratory. Calculation of different quantum
chemical descriptors like approximate molecular surface area
[SA(A)], molecular surface area grid [SA(G)], hydrophobicity (logP),
molecular volume (Vol), molecular polarizability (Pol), molecular
refractivity (Refr), hydration energy (HE) and frontier electron
density electrophilic (f(E)) were done using the computer program
Hyperchem Release 7.0 Pro. Package [41]. In Hyperchem software,
the 2D structures of these compounds were drawn. These were
converted to corresponding 3D structures. Energy minimization of
these structures were done using molecular mechanical (MMþ)
force fields without cut-off for non-bonded interactions, solvation
and constrains. These energy minimized structures were subjected
to geometrical optimization by semi-empirical AM1 (Austin model
1) method using Polak-Ribiere algorithm with an RMS gradient of

Table 7
Mass, IR, prton NMR and CHN analysis data of the final compounds (18–45).
Cpd
Mass (FAB)
IR (KBr, cmꢁ1
)
1H NMR (300MHz, CDCl3))
C, H, N % calcd/found
C
H
N
18
M þ Hþ peak at m/z 336
3481 (Asymmetric N–H str. of CONH2), 3376 (Symmetric N–
H str. of CONH2), 3146 (Ar C–H str.), 2861 (ali C–H str.), 1666
(C]O str. of CONH2), 1426 (Ar–C]CH str.), 1311 (S]O str of
SO2NH, asymmetric), 1158 (S]O str. of SO2NH, symmetric),
798, 767, 684 (Polynuclear-CH out of plane bending)
3315 (NH str. Of CONH), 3107 (Ar. CH Str), 2933 ali C–H str.),
1647 (C]O str. of COOH), 1556 (NH bend of CONH),
1458,1436, 1413 (Ar. C]CH str), 1357 (S]O str. of SO2NH,
asymmetric), 1161 (S]O str. of SO2NH, symmetric), 802,
767, 680 (Polynuclear-CH out of plane bending)
3301 (N–H str of CONH), 3091 (Ar C–H str.), 2958, 2871 (ali
C–H str.), 1643 (C]O str. of CONH), 1556 (N–H bend of
CONH), 1508, 1438 (Ar C]CH str), 1317 (S]O str of SO2NH,
asymmetric), 1154 (S]O str of SO2NH, symmetric), 802,
767, 680 (Polynuclear-CH out of plane bending)
d
90),
d
8.73 (s, 1H, SO2NH),
d
7.32–8.23 (m, 7H, H-20, H-30, H-40, H-60, H-70, H-80, H-
5.34 (m, 2H, CONH2-5), 3.67 (m, 1H, H-2),
2.01 (m, 2H, H2-3), 1.78 (m, 1H, HB-3)
53.57/53.96
5.06/4.96
12.50/12.68
d
5.85 (m, 2H, CONH2-1),
d
d
2.27 (m, 2H, H2-4),
d
19
20
21
M þ Hþ peak at m/z 364
M þ Hþ peak at m/z 392
M þ Hþ peak at m/z 420
d
90),
d
d
8.73 (s, 1H, SO2NH),
d
7.50–8.23 (m, 7H, H-20, H-30, H-40, H-60, H-70, H-80, H-
56.14/56.74
58.23/58.93
60.14/59.89
5.77/5.45
6.38/6.12
6.92/6.93
11.55/11.63
10.73/10.82
10.02/9.17
d
6.71 (m, 1H, CONH-1),
d
5.61 (m, 1H, CONH-5),
d
d
3.61 (m, 1H, H-2),
2.17 (m, 2H, H2-4),
2.72 (m, 3H, N–CH3-1%), d
1.87 (m, 2H, H2-3)
2.52 (m, 3H, N–CH3-100),
d
90),
d
d
8.76 (s, 1H, SO2NH),
6.58 (m, 1H, CONH-1),
3.24 (m, 2H, NH–CH2-100),
2.02 (m, 1H, HA-3),
1.77 (m, 1H, HB-3), 1.11–1.63 (m, 1H, CH3-200)
d
7.68–8.40 (m, 6H, H-20, H-30, H-40, H-60, H-70, H-80, H-
5.51 (m, 1H, CONH-5), 3.62 (m, 1H, H-2),
2.96 (m, 2H, NH–CH2-1%), 2.23 (m, 2H, H2-4),
0.80–
d
d
d
d
d
d
1.11 (m, 3H, CH3-2%)
8.75 (s, 1H, SO2NH),
90),
6.61 (m, 1H, CONH-1),
3.16–3.20(m, 2H, N–CH2-100,),
2H, H2-4), 2.04 (m, 1H, HA-3),
