QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors of beta-ketoacyl-acyl carrier protein synthase III.

Abstract

Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a attractive target since it is central to the initiation of fatty acid biosynthesis. Quantitative structure-activity relationship (QSAR) studies have been carried out on a series of benzoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity, aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R(1) position of the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S. aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobicity, aromaticity and presence of OH group (on x position of the nucleus) are conducive for the inhibitory activity.

Full text

Page 1

Original article
QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors
of b-ketoacyl-acyl carrier protein synthase III
Satyakam Singha, Love K. Sonia, Manish K. Guptab, Yenamandra S. Prabhakarb,
S.G. Kaskhedikara,*
aMolecular Modelling Study Group, CADD Laboratory, Department of Pharmacy, Shri G.S. Institute of Technology and Science,
23 Park Road, Indore 452 003, Madhya Pradesh, India
bMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, Uttar Pradesh, India
Received 19 December 2006; received in revised form 25 June 2007; accepted 28 June 2007
Available online 10 July 2007
Abstract
Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as at-
tractive targets for the development of new antibacterial agents. FabH, b-ketoacyl-ACP synthase III, is a attractive target since it is central
to the initiation of fatty acid biosynthesis. Quantitative structureeactivity relationship (QSAR) studies have been carried out on a series of ben-
zoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumo-
niae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in
cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity,
aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R1position of
the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S.
aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobocity, aromaticity and presence of OH
group (on x position of the nucleus) are conducive for the inhibitory activity.
? 2007 Elsevier Masson SAS. All rights reserved.
Keywords: QSAR; Benzoylaminobenzoic acid derivatives; b-Ketoacyl-acyl carrier protein synthase III inhibitors; HanscheFree-Wilson mixed approach
1. Introduction
The emergence of resistance in most of the pathogenic bac-
teria to the currently available antibacterial agents is the major
problem in the treatment of serious bacterial infections caused
by these organisms. These resistant strains curtail the life span
of the drug. Therefore, in recent years, the research has been
focused toward development of new antibacterial agents,
which may act through novel target, surpassing the problem
of acquired resistance. Fatty acid biosynthesis (FabH) is an es-
sential pathway for survival of prokaryotes [1]. The b-ke-
toacyl-acyl carrier protein (ACP) synthase III is a bacterial
condensing enzyme in Gram-positive and Gram-negative
bacteria that initiates the fatty acid biosynthesis (FAB) cycle
by catalyzing the first condensation step between acetyl
Co-A and malonyl-ACP [2] (Fig. 1). Large multifunctional
proteins termed type I fatty acid synthases catalyze these
essential reactions in eukaryotes [3]. In contrast, bacteria use
multiple enzymes to accomplish the same goal and are re-
ferred to as type II, or dissociated, fatty acid synthases [4].
Some benzoylaminobenzoic acid derivatives are reported as
inhibitors of b-ketoacyl-ACP synthase III. Previously this
enzyme is targeted by some synthetic derivatives like triclosan,
isoniazid and diazoborines, and some natural products like
cerulenin and thiolactomycin. These agents have various
shortcomings and limited to use [5] in comparison to the
benzoylaminobenzoic acid analogues.
Various sets of compounds were screened in enzymatic as-
says to generate leads that were co-crystallized with various
* Corresponding author. Tel./fax: þ91 0731 2546031.
E-mail address: sgkaskhedikar@rediffmail.com (S.G. Kaskhedikar).
0223-5234/$ - see front matter ? 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.06.018
Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1071e1080
http://www.elsevier.com/locate/ejmech

