Synthesis, antimicrobial, and QSAR studies of substituted benzamides

Article abstract of DOI:10.1016/j.bmc.2007.03.074

A series of new substituted benzamides were synthesized and tested in vitro for their antibacterial activity against Gram-positive and Gram-negative bacteria and as well for antifungal activity. The compounds 8i and 9 showed better activity among the different benzamides synthesized. The structural characteristics governing antibacterial activities of substituted benzamides were studied using QSAR methodology. The results showed that the antimicrobial activity could be modeled using the topological descriptors, molecular connectivity indices (²χ^v and ²χ) and Kiers shape index (κα₁). The low residual activity and high cross-validated r² values (r_cv²) observed indicated the predictive ability of the developed QSAR models.

Full text of DOI:10.1016/j.bmc.2007.03.074

Bioorganic & Medicinal Chemistry 15 (2007) 4113–4124
Synthesis, antimicrobial, and QSAR studies of
substituted benzamides
Anil Kumar,a Balasubramanian Narasimhanb and Devinder Kumara,*
aDepartment of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar 125001, India
bDepartment of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar 125001, India
Received 8 February 2007; revised 23 March 2007; accepted 23 March 2007
Available online 30 March 2007
Abstract—A series of new substituted benzamides were synthesized and tested in vitro for their antibacterial activity against Gram-
positive and Gram-negative bacteria and as well for antifungal activity. The compounds 8i and 9 showed better activity among the
different benzamides synthesized. The structural characteristics governing antibacterial activities of substituted benzamides were
studied using QSAR methodology. The results showed that the antimicrobial activity could be modeled using the topological
2
descriptors, molecular connectivity indices (2vv and v) and Kiers shape index (ja1). The low residual activity and high cross-vali-
dated r2 values (rc2vÞ observed indicated the predictive ability of the developed QSAR models.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Cl
Cl
H
Cl
Benzamides are important class of compounds that
show various types of biological activities.1–3 Oxycloza-
nide (Fig. 1) was reported as an antihelmintic agent
effective against Fasciola hepatica for the treatment of li-
ver fluke infection.1 The synthesis of some N-(o-
hydroxyphenyl)benzamides and phenylacetamides as
possible metabolites of antimicrobial active benzoxaz-
oles has been reported.4 There is also a report of biolog-
ical activity of benzamides as potent smooth muscle
relaxant and potassium channel activators.5
N
Cl
O
OH
OH
Cl
Figure 1. Structure of Oxyclozanide.
The success of QSAR approach can be explained by the
insight offered into the structural determination of chem-
ical properties, and the possibility to estimate the proper-
ties of new chemical compounds without the need to
synthesize and test them.11 Recently, we have reported
the development of useful QSAR models for antimicro-
bial activity12–15 and anti-inflammatory activity.16
Quantitative structure–activity relationship (QSAR)
represents an attempt to relate structural descriptors of
molecules with their physicochemical properties and
biological activities. It is widely used for the prediction
of physicochemical properties in chemical, environmen-
tal, and pharmaceutical areas.6,7 The main steps impli-
cated in this method include data collection, molecular
descriptor selection and procurement, correlation model
development, and finally model evaluation. At present,
many types of molecular descriptors have been proposed
to describe the structural features of the molecules.8–10
In view of these observations and in continuation of our
work related to the synthesis of bis(benzoxazole) natural
product UK-1 and its aza-analogs possessing anticancer
activity17 which involves benzamides as intermediate, it
was envisaged in the present investigation to undertake
the synthesis and evaluation of antimicrobial activity
of new substituted benzamides. Further, QSAR studies
were carried out to find out the correlation between anti-
microbial activities of synthesized benzamides with their
physiochemical properties for the first time. Hansch
analysis correlates biological activity values with
electronic, steric, and hydrophobic influences of struc-
tural variance through linear regression analysis.
Keywords: Benzamides; Antimicrobial activity; QSAR; Topological
descriptors.
*
Corresponding author. Tel.: +91 1662 263358; fax: +91 1662
276240; e-mail: dk_ic@yahoo.com
0968-0896/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.03.074

4114
A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
R4
R1
A series of new substituted benzamides (3a, 3b, 7a–i, 8a–
i, 9, 14a–c, 15a–c, 16) were synthesized by the reaction of
substituted anilines with substituted aromatic acids in
good to moderate yields using carbonyldiimidazole
(CDI) in THF in one pot. This method is important be-
cause it does not require the protection and deprotection
of hydroxyl group and conversion of acids to acid chlo-
rides for further reaction in order to obtain benzamides.
R3
R2
HOOC
NH2
OH
NH2
4
HO
6
5
CDI, THF
reflux
CDI, THF
reflux
R4
R1
R4
R3
R2
R3
R2
H
H
N
N
O
The benzamides (3a–e) were prepared by the reaction of
aniline (1) with substituted benzoic acids (2) (Scheme 1),
whereas 7a–i and 8a–i were generated by the reaction of
substituted benzoic acid (4) with 4-aminophenol (5) and
2-aminophenol (6), respectively (Scheme 2). However, 9
(Fig. 2) was prepared from 2-amino-3-carbmethoxyphe-
nol and 2-benzyloxybenzoic acid.17
O
R1
OH
HO
8
7
4a, 7a, 8a; R1, R2, R3, R4 = H
4b, 7b, 8b; R1 = OH, R2, R3, R4 = H
4c, 7c, 8c; R1, R3, R4 = H, R2 = CH3
4d, 7d, 8d; R1, R2, R4 = H, R3 = CH3
4e, 7e, 8e; R1, R3, R4 = H, R2 = Cl
4f, 7f, 8f; R2, R3, R4 = H, R1 = Cl
4g, 7g, 8g; R1, R3, = H, R2, R4 = NO2
Further, reaction of substituted anilines (10) with 2-
hydroxynaphthoic acid (11), 1-hydroxynaphthoic acid
(12), and cinnamic acid (13) resulted in the formation
of 14a–c, 15a–c, and 16, respectively (Scheme 3). The
structure of all the compounds was established by phys-
ical and spectroscopic methods (Table 1).