CH2-200),
1.24–1.12 (m, 2H, N–CH2-2%),
0.68–0.73 (m, 3H, 3H, N–CH2-3%)
8.78 (s, 1H, SO2NH),
7.61–8.43 (m, 7H, H-20, H-30, H-40, H-60, H-70, H-80, H-
90), 4.01 (m, 2H, N–CH-100,
6.35 (m, 1H, CONH-1), 5.50 (m, 1H, CONH-5),
N–CH-1%), 3.64 (m, 1H, H-2), 2.23 (m, 2H, H2-4), 2.04 (m, 1H, HA-3),
1.78 (m, 1H, HB-3), 0.83–0.75 (m,
1.24–1.14 (m, 6H, CH3-200, CH3-2’’’,),
6H, CH3-400, CH3-4&)
3294 (N–H str of CONH), 3101 (Ar C–H str.), 2960, 2871 (ali
C–H str.), 1645 (C]O str. of CONH), 1558(N–H bend of
CONH), 1436 (Ar C]CH str), 1319 (S]O str of SO2NH,
asymmetric), 1155 (S]O str of SO2NH, symmetric), 800,
767, 680 (Polynuclear-CH out of plane bending)
d
d
7.49–8.23 (m, 7H, H-20, H-30, H-40, H-60, H-70, H-80, H-
5.53 (m, 1H, CONH-5), 3.60 (m, 1H, H-2),
2.83–2.95 (m, 2H, N–CH2-1%), 2.23 (m,
1.78 (m, 1H, HB-3), 1.45–1.55 (m, 2H, N–
0.96–0.91 (m, 3H, 3H, N–CH2-300),
d
d
d
d
d
d
d
d
d
d
d
d
22
23
M þ Hþ peak at m/z 420
M þ Hþ peak at m/z 448
3295 (N–H str of CONH), 3079 (Ar C–H str.), 2973 (ali C–H
str.), 1643(C]O str. of CONH), 1550(N–H bend of CONH),
1454(Ar–C]CH str), 1329(S]O str of SO2NH, asymmetric),
1154 (S]O str of SO2NH, symmetric), 909, 836, 681
(Polynuclear-CH out of plane bending)
3309 (N–H str of CONH), 3087 (Ar C–H str.), 2977, 2935 (ali
C–H str.), 1642 (C]O str. of CONH), 1552(N–H bend of
CONH), 1436 (Ar C]CH str), 1323 (S]O str of SO2NH,
asymmetric), 1159 (S]O str of SO2NH, symmetric), 803,
768, 678 (Polynuclear-CH out of plane bending)
d
60.14/59.34
61.65/61.87
6.92/6.95
7.37/7.14
10.02/9.18
9.38/9.35
d
d
d
d
d
d
d
d
d
d
d
90),
d
8.77 (s, 1H, SO2NH),
7.49–8.21 (m, 7H, H-20, H-30, H-40, H-60, H-70, H-80, H-
5.34 (m, 1H, CONH-5), 3.67 (m, 1H, H-2),
2.90–2.96 (m, 2H, N–CH2-1%), 2.32 (m,
(m, 4H, N–CH2-200, N–CH2-2%),
2.07 (m, 1H, HA-3),
1.89–1.90 (m, 4H, N–CH2-300, N–CH2-3%), 1.13–1.18 (m, 3H, N–CH3-400),
0.73–0.78 (m, 3H, N–CH3-4%)
8.76 (s, 1H, SO2NH),
7.61–8.46 (m, 6H, H-20, H-30, H-40, H-60, H-70, H-80, H-
6.70 (m, 1H, CONH-1), 5.56 (m, 1H, CONH-5), 3.63 (m, 1H, H-2), 3.01
(m, 2H, NH–CH2-100),
2.76 (m, 2H, NH–CH2-1%), 2.29 (m, 2H, H2-4), 2.04
1.86 (m, 1H, HB-3),
1.70–1.86 (m, 2H, NH–CH2–CH-200, NH–
0.90–0.93 (d, 6H, CH3-400, CH3-4%),
d
5.58 (m, 1H, CONH-1),
d
d
3.28–3.30(m, 2H, N–CH2-100,),
d
d
2H, H2-4), 2.12–2.17
d
d
d
d
d
90),
d
24
M þ Hþ peak at m/z 448
3302(N–H str of CONH), 3095 (Ar C–H str.), 2959 (ali C–H
str.), 1647 (C]O str. of CONH), 1555 (N–H bend of CONH),
1444 (Ar–C]CH str), 1322 (S]O str of SO2NH, asymmetric),
1159 (S]O str of SO2NH, symmetric), 770, 680
d
61.65/61.54
7.37/7.15
9.38/9.39
d
d
d
d
d
d
(m, 1H, HA-3),
CH2–CH-2%),
300, CH3-3%)
d
d
(Polynuclear-CH out of plane bending)
d
d
0.70–0.74 (d, 2H, CH3-
25
26
27
M þ Hþ peak at m/z 475
M þ Hþ peak at m/z 499
M þ Hþ peak at m/z 516
3301 (N–H str of CONH), 3091 (Ar C–H str.), 2958, 2871 (ali
C–H str.), 1643 (C]O str. of CONH), 1556 (N–H bend of
CONH), 1508, 1438 (Ar C]CH str), 1317 (S]O str of SO2NH,
asymmetric), 1154 (S]O str of SO2NH, symmetric), 802,
767, 680 (Polynuclear-CH out of plane bending.