Page 2

pathogenic FabH proteins and subsequently optimized using
structure guided drug design methods [6e8]. Compound selec-
tionproceeded viasearchesofsubstructure; the pharmacophore
models describe specific areas for desired proteineligand inter-
action and limit the molecular volume to be appropriate for the
FabH active site [9]. This benzoylaminobenzoic acid as a lead
was obtained using structure-based drug design approach
[10]. Forty-six compounds were screened with this lead and
quantitative structureeactivity relationship (QSAR) studies
havebeenperformedtowardthisend.Thequantitativestructure
activity data are guiding further modifications of the current se-
ries [10] with the hopes of improving both enzymatic inhibition
and physical properties.
2. Experimental
The QSAR study on benzoylaminobenzoic acid derivatives
as b-ketoacyl-ACP synthase III inhibitors has been carried out
employing Hansch and Free-Wilson approach. The fatty acid
biosynthetic (FabH) inhibitory activities of the compounds
were taken as dependent parameter and different physico-
chemical properties as independent parameter. The biological
activity data (IC50in mm) for these b-ketoacyl-ACP synthase
III inhibitor derivatives, taken from literature [10], were con-
verted to negative logarithmic dose (?log IC50) in mole
(Fig. 2 and Table 1) to reduce skewness of data set for
QSAR studies. The values for physicochemical properties
viz. steric (molar refractivity or MR), hydrogen acceptor
(HA), hydrogen donor (HD), hydrophobic (p) and electronic
(field effect or F, resonance effect or R, sigma or s), were cal-
culated and/or computed from literature values [11e14]. The
list of various indicator variables employed for QSAR studies
is defined in Table 2. The calculated values of physicochemi-
cal parameters and different indicator variables are given in
Table 3. Some of the compounds reported in the original series
were excluded in the present study because of their nonspecific
quantitative activity data or presence of uncommon structural
feature.
The structure database of the compounds under study
(Fig. 2 and Table 1) has been generated in ChemDraw [15]
using the standard procedure. Dragon software [16] has been
used for the computation of different topological parameters
of this structure database. It offered 224 topological descrip-
tors for these molecules. As the number of topological descrip-
tors in the study is large, the model development involving
these variables is carried out in combinatorial protocol-multi-
ple linear regression (CP-MLR). The CP-MLR is a ‘filter’
based variable selection procedure for model development in
QSAR studies [17e25]. The procedure involves a combinato-
rial strategy with appropriately placed ‘filters’ interfaced with
MLR and extracts diverse models having unique combination
of descriptors from the data set. The filters set the thresholds
for the descriptors in terms of inter-parameter correlation cut-
off limits in subset regressions (filter-1), t-values of the regres-
sion coefficients (filter-2), internal explanatory power (filter-3;
square-root of adjusted multiple correlation coefficient of
regression equation, r-bar) and the external consistency (fil-
ter-4; q2i.e. cross-validated r2from the leave-one-out proce-
dure). Throughout this study, for the filter-1, -2, and -4 the
thresholds were assigned as 0.30, 2.0, and 0.3 ? q2? 1.0,
respectively, and for the filter-3 it was assigned as an initial
value of 0.71. In order to collect the descriptors with higher
information content, the threshold of filter-3 was successively
incremented with increasing number of descriptors (per equa-
tion) by considering the r-bar value of the preceding optimum
model as the new threshold for next generation. Further, any
chance correlations emerging from the study have been ruled
out in randomization test [19,25] by exploring correlations
with repeated randomization of the biological response.
Thecorrelationandregressionanalyseswereperformedusing
SYSTAT version 7.0.1. [26] and in-house program VALSTAT
[27]. The dataweretransferred tothe statistical program in order
to establish a correlation between physicochemical parameters
and?log IC50.Theequationswereselectedonthebasisofstatis-
tically significance i.e. the observed squared correlation coeffi-
cient (r2), the standard error of estimate (s), the sequential
Fischer test (F), the inter-correlation among the parameter
(ICAP), the cross-validated squared correlation coefficient using
leave-one-outprocedure(q2),predictedsquaredcorrelationcoef-
ficient(r2
pred)andthechancestatistics(evaluatedastheratioofthe
equivalent regression equations to the total number of random-
ized sets; a chance value of 0.001 corresponds to 0.1% chance
of fortuitous correlation).
3. Results and discussion
Initially the QSAR studies were performed on different
subsets of series, which were divided on the basis of substitu-
ents. Subsequently, the different subsets were combined in
a single set of series, to establish the correlation between the
biological activity of series and different physicochemical
properties. The Pearson inter-correlation matrix among the
physicochemical parameters for all the compounds has been
shown in Table 4. Several significant equations obtained for
different subsets and set of series have been given in Table 5
and the statistics of the significant QSAR equation has been
shown in Table 6.
H
N
COOH
R1
R2
O
x
y
(CH2)n
R
z
A
B
Fig. 2. Benzoylaminobenzoic acid derivatives as inhibitors of FabH and anti-
bacterial agents.
CoA
O
HO
ACP
OO
ACP
OO
FabH
CoA
Fig. 1. FabH-catalyzed initiation reaction of fatty acid biosynthesis.
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S. Singh et al. / European Journal of Medicinal Chemistry 43 (2008) 1071e1080

Page 3

Table 1
Structure and activity of benzoylaminobenzoic acid derivatives as inhibitors of FabH and antibacterial agents
H
N
COOH
R1
R2
O
x
y
(CH2)n
R
z
A
B
Compd no.
n
xyzR1
R2
?log IC50
3.796
5.796
5.796
4.943
5.076
5.658
5.215
5.678
5.569
5.420
5.959
3.733
4.602
4.420
5.495
5.921
6.538
6.569
4.658
6.959
7.252
7.018
6.795
5.678
6.387
6.657
7.552
6.102
6.328
6.619
6.244
6.481
6.602
6.795
4.996
4.367
3.538
e
5.222
6.387
5.000
5.432
5.357
5.301
7.207
8.398
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38b
39
40
41
42
43
44
45
46
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
2
2
2
2
2
2
2
2
2
2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
S
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
S
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH3
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
H
e
H
e
e
F
OH
H
H
H
H
OH
OH
Br
Br
Ph
OMe
F
Piperidinyl
Phenoxy
OCH2-cyclopentane
H
F
Br
Piperizinyl-1
4-Methyl piperazinyl-1
3,5-Dimethyl-piperazinyl-1
N-Morpholine
N-Thiomorpholine
Piperidinyl-1
3,5-Dimethylpiperidinyl-1
4-Pyrazolyle
3-Pyridyle
Phenyl
4-CF3-phenyl
4-Methylphenyl
4-Carboxyphenyl
4-Hydroxyphenyl
4-Ethoxyphenyl
4-SO2Me-phenyl
3-Isopropylphenyl
3-OCF3-phenyl
4-F-3-CH3-phenyl
3-Cl-4-F-phenyl
3,4-Difluorophenyl
3-Me-4-Cl-phenyl
2,4-Diflurophenyl
H
H
H
H
H
H
H
H
H
H
Br
Ph
SO2N(C2H5)2
SO2N(C2H5)2
SO2N(C2H5)2
SO2N(C2H5)2
SO2N(C2H5)2
SO2N(C2H5)2
SO2N(C2H5)2
SO2N(C2H5)2
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Phenoxy
Pyridoxy
O-m-Benzoic acid
O-p-Benzoic acid
O-p-Fluorophenyl
Phenoxy
Phenoxy
R1denotes various substitution parts, z substitution does not take the part of group because the biological activity analysis not represent the good result so we have
omitted one compound noted as first of this part, and R2substitution is done initially by the N,N-diethyl sulphonamide and then by the phenoxy group.
aCompound not included in study.
bNot included in study due to the fact that the compound does not have significant biological activity. A-Part represents the substitution with the five- or
six-membered aromatic, or heteroaromatic ring system.
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S. Singh et al. / European Journal of Medicinal Chemistry 43 (2008) 1071e1080