4h, 7h, 8h; R1 = Cl, R2, R3 = H, R4 = NO2
4i, 7i, 8i; R1 = NO2, R2 = OCH3, R3, R4 = H
Scheme
benzamides.
2. Synthesis
of
N-(2/4-hydroxyphenyl)
substituted
H3COOC
H
N
The substituted benzamides were evaluated for in vitro
antibacterial activity against Gram-positive Staphylo-
coccus aureus [MTCC 2901], Bacillus subtilis[MTCC
2063] and Gram-negative Escherichia coli [MTCC
1652], and in vitro antifungal activity against Aspergillus
ficcum [MTCC 8184] and Aspergillus parasiticus [MTCC
8189]. Double strength nutrient broth-I.P. and Sabou-
raud dextrose broth-I.P.18 were employed for bacterial
and fungal growth, respectively. Minimum inhibitory
concentrations were determined by means of standard
serial dilution19 and the ꢀlog MIC values are presented
in Table 2. All the compounds exhibited appreciable
in vitro activity against the tested strains compared to
reference ciprofloxacin and salicylic acid in case of anti-
bacterial and antifungal activity, respectively.
O
OCH2Ph
OH
Figure 2. Structure of N-(2-carbmethoxy-6-hydroxyphenyl)-2-
benzyloxybenzamide.
H
N
O
R2
R1
16
CDI, THF
reflux
HO
O
13
NH2
R1
The compound 9 showed significant activity against
B. subtilis, E. coli, and A. ficcum and A. parasiticus,
whereas 8i was most effective against S. aureus. Further,
the antibacterial activity of compounds 3a, 7g–i, 8g, 8i,
14a–c, 15b, and 15c was found to be more against B.
subtilis having ꢀlog BS more than 1.20, than the other
synthesized benzamides. Compounds 3a, 3b, 7e–i, 8f,
8g, 8i, 14a, and 15b were found to be more active against
S. aureus having ꢀlog SA more than 1.30, than that of
the other synthesized benzamides. Compounds 3a, 7d,
7g–i, 8c, 8g, 9, and 14a–c were found to be more active
R2
HO
10
HOOC
HOOC
OH
OH
12
CDI, THF
reflux
CDI, THF
reflux
11
HO
H
H
N
N
O
O
R2
R1
R2
R1
14
15
14a-15a; R1, R2 = H
14b-15b, 16; R1 = H, R2 = OH
14c-15c; R1 = OH, R2 = H
R2
R2
R1
H
N
Scheme 3. Synthesis of N-substituted naphthamides and 3-phenyl-
propenoic amide.
NH2
CDI, THF
reflux
+
O
R1
HOOC
3
1
2
against E. coli having ꢀlog EC more than 1.26, than the
other synthesized benzamides. Moreover, the antifungal
activity of compounds 3a, 7e–g, 8e, 8f, 8h, 8i, and 14a–c
was found to be more active against A. ficcum having
2a, 3a; R1 = OCH2Ph, R2 = H
2b, 3b; R1 = Cl, R2 = NO2
Scheme 1. Synthesis of substituted benzamides.

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
Table 1. Physical and spectroscopic data of benzamides
4115
Compound Mp Yield IR (cmꢀ1
)
1H NMR (d)
13C NMR (d)
Analytical data Calcd./
found
(°C) (%)
3a
3b
7a
107 64
133 66
142 40
3336, 1657, 5.17 (s, 2H, OCH2Ph), 7.00–7.02 71.7, 112.5, 119.7, 121.7,
1595, 1537, 1321 (m, 1H), 7.08–7.26 (m, 6H), 7.44– 121.8, 123.7, 128.6, 128.7,
C20H17NO2: C, 79.19; H,
5.65; N, 4.62%
7.51 (m, 6H), 8.32 (dd, J = 8.0,
1.8 Hz, 1H)
129.1, 132.6, 135.1, 138.5,
156.6, 162.9
C, 79.00; H, 5.43; N,
4.51%
3268, 1661,
1595, 1531,
1442, 1353,
1317, 1231
7.15 (t, J = 7.4 Hz, 1H), 7.33– 119.8, 123.9, 124.2, 124.7,
7.37 (m, 3H), 7.62 (d, J = 8.7 Hz, 128.4, 130.6, 137.1, 137.4,
C13H9ClN2O3: C, 56.43;
H, 3.28; N, 10.13%
1H), 7.70 (d, J = 6.9 Hz, 2H),
8.21 (dd, J = 8.7, 2.7 Hz, 1H)
137.8, 145.6, 162.5
C, 56.23; H, 3.02; N,
9.98%
3228, 1684,
1649, 1536,
1512, 1324
6.82 (d, J = 8.6 Hz, 2H), 7.41– 115.0, 122.1, 122.1, 127.1,
7.56 (m, 3H), 7.93 (d, J = 7.2 Hz, 127.8, 129.5, 130.1, 130.8,
C13H11NO2: C, 73.22; H,
5.20; N, 6.57%
2H), 8.04 (d, J = 7.2 Hz, 2H),
9.33 (br s, 1H)
132.2, 134.9, 165.5