3286 (N–H str of CONH), 3086(Ar C–H str.), 2929 (ali C–H
str.), 1643(C]O str. of CONH), 1551 (N–H bend of CONH),
1445 (Ar–C]C), 1320 (S]O str of SO2NH, asymmetric),
1154 (S]O str of SO2NH, symmetric), 893, 805, 771
(Polynuclear-CH out of plane bending)
3293 (N–H str. of CONH), 3083 (Ar C–H str.), 2929 (ali C–H
str.), 1647 (C]O str. of CONH), 1550 (N–H bend of CONH),
1442 (Ar C]CH str.), 1323 (S]O str. of SO2NH, asymmetric),
1150 (S]O str. of SO2NH, symmetric), 887, 834, 757, 680
(Polynuclear and mononuclear Ar.–CH out of plane
bending);
d
8.73 (s, 1H, SO2NH),
d
7.32–8.23 (m, 7H, H-20, H-30, H-40, H-60, H-70, H-80, H-
63.18/63.42
64.92/64.56
67.44/67.67
7.79/7.56
7.21/7.12
5.62/5.45
8.84/8.96
8.41/8.63
8.14/8.23
90),
d
d
5.85 (m, 1H, CONH2-1),
d
5.34 (m, 1H, CONH-5),
d
3.67 (m, 1H, H-2),
2.27 (m, 2H, H2-4),
1.56–1.29 (m, 12H, CH2-200, CH2-
0.97–0.74 (m, 6H, CH3-500, CH3-5%)
7.48–8.22 (m, 6H, H-20, H-30, H-40, H-60, H-70, H-80, H-
6.35 (m, 1H, CONH-1), 5.44 (m, 1H, CONH-5), 3.36 (m, 1H, H-2),
2.23 (m, 2H, H2-4), 2.02–2.09 (m, 2H, H2-3), 1.01–1.90 (m, 22H,
Cyclohexyl protons)
3.68 (m, 2H, N–CH2-100), 3.13 (m, 2H, N–CH2-100),
d d
d
2.01 (m, 2H, H2-3),
d 1.78 (m, 1H, HB-3), d
300, CH2-400, CH2-2%, CH2-3%, CH2-4%),
8.73 (s, 1H, SO2NH),
90),
d
d
d
d
d
d
d
d
d
8.72 (s, 1H, SO2NH),
90, H-200, H-300, H-500, H-600, H-700, H-800, H-2%, H-3%, H-5%, H-6%, H-7%, H-
8%), 6.93 (m, 1H, CONH-1), 5.82 (m, 1H, CONH-5), 4.04–4.41 (m, 4H,
NH–CH2-100, NH–CH2-1%),
3.70 (m, 1H, H-2), 2.29 (m, 2H, H2-4), 2.03 (m,
1H, HA-3), 1.77–1.84 (m, 1H, HB-3)
d
7.29–8.35 (m, 19H, H-20, H-30, H-40, H-60, H-70, H-80, H-
d
d
d
d
d
d

28
29
30
31
32
33
34
35
36
M þ Hþ peak at m/z 370
M þ Hþ peak at m/z 398
M þ Hþ peak at m/z 426
M þ Hþ peak at m/z 454
M þ Hþ peak at m/z 454
M þ Hþ peak at m/z 482
M þ Hþ peak at m/z 482
M þ Hþ peak at m/z 538
M þ Hþ peak at m/z 550
3480 (Asymmetric N–H str. of CONH2), 3336
(Symmetric N–H str. of CONH2), 3172 (Ar C–H str.),
2863 (ali C–H str.), 1664 (C]O str. of CONH2), 1424 (Ar–
C]CH str.), 1312 (S]O str of SO2NH, asymmetric), 1136
(S]O str. of SO2NH, symmetric), 831, 759, 683
(Polynuclear-CH out of plane bending)
3304, 3262 (N–H str. of CONH), 3109 (Ar C–H str.),
2943 (ali C–H str.), 1644 (C]O str. of CONH), 1567(N–H
bend of CONH), 1504, 1441 (Ar–C]CH str.), 1318 (S]O str
of SO2NH, asymmetric), 1146 (S]O str of SO2NH,
symmetric), 916, 834, 756, 688 (Polynuclear-CH out of plane
bending)
3301 (N–H str of CONH), 3091 (Ar C–H str.), 2958,
2871 (ali C–H str.), 1643 (C]O str. of CONH), 1556 (N–H
bend of CONH), 1508, 1438 (Ar C]CH str), 1317 (S]O str of
SO2NH, asymmetric), 1154 (S]O str of SO2NH,
symmetric), 1043 (Ar–Cl), 802, 767, 680 (Polynuclear-CH
out of plane bending).