Page 4

3.1. Study of compd nos. 2e21
First the correlation was sought between the first set of
compound i.e. for the compd nos. 2e21, when the A ring is
aromatic and is constant for these compounds, QSAR study re-
sulted in Eqs. (1) and (2):
?logIC50¼5:679ð?0:307Þ?1:326ð?0:633ÞIN4
þ0:988ð?0:709ÞIarom
n¼20;r¼0:822;r2¼0:676;s¼0:522;
F¼17:76;q2¼0:508;Spress¼0:644;
SDEP¼0:593;ICAP¼0:210;Chance?0:001
ð1Þ
?logIC50¼5:492ð?0:463Þ?1:217ð?0:662ÞIN4
þ0:956ð?0:709ÞIaromþ0:164ð?0:305Þp
n¼20;r¼0:837;r2¼0:701;s¼0:518;F¼12:50;
q2¼0:437;Spress¼0:710;SDEP¼0:635;
ICAP¼0:328;Chance?0:001
Eqs. (1) and (2) describe the good correlation coefficient value
r ¼ 0.822 and 0.837, respectively, of high statistical signifi-
cance (>99.99%). Eqs. (1) and (2) correlate the FabH enzyme
ð2Þ
inhibitoryactivityofbenzoylaminobenzoicacidderivativeswith
indicator variable IN4which denotes the presence of nitrogen
atomat4thpositioninthering(aromatic/aliphaticring)atR1sub-
stituents (Fig. 2). The negative sign in IN4indicates that nitrogen
atom in ring is not favorable for activity. Positive Iaromindicates
thepreferenceofaromaticringforbetterenzymeinhibitoryactiv-
ity. Eq. (2) correlates FabH inhibitory activity with IN4and two
additional parameters IHETEROand p (hydrophobocity). IHETERO
standsforthepresenceofaheteroatom(O,S,N)at4thpositionof
a six membered ring at R1. Its negative sign shows that hetero-
atom at this position is unfavorable for activity.
The positive sign of p shows that hydrophobicity is an im-
portant physicochemical property of these analogues for better
enzyme inhibitory activity. Hydrophobic substituents at R1po-
sition may involve in hydrophobic interaction with the en-
zyme, which results in better enzymeeinhibitor association.
The presence of heteroatom like nitrogen or oxygen in ring
at R1position may decrease the hydrophobicity. As a whole
Eqs. (1) and (2) indicate the preference of hydrophobic
atom/group at R1position.
3.2. Study of compd nos. 9e34
The correlation for the second set of compound (compd
nos. 9e34) resulted in Eqs. (3) and (4). In these compounds
diethylsulphonamide group has been replaced by phenoxy
group at R2position.
?logIC50¼5:924ð?0:175Þ?1:571ð?0:291ÞIN4
þ0:707ð?0:213ÞIarom
n¼26;r¼0:878;r2¼0:771;s¼0:464;
F¼38:636;q2¼0:707;Spress¼0:524;
SDEP¼0:493;ICAP¼0:497;Chance?0:001
ð3Þ
?logIC50¼5:725ð?0:264Þ?1:687ð?0:312ÞIN4
þ0:011ð?0:011ÞMRþ0:560ð?0:56ÞIarom
n¼26;r¼0:884;r2¼0:781;s¼0:475;
F¼26:129;q2¼0:698;Spress¼0:544;
SDEP¼0:500;ICAP¼0:497;Chance?0:001
Further data set was divided into a training set of 21 com-
pounds and a test set of 5 compounds (compd nos. 10, 11, 14,
23, 24) to ensure the robustness of the equation (Eq. (4a)) us-
ing the external cross-validation method.
ð4Þ
?log IC50¼ 5:848ð?0:869Þ?2:110ð?0:674ÞIN4
þ0:020ð?0:029ÞMRþ0:290ð?0:496ÞIarom
n ¼ 21; r ¼ 0:867; r2¼ 0:752; s ¼ 0:505;
F ¼ 17:163; q2¼ 0:576; Spress¼ 0:660;
SDEP¼ 0:594; ICAP ¼ 0:493; Chance ? 0:001;
r2
pred¼ 0:505
ð4aÞ
Table 2
Indicator variables used in the present study and their definitions
Indicator Variable Definition
In
Indicator variable having value 1 if n¼ 2 of the aryl
nucleus, value 0 if n ¼1, present at the same position
which means A ring is either pentacyclic aromatic
carboxylic acid or hexa cyclic aromatic carboxylic acid
Indicator variable having value 1 if heteroatom is
present at x position of the aryl nucleus, value 0 if
carbon is attached at the same position in A ring
Indicator variable having value 1 if electronegative
atom is present at R on substitution position (x) of the
aryl nucleus A, value 0 if R is absent at the same
position in A ring
Indicator variable having value 1 if electronegative
atom at R is specially the OH group at substitution
position (x) of the aryl nucleus, value 0 if OH is absent
at the same position in A ring
Indicator variable having value 1 if heteroatom is
present at y position of the aryl nucleus, value 0 if
carbon is attached at the same position in A ring
Indicator variable having value 1 if phenyl is present
at R1position of the benzene (B) nucleus, value 0 if
hydrogen is attached at the same position
Indicator variable having value 1 if any electronegative
group is present at 4th position in phenyl ring of R1
substitution present at the benzene B nucleus, value 0
if carbon is attached at the same position
Indicator variable having value 1 if nitrogen is present at 4th
position in aryl ring of the R1substitution of the benzene B
nucleus, value 0 if carbon is attached at the same position
Indicator variable having value 1 if the carbon with any
substitution is present at 4th position in Ring R1, value 0
if carbon without any substitution is present at the
same position
Ix
Ix-R
Ix-OH
Iy
Iarom
IHETERO
IN4
IpC
1074
S. Singh et al. / European Journal of Medicinal Chemistry 43 (2008) 1071e1080