C, 73.00; H, 4.97; N,
6.39%
7b
7c
152 50
3484, 3181,
1632, 1577,
1515, 1336, 1232 1H), 8.77 (br s, 1H)
6.83–6.97 (m, 4H), 7.35–7.43 (m, 115.2, 117.5, 118.4, 121.7,
C13H11NO3: C, 68.11; H,
4.84; N, 6.11%
3H), 7.89 (dd, J = 8.0, 1.2 Hz,
123.4, 127.2, 128.7, 135.4,
154.2, 160.3, 167.7
C, 67.91; H, 4.68; N,
6.07%
162 42
3321, 1686, 2.40 (s, 3H, CH3), 6.77 (m, 2H), 115.3, 119.0, 121.5, 122.2,
1588, 1513, 7.33–7.34 (m, 2H), 7.49–7.53 (m, 126.4, 127.8, 128.1, 129.9,
1414, 1311, 1214 2H), 7.72–7.74 (m, 2H), 9.10 (br 130.1, 131.6, 133.0, 137.5,
C14H13NO2: C, 73.99; H,
5.77; N, 6.16%
s, 1H)
168.3
C, 73.74; H, 5.59; N,
6.07%
7d
190 48
3294, 1686,
1590, 1536,
2.42 (s, 3H, CH3), 6.18 (d,
J = 8.8 Hz, 2H), 6.89 (d,
—
C14H13NO2: C, 73.99; H,
5.77; N, 6.16%
1434, 1311, 1215 J = 8.5 Hz, 2H), 6.88 (d,
J = 8.8 Hz, 2H), 7.52 (d,
J = 8.5 Hz, 2H), 9.12 (br s, 1H)
C, 73.79; H, 5.60; N,
5.96%
7e
238 58
3330, 1647,
1517, 1256
6.15 (d, J = 8.8 Hz, 2H), 6.78 (d, 114.8, 122.3, 127.8, 128.8,
C13H10ClNO2: C, 63.04;
H, 4.07; N, 5.66%
J = 8.5 Hz, 2H), 6.87 (d,
J = 8.8 Hz, 2H), 7.30 (d, J
= 8.5 Hz, 2H), 8.30 (br s, 1H),
9.12 (br s, 1H)
130.0, 133.3, 136.5, 153.6,
164.2
C, 62.85; H, 3.98; N,
5.41%
7f
178 61
3270, 1628,
6.80 (d, J = 8.7 Hz, 2H), 7.31–
115.0, 121.4, 126.4, 128.7,
C13H10ClNO2: C, 63.04;
H, 4.07; N, 5.66%
1593, 1514, 1252 7.43 (m, 3H), 7.49–7.55 (m, 3H), 129.4, 129.9, 130.2, 130.4,
8.79 (br s, 1H), 9.48 (br s, 1H) 136.5, 153.6, 164.5
C, 62.91; H, 3.88; N,
5.53%
7g
263 57
3349, 1652,
1603, 1545,
1344, 1222
6.84 (d, J = 8.7 Hz, 2H), 7.55 (d, 114.9, 120.0, 122.4, 127.7,
129.1, 138.2, 147.8, 154.1,
160.2
C13H9N3O6: C, 51.49; H,
2.99; N, 13.86%
J = 8.7 Hz, 2H), 9.12 (s, 1H),
9.36 (s, 2H), 10.4 (br s, 1H)
C, 51.22; H, 2.78; N,
13.71%
(continued on next page)

4116
A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
Table 1 (continued)
Compound Mp Yield IR (cmꢀ1
)
1H NMR (d)
13C NMR (d)
Analytical data Calcd./
found
(°C) (%)
7h
230 65
3259, 1659,
6.81 (d, J = 8.8 Hz, 2H), 7.49 (d, 115.0, 121.6, 123.8, 124.5,
J = 8.8 Hz, 2H), 7.63 (d, J 129.4, 130.6, 137.4, 137.8,
C13H9ClN2O4: C, 53.35;
H, 3.10; N, 9.57%
1614, 1540,
1509, 1455,
1353, 1321,
1240
= 8.8 Hz, 1H), 8.21 (dd, J = 8.7, 145.5, 153.9, 162.2
2.7 Hz, 1H), 8.39 (d, J = 2.7 Hz,
1H), 9.87 (br s, 1H)
C, 53.19; H, 2.96; N,
9.49%
7i
256 68
3502, 3443,
1653, 1540,
1480, 1338,
1262
3.96 (s, 3H, OCH3), 6.84 (t,
J = 7.6 Hz, 1H), 6.94 (d,
J = 7.1 Hz, 1H), 7.01 (t,
J = 7.1 Hz, 1H), 7.31 (d,
J = 8.4 Hz, 1H), 7.38 (d,
J = 7.6 Hz, 1H), 7.59 (t,
J = 8.0 Hz, 1H), 7.94 (d, J =
7.7 Hz, 1H)
56.3, 115.1, 115.5, 118.8,
119.1, 121.0, 125.0, 125.4,
129.8, 131.2, 139.0, 147.0,
150.7, 162.0
C14H12N2O5: C, 58.33;
H, 4.20; N, 9.72%
C, 58.17; H, 4.02; N, 9.57%
8a
8b
98 73
3297, 1645,
1616, 1551,
1455, 1240
7.33–7.36 (m, 2H), 7.49–7.53 (m, 110.6, 120.0, 124.6, 125.1,
3H), 7.56–7.59 (m, 1H), 7.75– 127.1, 127.6, 128.9, 131.5,
7.79 (m, 1H), 8.24–8.27 (m, 2H) 142.1, 150.7, 163.0
C13H11NO2: C, 73.22; H,
5.20; N, 6.57%
C, 73.05; H, 4.97; N, 6.51%
158 69
3265, 1615,
1558, 1456,
1368, 1227
6.86–7.14 (m, 5H), 7.39 (t,
J = 7.6 Hz, 1H), 7.86 (d,
J = 7.7 Hz, 1H), 7.93 (d,
J = 7.8 Hz, 1H)
—
C13H11NO3: C, 68.11; H,
4.84; N, 6.11%
C, 67.87; H, 4.65; N,
5.88%, 6.06%
8c
129 72
3416, 3094,
1645, 1540,
1455, 1281
2.32 (s, 3H, CH3), 7.79 (t,
J = 7.8 Hz, 1H), 6.88–6.98 (m,
2H), 7.21–7.28 (m, 2H), 7.61–
7.66 (m, 2H), 7.76–7.82 (m, 1H),
8.95 (br s, 1H)
—
C14H13NO2: C, 73.99; H,
5.77; N, 6.16%
C, 73.76; H, 5.69; N
8e
180 71