3297 (N–H str. of CONH), 3092 (Ar C–H str.), 2961(ali C–H
str.), 1647 (C]O str. of CONH), 1556 (N–H bend of CONH),
1438 (Ar C]CH str.) 1328 (S]O str. of SO2NH, asymmetric),
1154 (S]O str. of SO2NH, symmetric), 906, 836, 683
(Polynuclear Ar.–CH out of plane bending), 976
(Ar–Cl)
3296 (N–H str. of CONH), 3083 (Ar C–H str.),
2971 (ali C–H str.), 1643 (C]O str. of CONH),
1550 (N–H str of CONH), 1454 (Ar–C]CH str.),
1329 (S]O str of SO2NH, asymmetric), 1159 (S]O str of
SO2NH, symmetric), 837, 763, 681 (Polynuclear
Ar. –CH out of plane bending)
3309 (N–H str of CONH), 3087 (Ar C–H str.), 2977,
2935 (ali C–H str.), 1642 (C]O str. of CONH), 1552(N–H
bend of CONH), 1436 (Ar C]CH str), 1323 (S]O str of
SO2NH, asymmetric), 1159 (S]O str of SO2NH,
symmetric), 803, 768, 678 (Polynuclear-CH out of plane
bending),
3297 (N–H str. of CONH), 3093 (Ar C–H str.), 2958 (ali C–H
str.), 1646 (C]O str of CONH), 1556 (NH bend of CONH),
1440 (Ar–C]CH str.), 1320 (S]O str. of SO2NH,
asymmetric), 1153 (S]O str. of SO2NH, symmetric), 911,
835, 759, 682 (Polynuclear Ar.–CH out of plane bending);
d
8.73 (s, 1H, SO2NH),
H-70, H-80, H-90),
5.85 (m, 2H, CONH2-1),
(m, 1H, H-2), 2.27 (m, 2H, H2-4), 2.01 (m, 2H, H2-3), 1.78 (m, 1H, HB-3).
d
7.32–8.23 (m, 6H, H-20, H-30, H-60,
5.34 (m, 2H, CONH2-5),
48.71/48.10
51.26/51.01
53.52/53.56
55.51/55.78
55.51/55.65
57.26/57.67
57.26/56.98
60.26/60.45
63.35/63.56
4.32/4.11
4.77/4.78
5.40/5.76
5.95/5.87
5.95/5.76
6.43/6.76
6.43/6.23
7.28/7.57
5.10/5.45
11.35/11.29
10.55/10.43
9.86/9.56
9.25/9.54
9.25/9.65
8.71/8.46
8.71/8.98
7.82/7.92
7.64/7.87
d
d
d 3.67
d
d
d
d
8.73 (s, 1H, SO2NH),
6.71 (m, 1H, CONH-1),
d
7.50–8.23 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.61 (m, 1H, CONH-5), 3.61 (m, 1H, H-2), 2.72
2.52 (m, 3H, N–CH3-100),
2.17 (m, 2H, H2-4), 1.87 (m,
d
d
d
(m, 3H, N–CH3-1%),
2H, H2-3)
d
d
d
d
d
8.76 (s, 1H, SO2NH),
6.58 (m, 1H, CONH-1),
2.90 (m, 2H, NH–CH2-1%), 2.23 (m, 2H, H2-4),
1.77 (m, 1H, HB-3), 1.11–1.63 (m, 3H, CH3-200)
d
7.68–8.40 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
d
5.51 (m, 1H, CONH-5),
d
3.62 (m, 1H, H-2),
d
d
3.24
2.02
(m, 2H, NH–CH2-100),
(m, 1H, HA-3),
(m, 3H, CH3-2%)
d
d
d
0.80–1.11
d
d
8.75 (s, 1H, SO2NH),
6.61 (m, 1H, CONH-1),
d
7.49–8.23 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.53 (m, 1H, CONH-5), 3.60 (m, 1H, H-2), 3.16–
2.83–2.95 (m, 2H, N–CH2-1%), 2.23 (m, 2H, H2-4),
1.78 (m, 1H, HB-3),
1.45–1.55 (m, 2H, N–CH2-200),
1.24–1.12 (m, 2H, N–CH2-2%), 0.68–0.73
0.96–0.91 (m, 3H, N–CH3-300),