Page 5

Eqs. (3)e(4a) share the IN4and Iaromdescriptors with Eqs. (1)
and (2) with similar sign. These descriptors indicate that activ-
ity decreases with the presence of heteroatom and aliphatic
groups at R1(Fig. 2). The positive coefficient of MR shows
that the molar refractivity/bulkiness is an important physico-
chemical property for R1substitution. Here hydrophobicity
and MR are intercorrelated with 0.607. It indicates that
hydrophobic bulky groups may be important substituents for
better activity.
3.3. Study of compd nos. 9e46
In next step the study has been carried out with 37 com-
pounds together from compd nos. 9e46.
Table 3
Descriptors and their values used in the study
Compd no.
pb
MRc
IN4
Iarom
IHETERO
IpCsub
Ix
Iy
Ix-R
Ix-OH
?log IC50d
Obsd.Eq. (10)Eq. (11)
Calc. VelstatLoo predCalc. VelstatLoo pred
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38e
39
40
41
42
43
44
45
46
eee
0
0
0
0
0
0
0
0
0
0
1
1
1
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
e
0
0
0
0
0
0
0
0
e
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
e
0
0
0
0
0
0
0
1
e
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
e
0
0
0
0
0
0
0
0
e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
0
0
1
1
1
1
1
0
0
0
e
0
0
0
0
0
0
0
0
e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
1
e
0
0
0
0
0
0
0
0
e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
e
0
0
0
0
0
0
0
0
e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
e
1
1
0
0
0
0
1
1
e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
e
0
1
0
0
0
0
1
1
e
5.796
5.796
4.943
5.076
5.658
5.215
5.678
5.569
5.42
5.959
3.733
4.602
4.42
5.495
5.921
6.538
6.569
4.657
6.959
7.25
7.018
6.8
5.68
6.39
6.66
7.55
6.1
6.32
6.62
6.244
6.481
6.602
6.8
4.996
4.367
3.538
e
5.222
6.387
5.000
5.432
5.357
5.301
7.208
8.398
e
5.212
6.588
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
5.212
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
6.588
5.212
5.212
5.212
e
5.212
6.872
5.212
5.212
5.212
5.212
6.872
8.248
e
5.188
6.639
5.223
5.218
5.194
5.212
5.193
5.198
5.204
5.182
5.272
5.237
5.244
5.201
5.183
5.158
5.157
5.235
6.565
6.546
6.561
6.575
6.646
6.601
6.584
6.527
6.619
6.605
6.586
6.610
6.595
6.587
6.575
5.221
5.246
5.280
e
5.212
7.126
5.221
5.203
5.206
5.208
6.696
8.158
e
5.371
6.595
5.371
5.371
5.371
5.371
5.371
5.371
5.371
5.371
4.353
4.353
4.353
5.371
5.371
5.371
5.371
4.353
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
6.595
5.371
5.371
5.371
e
5.371
6.923
5.371
5.371
5.371
5.371
6.923
8.147
e
5.351
6.646
5.392
5.386
5.357
5.379
5.357
5.362
5.369
5.343
4.560
4.270
4.331
5.365
5.345
5.315
5.313
4.252
6.572
6.553
6.568
6.582
6.654
6.608
6.591
6.534
6.627
6.613
6.593
6.618
6.602
6.595
6.582
5.390
5.420
5.460
e
5.379
7.205
5.389
5.368
5.372
5.375
6.773
7.994
0.86
2.13
0.39
0.60
1.92
2.08
2.29
0.00
0.14
0.86
?0.018
0.864
1.172
0.31
0.928
1.69
2.75
?0.12
0.20
1.67
2.55
2.33
1.41
1.00
2.14
0.04
2.44
2.35
2.47
2.52
1.95
3.04
1.95
2.08
2.08
2.08
e
2.08
2.08
0.38
2.05
2.05
2.22
2.08
2.08
8.88
25.36
7.87
0.92
24.26
27.68
28.46
1.03
0.92
8.88
26.33
30.95
35.57
23.76
30.13
24.26
33.5
17.49
20.28
25.36
29.35
29.98
31.26
27.18
36.8
37.82
39.29
32.19
29.87
30.25
25.14
34.98
25.14
27.68
27.68
27.68
e
27.68
27.68
26.95
34.61
34.61
28.6
27.68
27.68
aCompound not included in the study.
bHydrophobicity.
cMolar refractivity.
dObserved and calculated enzyme inhibitory activity.
eNot included in the study as the compound does not have significant biological activity.
1075
S. Singh et al. / European Journal of Medicinal Chemistry 43 (2008) 1071e1080