3388, 3094, 6.87 (dd, J = 7.8, 1.4 Hz, 1H), 6.96 109.4, 116.1, 119.4, 121.2,
1652, 1590, (dd, J = 8.0, 1.4 Hz, 1H), 7.00– 124.9, 125.9, 128.3, 128.5,
1539, 1453, 1283 7.04 (m, 1H), 7.44 (d, J = 8.5 Hz, 2 132.5, 137.3, 147.2, 164.5
C13H10ClNO2: C, 63.04;
H, 4.07; N, 5.66%
H), 7.91 (d, J = 8.5 Hz, 2H), 7.93–
7.95 (m, 1H)
C, 62.89; H, 3.92; N,
5.46%
8f
171 71
3215, 1633,
1595, 1524,
1455, 1328, 1292 7.95 (m, 4H), 7.91 (m, 1H)
6.88–6.92 (m, 1H), 7.00–7.04 (m, 109.4, 116.1, 119.4, 121.2,
C13H10ClNO2: C, 63.04;
H, 4.07; N, 5.66%
1H), 7.41–7.49 (m, 2H), 7.89–
124.9, 125.9, 128.3, 128.5,
132.5, 137.3, 147.2, 164.5
C, 62.94; H, 3.95; N, 5.40%
8g
126 65
3327, 1648,
1611, 1593,
1542, 1455,
1344, 1251
6.86 (d, J = 7.8 Hz, 1H), 7.01–
115.0, 120.6, 124.4, 127.8,
C13H9N3O6: C, 51.49; H,
2.99; N, 13.86%
7.04 (m, 1H), 7.41–7.47 (m, 2H), 128.2, 138.0, 147.8, 154.4,
9.12 (s, 1H), 9.35 (s, 2H), 10.4 (br 160.7
s, 1H)
C, 51.34; H, 2.80; N,
13.65%
8h
170 80
3216, 1652,
1541, 1480,
1349, 1253
6.63–6.79 (m, 1H), 6.88–7.32 (m, 109.2, 115.8, 119.7, 120.8,
2H), 7.64 (d, J = 8.7 Hz, 1H), 8.07 121.5, 123.2 124.6, 125.3,
C13H9ClN2O4: C, 53.35;
H, 3.10; N, 9.57%
(dd, J = 8.0, 1.4 Hz, 1H), 8.23
131.1, 136.4, 137.6, 145.9,
(dd, J = 8.7, 2.7 Hz, 1H), 8.56 (d, 146.7, 162.2
J = 2.7 Hz, 1H), 9.07 (br s, 1H)
C, 53.19; H, 2.97; N, 9.41%

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
4117
Table 1 (continued)
Compound Mp Yield IR (cmꢀ1
)
1H NMR (d)
13C NMR (d)
Analytical data Calcd./
found
(°C) (%)
8i
241 60
3305, 1650,
1644, 1607,
1574, 1508,
3.96 (s, 3H, OCH3), 6.71–6.75
(m, 2H), 7.07 (d, J = 8.8 Hz, 1H),
7.18–7.20 (m, 2H), 7.40 (dd,
—
C14H12N2O5: C, 58.33;
H, 4.20; N, 9.72%
1457, 1373, 1299 J = 8.8, 8.2 Hz, 1H), 7.59 (d,
J = 8.2 Hz, 1H)
C, 58.20; H, 3.98; N,
9.62%
14a
136 52
3218, 1630,
1601, 1508,
1456, 1405,
1277, 1216
6.75–6.79 (m, 1H), 7.09–7.45 (m,
6H), 7.63 (d, J = 8.2 Hz, 1H),
7.65–7.77 (m, 3H)
—
C17H13NO2: C, 77.55; H,
4.98; N, 5.32%
C, 77.36; H, 4.75; N,
5.09%
14b
149 50
3206, 1616,
1585, 1541,
1506, 1456,
6.78 (d, J = 8.8 Hz, 1H), 7.20 (d, 107.1, 115.1, 117.3, 122.1,
J = 8.8 Hz, 1H), 7.35–7.50 (m,
6H), 7.80 (d, J = 8.9 Hz, 1H),
C17H13NO3: C, 73.11; H,
4.69; N, 5.02%
123.2, 123.9, 125.0, 125.1,
126.8, 128.3, 128.5, 135.7,
1394, 1305, 1222 8.30 (d, J = 8.2 Hz, 1H), 8.82 (br 154.4, 160.3, 169.2
s, 1H), 9.51 (br s, 1H)
C, 72.88; H, 4.48; N,
4.82%
14c
168 54
3219, 1630,
1601, 1512,
1456, 1405,
6.90–7.02 (m, 3H), 7.31–7.35 (m,
1H), 7.57–7.79 (m, 4H), 8.07 (d,
J = 8.0 Hz, 1H), 8.41 (d,
C17H13NO3: C, 73.11; H,
4.69; N, 5.02%
1362, 1277, 1216 J = 8.2 Hz, 1H), 9.40 (br s, 1H)
C, 72.90; H, 4.48; N,
4.88%
15a
175 59
3354, 1615,
1541, 1508,
6.72 (d, J = 7.4 Hz, 1H), 6.81 (t,
J = 8.8, 0.8 Hz, 1H), 7.04–7.07
—
C17H13NO2: C, 77.55; H,
4.98; N, 5.32%
1448, 1298, 1240 (m, 2H), 7.15–7.20 (m, 1H), 7.27–
7.31 (m, 1H), 7.36–7.40 (m, 1H),
7.60 (d, J = 8.0 Hz, 1H), 7.68–
7.74 (m, 2H)
C, 77.39; H, 4.77; N,
5.14%
15b
15c
16
180 52
210 48
118 74
3361, 1633,
1600, 1558,
1508, 1466,
1405, 1245
6.76 (d, J = 8.8 Hz, 1H), 7.19 (d,
J = 8.8 Hz, 1H), 7.30–7.52 (m,
6H), 7.83 (d, J = 8.8 Hz, 1H),
8.32 (d, J = 8.2 Hz, 1H), 8.80 (br
s, 1H), 9.40 (br s, 1H)
—
C17H13NO3: C, 73.11; H,
4.69; N, 5.02%
C, 72.92; H, 4.47; N,
4.89%
3310, 1635,
1598, 1576,
1540, 1456, 1242 4H), 8.08 (d, J = 8.0 Hz, 1H),
6.86–7.00 (m, 3H), 7.31 (d,
106.9, 115.4, 117.9, 119.4,
121.2, 121.4, 123.2, 124.9,
125.0, 125.2, 125.4, 126.9,
C17H13NO3: C, 73.11; H,
4.69; N, 5.02%