d
d
d
3.20(m, 2H, N–CH2-100),
d
d
d
d
2.04 (m, 1H, HA-3),
d
d
d
d
(m, 3H, N–CH3-3%)
d
8.77 (s, 1H, SO2NH),
6.35 (m, 1H, CONH-1),
3.66–3.72 (m, 1H, N–CH-100),
2.04 (m, 1H, HA-3), 1.78 (m, 1H, HB-3),
’’’,), 0.83–0.75 (m, 6H, CH3-300, CH3-3&)
d
7.61–8.42 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90)
5.50 (m, 1H, CONH-5), 4.02–4.09 (m, 1H, N–CH-
3.61 (m, 1H, H-2), 2.23 (m, 2H, H2-4),
1.24–1.14 (m, 6H, CH3-200, CH3-
d
100),
d
d
d
d
d
d
d
d
2
d
d
d
8.77 (s, 1H, SO2NH),
d
7.49–8.21 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.34 (m, 1H, CONH-5), 3.67 (m, 1H, H-2), 3.28–
2.90–2.96 (m, 2H, N–CH2-1%), 2.31 (m, 2H, H2-4),
(m, 4H, N–CH2-200, N–CH2-2%),
2.07 (m, 1H, HA-3), 1.89–
1.13–1.18 (m, 3H, N–CH3-400),
0.73–
5.58 (m, 1H, CONH-1),
d
d
d
3.30(m, 2H, N–CH2-100),
d
d
d
2.10–2.19
d
d
d
1.90 (m, 4H, N–CH2-300, N–CH2-3%),
d
d
0.78 (m, 3H, N–CH3-4%)
d
d
2H, NH–CH2-100),
1H, HA-3),
CH2–CH-2%),
300, CH3-3%)
d
8.76 (s, 1H, SO2NH),
6.71 (m, 1H, CONH-1),
2.76 (m, 2H, NH–CH2-1%),
1.86 (m, 1H, HB-3),
1.70–1.86 (m, 2H, NH–CH2–CH-200, NH–
0.90–0.92 (d, 6H, CH3-400, CH3-4%),
0.70–0.72 (d, 2H, CH3-
d
7.61–8.42 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.58 (m, 1H, CONH-5), 3.63 (m, 1H, H-2), 3.02 (m,
2.27 (m, 2H, H2-4), 2.04 (m,
d
d
d
d
d
d
d
d
d
3296 (N–H str. of CONH), 3092 (Ar C–H str.), 2962 (ali C–H
str.), 2874 (ali CH str), 1647 (C]O str. of CONH),
1556 (N–H bend of CONH), 1439 (Ar C]C str), 1328 (S]O
str. of SO2NH, asymmetric), 1153 (S]O str. of SO2NH,
symmetric), 909, 762, 682 (Polynuclear Ar.–CH out of plane
bending)
3293 (N–H str. of CONH), 3083 (Ar C–H str.), 2929 (ali C–H
str.), 1647 (C]O str. of CONH), 1550 (N–H bend of CONH),
1442 (Ar C]CH str.), 1323 (S]O str. of SO2NH, asymmetric),
1150 (S]O str. of SO2NH, symmetric), 887, 834, 757, 680
(Polynuclear and mononuclear Ar.–CH out of plane
bending);
8.30 (1H, SO2NH),
6.77 (m, 1H, CONH-1),
d
7.54–7.90 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.57 (m, 1H, CONH-5), 3.64 (m, 1H, H-2), 3.21–
3.03–3.09 (m, 2H, NH–CH2-1%), 2.29 (m, 2H,
1.86–1.91 (m, 1H, HB-3), 0.83–1.63 (m,
d
d
d
d
3.33 (m, 2H, NH–CH2-100),
d
d
H2-4), 1.98–2.00 (m, 1H, HA-3),
22H, CH2-200, CH2-300, CH2-400, CH2-500, CH2-600, CH2-2%, CH2-3%, CH2-4%,
CH2-5%, CH2-6%)
8.72 (s, 1H, SO2NH),
H-80, H-200, H-300, H-400, H-500, H-600),
(m, 1H, CONH-5),
4.04–4.41 (m, 4H, NH–CH2-100, NH–CH2-1%),
1H, H-2), 2.29 (m, 2H, H2-4),
1H, HB-3)
d
d
d
d
7.29–8.35 (m, 11H, H-20, H-30, H-50, H-60, H-70,
6.93 (m, 1H, CONH-1), 5.82