Page 6

?logIC50¼5:158ð?0:309Þþ1:478ð?0:456ÞIarom
þ1:679ð?0:827ÞIx-OH
n¼37;r¼0:792;r2¼0:628;s¼0:674;
F¼26:769;q2¼0:0:575;Spress¼0:721;
SDEP¼0:691;ICAP¼0:059;Chance?0:001
?logIC50¼5:364ð?0:313Þ?1:011ð?0:693ÞIN4
þ1:281ð?0:433ÞIaromþ1:539ð?0:753ÞIx-OH
n¼37; r¼0:840; r2¼0:706; s¼0:607;
F¼26:536; q2¼0:645; Spress¼0:668;
SDEP¼0:631; ICAP¼0:303; Chance?0:001
Eqs. (5) and (6) correlate the activity with Iaromand Ix-OH. The
positive sign in Iaromindicates that aromatic substituents should
bepreferredoveraliphaticones.Ix-OHshowsthathydroxylgroup
atthispositionisfavorableforbetterenzymeinhibitoryactivity.
IN4denotes the presence of N atom in the ring (aromatic/ali-
phatic ring) at R1substituents (Fig. 2). The negative sign in IN4
indicates that nitrogen atom in ring is not favorable for activity.
ð5Þ
ð6Þ
3.4. Study of compd nos. 21e46
Eqs. (7) and (8) resulted from the QSAR study of fourth set
of compound (compd nos. 21e46)
?logIC50¼4:9:9ð?0:375Þþ1:694ð?0:460ÞIarom
þ1:856ð?0:693ÞIx-OH
n¼25; r¼0:880; r2¼0:774; s¼0:530;
F¼37:771; q2¼0:711; Spress¼0:600;
SDEP¼0:563; ICAP¼0:201; Chance?0:001
ð7Þ
?logIC50¼5:218??0:370?þ1:404??0:426?Iarom
?1:368??0:620?Iyþ1:576??0:516?Ix-R
n¼25;r¼0:926;r2¼0:858;s¼0:430;
F¼42:380;q2¼0:799;Spress¼0:512;
SDEP¼0:469;ICAP¼0:452;Chance?0:001
ð8Þ
Table 4
Pearson inter-correlation matrix among the physicochemical parameters of benzoylaminobenzoic acid derivatives for compounds 2e46
p
MR
IN4
Iarom
IHETERO
In
Ix
Ix-R
Iy
Ix-OH
p
MR
IN4
Iarom
IHETERO
In
Ix
Ix-R
Iy
Ix-OH
1.00
0.580
?0.383
0.313
?0.460
?0.131
0.131
0.162
0.189
0.162
1.00
0.064
0.353
0.071
?0.046
0.046
0.057
0.067
0.057
1.00
?0.251
0.796
0.069
?0.069
?0.086
?0.100
?0.086
1.00
?0.315
?0.173
?0.173
?0.215
?0.089
?0.029
1.000
0.087
?0.087
?0.107
?0.126
?0.107
1.00
?0.476
?0.374
0.069
0.059
1.00
0.374
?0.069
?0.059
1.00
0.228
0.855
1.00
?0.073 1.00
Table 5
Statistically significant QSAR models of benzoylaminobenzoic acid derivatives with their FabH inhibitory activity
Eq. No.Equations
Compd nos. 2e21
1
2
Compd nos. 9e34
3
4
4a
Compd nos. 9e46
5
6
Compd nos. 21e46
7
8
Compd nos. 9, 35e46
9
Compd nos. 2e46
10
11
12
13
14
15
?log IC50¼ 5.679(?0.307)?1.326(?0.633)IN4þ0.988(?0.709)Iarom
?log IC50¼ 5.492(?0.463)?1.217(?0.662)IN4þ0.956(?0.709)Iaromþ0.164(?0.305)p
?log IC50¼ 5.924(?0.175)?1.571(?0.291)IN4þ0.707(?0.213)Iarom
?log IC50¼ 5.725(?0.264)?1.687(?0.312)IN4þ0.011(?0.011)MRþ0.560(?0.56)Iarom
?log IC50¼ 5.848(?0.869)?2.110(?0.674)IN4þ0.020(?0.029)MRþ0.290(?0.496)Iarom
?log IC50¼ 5.158(?0.309)þ1.478(?0.456)Iaromþ1.679(?0.827)Ix-OH
?log IC50¼ 5.36(?0.313)?1.01(?0.693)IN4þ1.28(?0.433)Iaromþ1.53(?0.753)Ix-OH
?log IC50¼ 4.909(?0.375)þ1.694(?0.460)Iaromþ1.856(?0.693)Ix-OH
?log IC50¼ 5.218(?0.37)þ1.404(?0.42)Iarom?1.368(?0.62)Iyþ1.576(? 0.51)Ix-R
?log IC50¼ 5.275(?0.606447) þ2.05517(?1.05)Ix?0.900167(?1.0504)Ix-OH
?log IC50¼ 5.212(?0.127)þ1.376(?0.200)Iaromþ1.660(?0.386)Ix-OH
?log IC50¼ 5.371(?0.125)?1.018(?0.316)IN4þ1.224(?0.186)Iaromþ1.552(?0.350)Ix-OH
?log IC50¼ 5.532(?0.118)?1.179(?0.280)IN4þ1.070(?0.168)Iaromþ1.443(?0.307)Ix-OH?1.156(?0.316)Iy
?log IC50¼ 5.577(?0.114)?1.224(?0.267)IN4þ1.026(?0.161)Iaromþ1.412(?0.293)Ix-OH?0.851(?0.381)Ix?0.918(?0.319)Iy
?log IC50¼ 1.248(?0.924)þ0.383(?0.065)X1sol?0.029(?0.004)T (N/O)
?log IC50¼ 3.987(?0.254)þ0.013(?0.002)MPC10?1.896(?0.277)IN4þ1.786(?0.315)Ix-OH
1076
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Page 7