J = 8.8 Hz, 1H), 7.50–7.77 (m,
8.40 (d, J = 8.2 Hz, 1H), 9.20 (br 128.5, 135.8, 147.2, 160.3,
s, 1H)
168.5
C, 72.90; H, 4.51; N,
4.88%
3338, 3058,
1661, 1616,
1590, 1537,
6.81–7.87 (m, 2H), 6.96–7.14 (m,
4H), 7.36–7.40 (m, 2H), 7.53–
7.58 (m, 2H), 7.42 (d,
—
C15H13NO2: C, 75.30; H,
5.48; N, 5.85%
1453, 1348, 1254 J = 15.6 Hz, 1H), 9.45 (br s, 1H),
9.84 (br s, 1H)
C, 75.22; H, 5.21; N,
5.72%

4118
A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
Table 2. Antimicrobial activity of substituted benzamides
Entry
Compound
ꢀlogBS
ꢀlogSA
ꢀlogEC
ꢀlogAF
ꢀlogAP
1
2
3a
3b
7a
7b
7c
1.30
1.15
0.93
0.96
1.04
0.96
1.00
1.00
1.38
1.27
1.26
0.93
0.96
0.96
0.96
1.10
1.00
1.38
1.07
1.41
1.48
1.35
1.35
1.35
1.13
1.25
1.20
0.98
0.17
3.33b
1.39
1.35
1.23
1.26
1.26
1.26
1.30
1.30
1.38
1.37
1.36
1.11
1.26
1.16
1.16
1.16
1.30
1.38
1.26
1.41
1.48
1.35
1.23
1.23
1.26
1.32
1.25
1.28
0.08
3.33b
1.30
1.20
1.23
1.20
1.20
1.26
1.17
1.17
1.38
1.27
1.26
1.23
1.12
1.26
1.20
1.20
1.20
1.38
1.20
1.41
1.35
1.35
1.35
1.29
1.17
1.22
1.21
1.16
0.07
3.33b
1.69
1.55
1.53
1.56
1.56
1.56
1.60
1.60
1.69
1.58
1.36
1.43
1.45
1.56
1.56
1.60
1.60
1.58
1.67
1.71
1.78
1.65
1.65
1.65
1.44
1.57
1.58
1.58
0.09
3.10c
1.69
1.42
1.24
1.26
1.26
1.32
1.30
1.31
1.69
1.58
1.53
1.23
1.20
1.30
1.26
1.30
1.30
1.69
1.52
1.71
1.83
1.65
1.65
1.35
1.30
1.62
1.62
1.58
0.19
3.10c
3
4
5
6
7d
7e
7
8
7f
9
7g
7h
7i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
SDa
S
8a
8b
8c
8d
8e
8f
8g
8h
8i
9
14a
14b
14c
15a
15b
15c
16
ꢀlogBS, ꢀlog (1/MIC in lM/mL) B. subtilis; ꢀlogSA, ꢀlog (1/MIC in lM/mL) S. aureus; ꢀlogEC, ꢀlog (1/MIC in lM/mL) E. coli; ꢀlogAF, ꢀlog
(1/MIC in lM/mL) A. ficcum; ꢀlogAP, ꢀlog (1/MIC in lM/mL) A. parasiticus.
a Standard deviation.
b Ciprofloxacin.
c Salicylic acid.
ꢀlog AF more than 1.60, than that of the other synthe-
sized benzamides. Compounds 3a, 7g, 7h, 8g, 8i, 14a,
14b, 15b, and 15c were found to be more active against
A. parasiticus having ꢀlog AP more than 1.58, than the
other synthesized benzamides.
tal (LUMO),26 dipole moment (l), electronic energy
(Ele.E), nuclear energy (Nu.E), and molecular surface
area (SA).27 The values of selected descriptors used in
regression analysis are presented in Table 3.
In the present investigation, a set of benzamides consist-
ing of 28 molecules was used for linear regression model
generation. The reference drugs were not included in
model generation as they belong to a different structural
series. A correlation matrix (Table 4) was constructed to
find the interrelationship among the parameters, which
shows that each parameter selected in the study is highly
correlated with the other (r > 0.7) except the descriptor
logP, ionization potential (IP), LUMO, and HOMO.
Any combination of these descriptors in multiple regres-
sion analysis may result with a model suffering from
multi-colinearity.
Analysis of the results indicates that the presence of
OCH2Ph, COOMe, and OH in compound 9 strongly en-
hances the activity. Further, a general trend showed that
the presence of electron withdrawing groups (NO2, Cl)
leads to increase in the activity in comparison to the
presence of electron-releasing group.
In an effort to determine the role of structural features,
QSAR studies were undertaken using the linear free en-
ergy relationship model (LFER) of Hansch and Fujita.20
Biological activity data determined as MIC values were
first transformed to ꢀlogMIC on a molar basis, which
was used as a dependent variable in the QSAR study.