d
d
d
d 3.70 (m,
d 2.03 (m, 1H, HA-3), d 1.77–1.84 (m,
(continued on next page)

Table 7 (continued)
Cpd
Mass (FAB)
IR (KBr, cmꢁ1
)
1H NMR (300MHz, CDCl3))
C, H, N % calcd/found
C
H
N
37
M þ Hþ peak at m/z 414
3473 (Asymmetric N–H str. of CONH2), 3375 (Symmetric N–
H str. of CONH2), 3178 (Ar C–H str.), 2861 (ali C–H str.), 1668
(C]O str. of CONH2), 1500, 1423 (Ar–C]CH str), 1313 (S]O
str of SO2NH, asymmetric), 1137 (S]O str. of SO2NH,
symmetric), 831, 758, 679 (Polynuclear-CH out of plane
bending)
d
d
8.73 (s, 1H, SO2NH),
5.85 (m, 2H, CONH2-1),
2.01 (m, 2H, H2-3), 1.78 (m, 1H, HB-3)
d
7.32–8.23 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.34 (m, 2H, CONH2-5), 3.67 (m, 1H, H-2), 2.27
43.44/43.08
3.86/3.97
10.14/10.35
d
d
d
(m, 2H, H2-4),
d
38
39
M þ Hþ peak at m/z 442
M þ Hþ peak at m/z 470
3315 (NH str. Of CONH), 3107 (Ar. CH Str), 2933 ali C–H str.),
1647 (C]O str. of COOH), 1556 (NH bend of CONH),
1458,1436, 1413 (Ar. C]CH str), 1357 (S]O str. of SO2NH,
asymmetric), 1161 (S]O str. of SO2NH, symmetric), 802,
767, 680 (Polynuclear-CH out of plane bending)
3297 (N–H str. of CONH), 3099 (Ar C–H str.), 2976 (ali C–H
str.), 1643 (C]O str of CONH), 1559 (NH bend of CONH),
1502, 1440 (Ar–C]CH str), 1323 (S]O str. of SO2NH,
asymmetric), 1150 (S]O str. of SO2NH, symmetric), 887,
834, 757, 680 (Polynuclear Ar.–CH out of plane bending),
997 (Ar–Br);
3294 (N–H str of CONH), 3101 (Ar C–H str.), 2960, 2871 (ali
C–H str.), 1645 (C]O str. of CONH), 1558(N–H bend of
CONH), 1436 (Ar C]CH str), 1319 (S]O str of SO2NH,
asymmetric), 1155 (S]O str of SO2NH, symmetric), 800,
767, 680 (Polynuclear-CH out of plane bending)
d
d
8.73 (s, 1H, SO2NH),
6.71 (m, 1H, CONH-1),
d
7.50–8.23 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.61 (m, 1H, CONH-5), 3.61 (m, 1H, H-2), 2.72
2.52 (m, 3H, N–CH3-100),
2.17 (m, 2H, H2-4), 1.87 (m,
46.15/45.98
48.51/48.76
4.52/4.68
5.11/5.34
9.49/9.76
8.94/8.93
d
d
d
(m, 3H, N–CH3-1%),
2H, H2-3)
d
d
d
d
d
8.76 (s, 1H, SO2NH),
6.58 (m, 1H, CONH-1),
2.94 (m, 2H, NH–CH2-1%),
1.77 (m, 1H, HB-3), 1.11–1.63 (m, 1H, CH3-200)
d
7.68–8.40 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
d
5.51 (m, 1H, CONH-5),
d
3.62 (m, 1H, H-2),
d
d
3.24
2.02
(m, 2H, NH–CH2-100),
(m, 1H, HA-3),
(m, 3H, CH3-2%)
d
d 2.23 (m, 2H, H2-4),
d
d 0.80–1.11
40
M þ Hþ peak at m/z 499
d
d
8.75 (s, 1H, SO2NH),
6.61 (m, 1H, CONH-1),
d
7.49–8.23 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.53 (m, 1H, CONH-5), 3.60 (m, 1H, H-2), 3.16–