Eqs. (7) and (8) correlate the activity with Iarom, Ix-OHand Ix-R.
The positive sign in Iaromindicates that aromatic substituents
should be preferred over aliphatic ones. Ix-OHand Ix-Rshow
that hydroxyl group at this position is favorable for better en-
zyme inhibitory activity.
Iyparameter indicates the presence of a heteroatom in place
of carbon at y positions (Fig. 2). The negative sign associated
with this indicator parameter shows that heterocyclic ring sys-
tem at this position is unfavorable for activity.
3.5. Study of compd nos. 9, 35e46
The study of the fifth set (compd nos. 9, 35e46) resulted in
Eq. (9):
?logIC50¼5:275ð?0:606447Þþ2:05517ð?1:0504ÞIx
?0:900167ð?1:0504ÞIx-OH
n¼12;r¼0:889;r2¼0:790;s¼0:644;
F¼16:99;q2¼0:541;Spress¼0:953;
SDEP¼0:825;ICAP¼0:333;Chance?0:001
ð9Þ
Eq. (9) shows the correlation of activity for these compounds
with dummy parameters Ix-OHand Ix. Ixindicates the presence
of a heteroatom in place of carbon at x positions (Fig. 2). Ix-OH
is an indicator parameter for the presence of hydroxyl group
attached at x; the negative sign associated with these indicator
parameters shows that heterocyclic ring system is unfavorable
for activity. The positive sign of this parameter shows that at
this position it favors for better enzyme inhibitory activity.
3.6. Study of compd nos. 2e46
Finally all the compounds were taken together in a single
set and the correlation was established to observe the effect
of physicochemical properties on the biological activity.
?logIC50¼5:212ð?0:127Þþ1:376ð?0:200ÞIarom
þ1:660ð?0:386ÞIx-OH
n¼44;r¼0:782;r2¼0:611;s¼0:644;
F¼32:191;q2¼0:563;Spress¼0:682;SDEP¼0:658;
ICAP¼0:029;Chance?0:001
ð10Þ
?logIC50¼5:371ð?0:125Þ?1:018ð?0:316ÞIN4
þ1:224ð?0:186ÞIaromþ1:552ð?0:350ÞIx-OH
n¼44;r¼0:831;r2¼0:691;s¼0:581;
F¼29:811;q2¼0:636;Spress¼0:630;
SDEP¼0:601;ICAP¼0:250;Chance?0:001
?logIC50¼5:532??0:118??1:018??0:316?IN4
?1:156??0:316?Iy
n¼44;r¼0:877;r2¼0:770;s¼0:508;
F¼32:618;q2¼0:681;Spress¼0:597;SDEP¼0:562;
ICAP¼0:250;Chance?0:001
?logIC50¼5:577??0:114??1:224??0:267?IN4
?0:851??0:381?Ix?0:918??0:319?Iy
n¼44;r¼0:893;r2¼0:797;s¼0:484;
F¼29:764;q2¼0:713;Spress¼0:574;SDEP¼0:534;
ICAP¼0:373;Chance?0:001
ð11Þ
þ1:070??0:168?Iaromþ1:443??0:307?Ix-OH
ð12Þ
þ1:026??0:161?Iaromþ1:412??0:293?Ix-OH
ð13Þ
Eq. (10) correlates the activity with Iaromand Ix-OH. Iaromindi-
cates that aromatic substituents should be preferred over ali-
phatic ones. Ix-OHshows that hydroxyl group at this position
Table 6
QSAR statistics of significant equations
Eq. no.
nrr2
sFq2
Spress
SDEP
ICAPChance
1
2
3
4
4a
5
6
7
8
9
10
11
12
13
14
15
20
20
26
26
21
37
37
25
25
12
44
44
44
44
44
44
0.822
0.816
0.878
0.884
0.867
0.792
0.840
0.880
0.926
0.889
0.782
0.831
0.877
0.893
0.769
0.868
0.676
0.666
0.771
0.781
0.752
0.628
0.706
0.774
0.858
0.790
0.611
0.691
0.770
0.797
0.592
0.753
0.522
0.547
0.464
0.475
0.505
0.674
0.607
0.530
0.430
0.644
0.644
0.581
0.508
0.484
0.660
0.520
17.76
10.636
38.636
26.129
17.163
26.769
26.536
37.771
42.380
16.99
32.191
29.811
32.618
29.764
29.752
40.570
0.508
0.437
0.707
0.698
0.567
0.575
0.645
0.711
0.799
0.541
0.563
0.636
0.681
0.713
0.530
0.701
0.6439
0.710
0.524
0.544
0.660
0.721
0.668
0.600
0.512
0.953
0.682
0.630
0.597
0.574
0.707
0.571
0.593
0.635
0.493
0.500
0.594
0.691
0.631
0.563
0.469
0.825
0.658
0.601
0.562
0.534
0.683
0.545
0.210
0.328
0.497
0.498
0.493
0.059
0.303
0.201
0.452
0.333
0.029
0.250
0.250
0.373
0.286
0.168
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
1077
S. Singh et al. / European Journal of Medicinal Chemistry 43 (2008) 1071e1080