These were correlated with different molecular descrip-
tors like log of octanol–water partition coefficient
(logP),20 molar refractivity (MR),21 Kier’s molecular
connectivity (2vv) and shape (j1,ja1) topological indi-
ces,22 Randic topological index (R),23 Balban topologi-
cal index (J),24 Wiener topological index (W),25 Total
energy (Te),12 energies of highest occupied molecular
orbital (HOMO) and lowest unoccupied molecular orbi-
The correlation of various descriptors with antimicro-
bial activity is presented in Table 5. From Table 5 it
was evident that the topological parameters, valence
molecular connectivity indices and shape indices (2v,
2vv, and ja1), for the benzamides have been found to ex-
hibit best correlation and high statistical significance
(p > 0.01). The resulting best-fit models applying the
principle of Parsimony are reported in Eqs. 1–6 together
with statistical parameters of regression. It is important

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
Table 3. Values of selected descriptors used in the linear regression analysis
4119
Entry
logP
MR
0v
0vv
1v
1vv
2v
2vv
IP
LUMO
HOMO
1
2
4.33
3.28
2.52
2.24
2.99
2.99
3.04
3.04
2.43
3.00
2.22
2.52
2.24
2.99
2.99
3.04
3.04
3.00
2.43
4.05
3.78
3.24
3.24
3.24
2.24
3.53
3.53
2.93
90.39
15.91
13.83
11.38
12.25
12.25
12.25
12.25
12.25
16.28
14.70
15.41
11.38
12.25
12.25
12.25
12.25
12.25
14.70
16.28
16.78
19.93
14.82
14.82
14.82
12.25
13.95
13.95
12.79
12.61
10.49
8.55
11.33
9.08
7.75
8.16
8.15
8.15
8.15
8.16
10.36
9.47
10.02
7.77
8.18
8.16
8.16
8.18
8.16
9.49
10.38
11.74
13.60
10.16
10.16
10.15
8.16
9.75
9.75
8.74
7.45
5.79
4.91
5.05
5.32
5.32
5.42
5.42
5.91
5.92
5.94
4.92
5.06
5.33
5.33
5.43
5.42
5.93
5.91
7.59
8.57
6.47
6.47
6.46
5.05
6.33
6.33
5.57
9.51
5.09
4.18
3.37
3.52
3.87
3.87
3.98
3.92
4.25
4.36
4.11
3.34
3.49
3.84
3.84
3.89
3.95
4.33
4.22
5.24
5.92
4.65
4.65
4.68
3.52
4.50
4.50
3.78
8.59
9.07
8.44
8.59
8.45
8.43
8.52
8.47
8.96
8.75
8.53
8.58
9.04
8.56
8.55
8.58
8.67
8.87
9.10
8.46
9.01
8.44
8.59
8.34
8.60
8.62
8.70
8.44
ꢀ0.24
ꢀ1.63
ꢀ0.42
ꢀ0.42
ꢀ0.25
ꢀ0.30
ꢀ0.71
ꢀ0.47
ꢀ2.13
ꢀ1.64
ꢀ1.05
ꢀ0.23
ꢀ0.50
ꢀ0.19
ꢀ0.24
ꢀ0.38
ꢀ0.52
ꢀ1.55
ꢀ2.04
ꢀ0.19
ꢀ0.60
ꢀ0.68
ꢀ0.60
ꢀ0.76
ꢀ0.42
ꢀ0.76
ꢀ0.66
ꢀ0.34
ꢀ8.59
ꢀ9.07
ꢀ8.44
ꢀ8.59
ꢀ8.45
ꢀ8.43
ꢀ8.52
ꢀ8.47
ꢀ8.96
ꢀ8.75
ꢀ8.53
ꢀ8.58
ꢀ9.04
ꢀ8.56
ꢀ8.55
ꢀ8.58
ꢀ8.67
ꢀ8.87
ꢀ9.10
ꢀ8.46
ꢀ9.01
ꢀ8.44
ꢀ8.59
ꢀ8.34
ꢀ8.60
ꢀ8.62
ꢀ8.70
ꢀ8.44
71.44
61.01
62.70
66.05
66.05
65.81
65.81
75.66
73.14
74.79
61.01
62.70
66.05
66.05
65.81
65.81
73.14
75.66
92.08
103.61
79.15
79.15
79.15
62.70
77.46
77.46
71.25
8.18
6.74
7.26
7.37
7.36
7.36
7.26
9.81
8.80
8.92
6.63
7.16
7.27
7.25
7.16
7.25
8.69
9.71
10.02
11.62
9.08
9.04
9.18
7.26
8.56
8.53
7.55
3
4
8.92
9.47
5
6
9.47
9.67
7
8
9.67
9
10.92
10.86
11.07
8.55
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
8.92
9.47
9.47
9.67
9.67
10.86
10.92
12.98
15.22
11.08
11.08
11.08
8.92
10.71
10.71
9.71
Table 4. Correlation matrix for logBS with molecular descriptors
logBS logP MR
0v 0vv 1v 1vv
logBS 1.000
2v
2vv
j1
j2
ja1
ja2
IP
LUMO HOMO
logP
MR
0v
0.433
0.848
0.905
0.841
0.899
0.823
0.934
0.841
0.870
0.763
0.850
0.729
1.000
0.719 1.000
0.455 0.929 1.000
0.676 0.984 0.951 1.000
0.581 0.980 0.978 0.976 1.000
0.763 0.994 0.899 0.980 0.962 1.000
0.486 0.934 0.993 0.945 0.978 0.905 1.000
0.778 0.976 0.894 0.974 0.942 0.985 0.910 1.000
0.420 0.909 0.994 0.940 0.963 0.875 0.977 0.863 1.000
0.522 0.924 0.933 0.937 0.942 0.899 0.902 0.848 0.952 1.000
0.422 0.898 0.987 0.942 0.949 0.868 0.964 0.861 0.996 0.949 1.000
0.542 0.913 0.915 0.938 0.922 0.895 0.878 0.849 0.938 0.994 0.944 1.000
0vv
1v
1vv
2v
2vv
j1
j2
ja1
ja2
IP
0.278 ꢀ0.137 0.196 0.413 0.270 0.305 0.163 0.372 0.171 0.443 0.342 0.453 0.337 1.000
LUMO ꢀ0.444 0.229 ꢀ0.138 ꢀ0.431 ꢀ0.214 ꢀ0.272 ꢀ0.079 ꢀ0.437 ꢀ0.151 ꢀ0.443 ꢀ0.226 ꢀ0.448 ꢀ0.206 ꢀ0.667 1.000
HOMO ꢀ0.278 0.137 ꢀ0.196 ꢀ0.413 ꢀ0.270 ꢀ0.305 ꢀ0.163 ꢀ0.372 ꢀ0.171 ꢀ0.443 ꢀ0.342 ꢀ0.453 ꢀ0.337 ꢀ1.000 0.667
1.000
to note that all these models were developed by using the
entire set (n = 28), since no outliers were identified.