2.83–2.95 (m, 2H, N–CH2-1%), 2.04 (m, 1H, HA-
1.45–1.55 (m, 2H, N–CH2-200),
50.56/50.55
5.62/5.38
8.43/8.45
d
d
d
3.20(m, 2H, N–CH2-100,),
d
d
3), 1.78 (m, 1H, HB-3),
N–CH2-2%),
CH2-3%)
d
d
d
1.24–1.12 (m, 2H,
d
0.96–0.91 (m, 3H, 3H, N–CH2-300),
d
0.68–0.73 (m, 3H, 3H, N–
41
42
M þ Hþ peak at m/z 555
M þ Hþ peak at m/z 595
3310, 3238 (N–H str of CONH), 3097 (Ar C–H str.), 2929,
2859 (ali C–H str.), 1642 (C]O str. of CONH), 1554 (N–H
bend of CONH), 1438 (Ar C]CH str), 1341 (S]O str of
SO2NH, asymmetric), 1159 (S]O str of SO2NH, symmetric),
835, 762, 679 (Polynuclear-CH out of plane bending)
3293 (N–H str. of CONH), 3083 (Ar C–H str.), 2929 (ali C–H
str.), 1647 (C]O str. of CONH), 1550 (N–H bend of CONH),
1442 (Ar C]CH str.), 1323 (S]O str. of SO2NH, asymmetric),
1150 (S]O str. of SO2NH, symmetric), 887, 834, 757, 680
(Polynuclear and mononuclear Ar.–CH out of plane
bending).
d
8.73 (s, 1H, SO2NH),
5.85 (m, 1H, CONH2-1),
d
7.32–8.23 (m, 6H, H-20, H-30, H-60, H-70, H-80, H-90),
5.34 (m, 1H, CONH-5), 3.67 (m, 1H, H-2), 3.68
2.27 (m, 2H, H2-4), 2.01 (m,
54.10/54.65
58.53/58.67
4.71/4.72
4.71/4.87
7.57/7.76
7.06/7.32
d
d
d
d
(m, 2H, N–CH2-100),
d
(m, 2H, N–CH2-100), 3.13
d
d
2H, H2-3), 1.78 (m, 1H, HB-3), 1.56–1.29 (m, 12H, CH2-200, CH2-300, CH2-400,
CH2-2%, CH2-3%, CH2-4%), 0.97–0.74 (m, 6H, CH3-500, CH3-5%)
d
8.72 (s, 1H, SO2NH),
H-200, H-300, H-400, H-500, H-600),
5),
4.04–4.41 (m, 4H, NH–CH2-100, NH–CH2-1%),
(m, 2H, H2-4), 2.03 (m, 1H, HA-3), 1.77–1.84 (m, 1H, HB-3)
d
7.29–8.35 (m, 11H, H-20, H-30, H-60, H-70, H-80, H-90,
d
6.93 (m, 1H, CONH-1),
d 5.82 (m, 1H, CONH-
d
d
3.70 (m, 1H, H-2), 2.29
d
d
43
44
45
M þ Hþ peak at m/z 546
M þ Hþ peak at m/z 529
M þ Hþ peak at m/z 533
3294 (N–H str. of CONH), 3092 (Ar C–H str.), 2955, 2870 (ali
C–H str.), 1650 (C]O str. of CONH), 1552 (N–H bend of
CONH), 1458 (Ar C]CH str.), 1331 (S]O str. of SO2NH,
asymmetric), 1094, 1062 (C–O str. of C–OCH3), 819, 752, 641
(Polynuclear Ar.–CH out of plane bending).
3306, 3239 (N–H str. of CONH), 3074 (Ar C–H str.), 2929 (ali
C–H str.), 1649 (C]O str of CONH), 1545 (NH bend of
CONH), 1443 (Ar–C]CH str.), 1378 (S]O str. of SO2NH,
asymmetric), 1150 (S]O str. of SO2NH, symmetric), 1073
(C–O str. of C–OCH3), 804
3307, 3238 (N–H str. of CONH), 3074 (Ar C–H str.), 2929 (ali
C–H str.), 1649 (C]O str of CONH), 1555 (NH bend of
CONH), 1448 (Ar–C]CH str.), 1323 (S]O str. of SO2NH,
asymmetric), 1159 (S]O str. of SO2NH, symmetric), 1073
(C–O str. of C–OCH3), 809, 690 (Polynuclear Ar.–CH out of
plane bending).