Page 8

is favorable for better enzyme inhibitory activity. Eqs. (10),
(11) and (13) have been derived by successive addition of
IN4, Iyand Ixto Eq. (9). IN4denotes the presence of N atom
in the ring (aromatic/aliphatic ring) at R1substituents. The
negative sign in IN4indicates that nitrogen atom in ring is
not favorable for activity. The Ixand Iyparameters indicate
the presence of a heteroatom in place of carbon at x and y po-
sitions, respectively (Fig. 2). The negative sign associated with
these indicator parameters shows that heterocyclic ring system
is unfavorable for activity.
The correlation was also established to observe the effect of
topological parameters on the biological activity. Statistically
significant di- and tri-variant expressions were selected.
?logIC50¼1:248ð?0:924Þþ0:383ð?0:065ÞX1sol
?0:029ð?0:004ÞTðN/OÞ
n¼44;r¼0:769;r2¼0:592;s¼0:660;
F¼29:752;q2¼0:530;Spress¼0:707;
SDEP¼0:683;ICAP¼0:286;Chance?0:001
ð14Þ
?logIC50¼3:987ð?0:254Þþ0:013ð?0:002ÞMPC10
?1:896ð?0:277ÞIN4þ1:786ð?0:315ÞIx-OH
n¼44;r¼0:868;r2¼0:753;s¼0:520;
F¼40:570;q2¼0:701;Spress¼0:571;
SDEP¼0:545;ICAP¼0:168;Chance?0:001
Study suggested that topological parameters alone are not
adequate to explain the activity, therefore indicator variables
were incorporated in equation development. Di-variant expres-
sion (Eq. (14)) solely depends on the topological parameters
and it has explained moderate variance in the activity. Incorpo-
ration of indicator variable(s) causes significant improvement
in the correlation (Eq. (15)). Eq. (14) has also improved signif-
icantly by the addition of indicator parameter Ix-OH(r ¼ 0.846,
Q2¼0.657, F ¼ 33.51). X1soland T (N/O) contributed posi-
tively and negatively to Eq. (14), respectively. X1solis solva-
tion connectivity index and T (N/O), sum of topological
ð15Þ
distances between nitrogen and oxygen, is a simple molecular
descriptor calculated by summing topological distances be-
tween all pairs of nitrogen and oxygen. The negative contribu-
tion of T (N/O) suggests that increase in the topological
distance between nitrogen and oxygen would decrease the en-
zyme inhibitory activity.
Tri-variant expression (Eq. (15)) showed better correlation
coefficient, which explains more than 75% variance in the ac-
tivity. Eq. (15) contributed positively by MPC and indicator
variable Ix-OHwhile another indicator variable IN4contributed
negatively. MPC, molecular path counts, is obtained from H-
depleted molecular graph, based on the graph path, which is
a walk without any repeated vertices or edges. The molecular
path count MPCkof order k is the total number of paths of
length k in the graph. The positive contribution of MPC10sug-
gests that increase in the total number of paths of length 10 is
favorable for better enzyme inhibitory activity.
3.7. Study of benzoylaminobenzoic acid derivatives
against some pathogenic bacteria
In the continuation of the QSAR study, the correlation be-
tween the inhibitory activity in some pathogenic bacteria and
physicochemical parameter has also been established. Eqs.
(18)e(21), shown in Table 7, have been derived with the in
vitro antibacterial activity of 10 most potent compounds. Inter-
estingly p (hydrophobicity) is the common descriptor in all the
equations (Eqs. (16)e(19)) derived with the antibacterial ac-
tivity against Staphylococcus aureus, Streptococcus pneumo-
niae,
Streptococcuspyogenes,
Neisseria meningitidis and Escherichia coli. The statistics for
Eqs. (16)e(19) has been given in Table 8. The value of calcu-
lated and predicted inhibitory activity data has been given in
Table 9.
The coefficient of p in all these equations is in a narrow
range (p¼ 0.239e0.474). It shows that p is the major physi-
cochemical property related to the antibacterial activity. Its
positive sign shows that the antibacterial activity in these an-
alogues will increase with the hydrophobicity. The hydropho-
bicity of compound increases the passage of compound
Enterococcusfaecalis,
Table 7
Statistically significant QSAR models of some benzoylaminobenzoic acid derivatives against some pathogenic bacteria
Eq. No.Equations
16
17
18
19
?log MICS.aureus¼4.415(?0.301)þ 0.323(?0.131)p?0.587(?0.259)Ix-R
?log MICS.pneumoniae¼4.626(?0.342)þ 0.474(?0.149)p?1.109(?0.294)Ix-R
?log MICN.meningitidis¼4.912(?0.300)þ0.265(?0.101)pþ0.477(?0.199)Iarom
?log MICE.coli¼ 4.780(?0.309)þ0.258(?0.104)p þ0.588(?0.205)Iarom
Table 8
QSAR statistics of significant equations
Eq. no.
nrr2
sFq2
Spress
SDEP
ICAPChance
16
17
18
19
10
10
10
10
0.952
0.883
0.776
0.796
0.907
0.779
0.602
0.633
0.134
0.372
0.247
0.254
34.167
12.357
5.296
6. 059
0.629
0.052
0.0028
?0.039
0.267
0.771
0.390
0.428
0.223
0.645
0.327
0.358
0.0171
0.017
0.195
0.195
<0.002
<0.007
<0.019
<0.02
1078
S. Singh et al. / European Journal of Medicinal Chemistry 43 (2008) 1071e1080