QSAR model for antibacterial activity against S. aureus
ꢀlogSA ¼ 0:065ja1 þ 0:920
ð2Þ
The quality of the models is indicated by the following
parameters: r, correlation coefficient; F, Fisher’s statis-
tics; and s, standard error of estimation, r2cv, cross-vali-
dated r2 obtained by ‘leave one out’ (LOO) method.
n = 28, r = 0.810, F = 49.82, s = 0.051, r2cv ¼ 0:608.
QSAR model for antibacterial activity against E. coli
ꢀlogEC ¼ 0:0492v þ 0:840
ð3Þ
n = 28, r = 0.784, F = 41.72, s = 0.048, r2cv ¼ 0:529.
ꢀlogEC ¼ 0:0542v ꢀ 0:075IP þ 1:446
QSAR model for antibacterial activity against B. subtilis
ꢀlogBS ¼ 0:1372v þ 0:019
ð1Þ
ð4Þ
n = 28, r = 0.934, F = 178.89, s = 0.064, r2cv ¼ 0:837.
n = 28, r = 0.785, F = 23.65, s = 0.047, r2cv ¼ 0:534.

4120
A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
Table 5. Correlation of molecular descriptors with antimicrobial activity of substituted benzamides
ꢀlogBS
ꢀlogSA
ꢀlogEC
ꢀlogAN
ꢀlogAP
logP
MR
0v
0.433
0.848
0.905
0.841
0.899
0.823
0.934
0.841
0.870
0.763
0.850
0.729
0.899
ꢀ0.362
0.831
ꢀ0.860
ꢀ0.884
0.879
0.821
0.278
ꢀ0.444
ꢀ0.278
0.348
0.713
0.786
0.751
0.754
0.689
0.769
0.676
0.803
0.784
0.811
0.787
0.754
ꢀ0.088
0.760
ꢀ0.791
ꢀ0.783
0.775
0.737
0.367
ꢀ0.429
ꢀ0.367
0.340
0.696
0.761
0.681
0.748
0.663
0.785
0.671
0.741
0.663
0.713
0.620
0.748
ꢀ0.281
0.712
ꢀ0.708
ꢀ0.743
0.741
0.698
0.110
ꢀ0.307
ꢀ0.110
0.695
0.696
0.612
0.693
0.643
0.710
0.644
0.757
0.590
0.588
0.597
0.600
0.643
ꢀ0.472
0.654
ꢀ0.524
ꢀ0.600
0.605
0.663
0.101
ꢀ0.121
ꢀ0.101
0.513
0.867
0.885
0.844
0.890
0.829
0.899
0.822
0.869
0.825
0.848
0.793
0.890
ꢀ0.379
0.839
ꢀ0.821
ꢀ0.860
0.858
0.839
0.311
ꢀ0.414
ꢀ0.311
0vv
1v
1vv
2v
2vv
j1
j2
ja1
ja2
R
B
W
Te
Ele.E
Nu.E
SA
IP
LUMO
HOMO
Table 6. Observed and predicted antimicrobial activity of substituted benzamides using the best QSAR models
Entry
ꢀlogBS using Eq. 1
ꢀlog SA using Eq. 2
ꢀlogEC using Eq. 4
ꢀlogAF using Eq. 5
ꢀlogAP using Eq. 6
Obs.
Pred.
Res.
Obs.
Pred.
Res.
Obs.
Pred.
Res.
Obs.
Pred.
Res.
Obs.
Pred.
Res.