d
8.72 (s, 1H, SO2NH),
H-200, H-300, H-400, H-500, H-600),
5),
4.18–4.41 (m, 4H, NH–CH2-100, NH–CH2-1%),
d
7.29–8.35 (m, 11H, H-30, H-40, H-60, H-70, H-80, H-90,
6.93 (m, 1H, CONH-1), 5.82 (m, 1H, CONH-
4.05 (s, 3H, OCH3), 3.70
2.03 (m, 1H, HA-3), 1.77–1.84 (m, 1H, HB-
65.97/65.65
63.52/60.01
62.92/59.36
5.86/5.76
7.37/6.93
7.58/7.41
7.70/7.87
7.94/7.69
7.87/6.75
d
d
d
d
d
(m, 1H, H-2), 2.29 (m, 2H, H2-4),
3)
d
d
d
d
8.73 (s, 1H, SO2NH),
5.85 (m, 1H, CONH2-1),
2.27 (m, 2H, H2-4),
1.05–1.93 (m, 22H, Cyclohexyl protons).
d
7.32–8.23 (m, 6H, H-30, H-40, H-60, H-70, H-80, H-90),
5.34 (m, 1H, CONH-5), 4.06 (s, 3H, OCH3), 3.67
2.01 (m, 2H, H2-3), 1.78 (m, 1H, HB-3),
d
d
d
(m, 1H, H-2),
d
d
d
d
8.30 (1H, SO2NH),
6.77 (m, 1H, CONH-1),
3.21–3.33 (m, 2H, NH–CH2-100),
2.29 (m, 2H, H2-4), 1.98–2.00 (m, 1H, HA-3),
0.83–1.63 (m, 22H, CH2-200, CH2-300, CH2-400, CH2-500, CH2-600, CH2-2%,
CH2-3%, CH2-4%, CH2-5%, CH2-6%)
d
7.40–7.91 (m, 6H, H-30, H-40, H-60, H-70, H-80, H-90),
5.57 (m, 1H, CONH-5), 4.08 (s, 3H, OCH3), 3.64
3.03–3.09 (m, 2H, NH–CH2-
1.86–1.91 (m, 1H, HB-
d
d
d
d
(m, 1H, H-2),
1%),
3),
d
d
d
d
d
d

A.K. Halder et al. / European Journal of Medicinal Chemistry 45 (2010) 1760–1771
[4] V.S. Klimberg, J.L. McClellan, Am. J. Surg. 172 (1996) 418–424.
1771
0.1 kcal/Å mol. Dragon software [42] was utilized for the calculation
of different topological and constitutional descriptors. The topo-
logical descriptors used are information content index (neighbor-
hood symmetry of 0-order) (IC0), structural information content
(neighborhood symmetry of 0-order) (SIC0), information content
index (neighborhood symmetry of 1-order) (IC1), structural
information content (neighborhood symmetry of 1-order) (SIC1),
information content index (neighborhood symmetry of 2-order)
(IC2), structural information content (neighborhood symmetry of
2-order) (SIC2), information content index (neighborhood
symmetry of 3-order) (IC3), structural information content (neigh-
borhood symmetry of 3-order), (SIC3) information content index
(neighborhood symmetry of 4-order) (IC4), structural information
content (neighborhood symmetry of 4-order) (SIC4), information
content index (neighborhood symmetry of 5-order) (IC5) and
structural information content (neighborhood symmetry of 5-
order) (SIC5) [43–45]. The constitutional descriptors are mean
atomic van der Waals volume scaled on carbon atom (Mv), mean
atomic Sanderson electronegativity scaled on carbon atom (Me),
mean atomic polarizability scaled on carbon atom (Mp), mean
electrotopological state (Ms), rotatable bond fraction (RBF), number
of chlorine atoms (nCl) and number of bromine atom (nBr) [46].
Electronic descriptor Wang-Ford charge was calculated by Chem 3D
Pro package [47]. The general structure of these compounds was
drawn first in Chem draw ultra ver 5.0. It was saved as the template
structure. This template structure was modified to draw all struc-
tures given in the dataset and saved. The numberings of atoms were
done according to that of ETSA and RTSA models. To create 3-D
models, all these structures were transformed to Chem 3D ver 5.0.
Finally the model was cleaned up. Energy minimization was done
under MOPAC module using RHF (restricted Hartee-Fock: closed
shell) wave function. The energy minimized geometry was used to
calculate Wang-Ford charges. Multiple linear regression analysis
was performed by the computer program ‘Multiregress’[48]
developed in our laboratory.
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