Page 9

through the lipid membrane of microbes so that more drugs
are available to the target receptor and shows better activity.
Ix-OHis an indicator parameter for the presence of hydroxyl
group attached at x (N). This hydroxyl group has favorable
interaction with the target enzyme. The positive Ix-OH
shows that hydroxyl group at this position is favorable for bet-
ter activity against given microbes and acts as potent inhibitor
of that enzyme. Also the positive sign in the Iaromindicates
that aromatic substituents should be preferred over aliphatic
ones.
4. Conclusion
The present study provides important structural insights in
designing better inhibitors of b-ketoacyl-acyl carrier protein
synthase III. QSAR study revealed that parameters hydropho-
bicity (p), aromaticity, molar refractivity, and presence of hy-
droxyl group in A ring contribute significantly to inhibitory
activity. The substituents that increase the lipophilicity, aroma-
ticity and molar refractivity at both positions R1and R2will
enhance the inhibitory activity. Whereas the presence of nitro-
gen and any other electronegative substituents at 4th position
in R1ring, and the presence of heteroatom in A ring at x
and y positions is not favorable for inhibitory activity. The pa-
rameter Ix-R, represents the presence of hydroxyl group at po-
sition R, increases the biological activity indicating hydrogen
bond interaction with the receptor. Thus substitution of more
bulky group at R1position and substitution with electronega-
tive group capable of forming hydrogen bond interaction
with receptor at the Ix-Rposition are conducive for the inhibi-
tory activity. The hydrophobic character of compound is also
important for the inhibitory activity.
Acknowledgments
Authors are thankful to the Director, Central Drug Research
Institute, Lucknow and Director, Shri G.S. Institute of Tech-
nology and Science, Indore for providing facilities to complete
this work. The author S.S. is thankful to AICTE, New Delhi,
for providing fellowship. C.D.R.I. communication no.: 7307.
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Table 9
Observed and calculated inhibitory activity data of some selected benzoylaminobenzoic acid derivatives against some given microbes
Compd no.
?log MIC
S. aureusS. pneumoniaeN. meningitidisE. coli
Obsd.Calc.Pred. (Loo)Obsd.Calc.Pred. (Loo)Obsd.Calc.Pred. (Loo)Obsd.Calc.Pred. (Loo)
18
21
22
27
28
30
33
34
45
46
5.252
4.947
5.252
4.347
5.252
5.252
5.252
5.252
4.347
4.658
5.306
4.957
5.242
4.429
5.208
5.216
5.400
5.047
4.502
4.502
5.320
4.959
5.240
4.796
5.199
5.210
5.454
5.017
4.658
4.347
5.553
5.854
6.155
4.347
5.854
6.155
5.553
5.553
4.347
4.658
5.929
5.417
5.834
4.645
5.784
5.796
6.066
5.550
4.502
4.502
6.018
5.337
5.776
5.982
5.771
5.736
6.250
5.550
4.658
4.347
5.553
5.854
5.854
5.252
5.854
6.155
6.155
6.444
5.553
5.854
5.923
5.906
5.986
5.262
5.716
5.956
5.945
5.969
5.932
5.932
5.738
5.828
6.109
5.945
6.070
6.024
6.213
5.829
5.368
5.953
5.252
5.854
6.155
5.252
5.553
6.155
6.155
6.155
5.553
5.854
5.489
5.799
6.025
5.378
5.998
6.005
6.152
5.871
5.316
5.904
5.744
5.789
5.999
5.845
6.078
5.977
6.151
5.830
5.060
5.912
1079
S. Singh et al. / European Journal of Medicinal Chemistry 43 (2008) 1071e1080

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