1
2
1.30
1.15
0.93
0.96
1.04
0.96
1.00
1.00
1.38
1.27
1.26
0.93
0.96
0.96
0.96
1.10
1.00
1.38
1.07
1.41
1.48
1.35
1.35
1.35
1.13
1.25
1.20
0.98
1.32
1.14
0.94
1.01
1.03
1.03
1.03
1.01
1.36
1.22
1.24
0.93
1.00
1.01
1.01
1.01
1.00
1.35
1.21
1.39
1.61
1.26
1.26
1.28
1.01
1.19
1.19
1.05
ꢀ0.02
0.01
1.39
1.35
1.23
1.26
1.26
1.26
1.30
1.30
1.38
1.37
1.36
1.11
1.26
1.16
1.16
1.16
1.30
1.38
1.26
1.41
1.48
1.35
1.23
1.23
1.26
1.32
1.25
1.28
1.36
1.30
1.20
1.23
1.24
1.24
1.25
1.25
1.37
1.33
1.35
1.20
1.23
1.24
1.24
1.25
1.25
1.37
1.33
1.39
1.51
1.30
1.30
1.30
1.23
1.27
1.27
1.26
0.03
1.30
1.20
1.23
1.20
1.20
1.26
1.17
1.17
1.38
1.27
1.26
1.23
1.12
1.26
1.20
1.20
1.20
1.38
1.20
1.41
1.35
1.35
1.35
1.29
1.17
1.22
1.21
1.16
1.32
1.21
1.18
1.20
1.22
1.22
1.21
1.21
1.31
1.27
1.29
1.17
1.16
1.20
1.20
1.19
1.19
1.29
1.26
1.36
1.40
1.31
1.30
1.32
1.20
1.27
1.26
1.23
ꢀ0.02
ꢀ0.01
0.05
1.69
1.55
1.53
1.56
1.56
1.56
1.60
1.60
1.69
1.58
1.36
1.43
1.45
1.56
1.56
1.60
1.60
1.58
1.67
1.71
1.78
1.65
1.65
1.65
1.44
1.57
1.58
1.58
1.69
1.58
1.49
1.51
1.55
1.55
1.56
1.55
1.59
1.61
1.58
1.49
1.50
1.55
1.54
1.56
1.55
1.59
1.60
1.71
1.78
1.64
1.64
1.64
1.51
1.62
1.62
1.54
0.00
1.69
1.42
1.24
1.26
1.26
1.32
1.30
1.31
1.69
1.58
1.53
1.23
1.20
1.30
1.26
1.30
1.30
1.69
1.52
1.71
1.83
1.65
1.65
1.35
1.30
1.62
1.62
1.58
1.70
1.43
1.27
1.32
1.32
1.32
1.32
1.32
1.59
1.48
1.55
1.27
1.32
1.32
1.32
1.32
1.32
1.59
1.48
1.75
1.98
1.56
1.56
1.56
1.32
1.51
1.51
1.39
ꢀ0.01
ꢀ0.01
ꢀ0.03
ꢀ0.06
ꢀ0.06
0.00
0.05
0.03
ꢀ0.03
0.04
0.05
3
ꢀ0.01
ꢀ0.05
0.01
4
0.03
0.02
0.00
ꢀ0.02
0.04
5
0.01
0.01
6
ꢀ0.07
ꢀ0.03
ꢀ0.01
0.02
0.02
0.05
7
ꢀ0.04
ꢀ0.04
0.07
0.04
0.05
ꢀ0.02
ꢀ0.01
0.10
8
0.05
0.01
9
0.10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
0.05
0.02
0.04
0.01
0.00
ꢀ0.03
0.06
ꢀ0.03
ꢀ0.22
ꢀ0.06
ꢀ0.05
0.01
0.10
ꢀ0.02
ꢀ0.04
ꢀ0.12
ꢀ0.02
ꢀ0.06
ꢀ0.02
ꢀ0.02
0.10
0.00
ꢀ0.09
0.03
ꢀ0.04
ꢀ0.05
ꢀ0.05
0.09
ꢀ0.04
0.06
0.00
ꢀ0.08
ꢀ0.08
ꢀ0.09
0.05
0.02
0.04
0.01
0.01
0.00
0.03
0.05
0.01
ꢀ0.07
0.02
0.09
ꢀ0.06
0.05
ꢀ0.01
0.07
0.00
ꢀ0.14
0.02
0.04
ꢀ0.04
ꢀ0.15
0.09
ꢀ0.13
0.09
0.09
ꢀ0.03
0.05
ꢀ0.05
0.04
0.05
0.00
0.01
ꢀ0.07
ꢀ0.07
0.03
0.01
0.01
0.09
0.07
0.12
ꢀ0.03
ꢀ0.03
ꢀ0.05
ꢀ0.05
ꢀ0.07
ꢀ0.21
ꢀ0.02
0.11
ꢀ0.07
ꢀ0.05
ꢀ0.04
0.04
0.06
0.01
0.05
ꢀ0.02
0.02
0.11
0.19
ꢀ0.07
QSAR model for antifungal activity against
A. ficcum
QSAR model for antifungal activity against A.
parasiticus
ꢀlogAF ¼ 0:1142vv þ 1:104
ð5Þ
ꢀlogAP ¼ 0:1211v þ 0:330
ð6Þ
n = 28, r = 0.757, F = 34.93, s = 0.060, r2cv ¼ 0:529.
n = 28, r = 0.899, F = 98.63, s = 0.089, r2cv ¼ 0:733.

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
4121
2
.2
The coefficient of v in the mono-parametric model in
Eq. 1 is positive indicating thereby that antibacterial
activity of benzamides against B. subtilis is directly pro-
portional to the magnitude of 2v. The antibacterial
.1
2
activity increases with an increase in magnitude of v.
This is evidenced by the values of 2v in Table 3. The val-
2
ues of v for compounds 8i (entry 20) and 9 (entry 21)
are 10.02 and 11.62, respectively, which are higher than
the v values of other compounds which make them the
0.0
2
most active compounds against B. subtilis with ꢀlogBS
of 1.41 and 1.48 (Table 2), respectively. Similarly the
compounds 7a (entry 3) and 8a (entry 12) having the
-.1
2
minimum v values of 6.74 and 6.63, respectively, have
minimum activity. Similar trend was observed in case
of S. aureus, E. coli, A. ficcum, and A. parasiticus with
-. 2
2
2
2
ja1, v, vv, and v, respectively.
.9
1.0
1.1
1.2
1.3
1.4
1.5
Observed log BS
In order to confirm our results we have predicted the
activities of benzamide derivatives using the model ex-
pressed by Eqs. 1–6 [except (3)] and compared them with
the observed values. The data presented in Table 6 show
that the observed and the estimated activities are very
close to each other evidenced by low values of residual
activity.
Figure 4. Plot of residual logBS activity values against the experi-
mental logBS values.
To investigate the existence of a systemic error in devel-
oping the QSAR model, the residuals of linear regres-
sion predicted values of ꢀlogBS were plotted against
the observed ꢀlogBS values in Figure 4. The propaga-
tion of the residuals on both sides of zero indicates that
no systemic error exists in the development of linear
regression model.30
The cross-validation of the models was also done by
leave one out (LOO) technique.28 The high cross-vali-
dated correlation coefficient (r2cv or q2) values obtained
for the best QSAR models indicated their reliability in
predicting the antimicrobial activity of substituted ben-
zamides. But one should not forget the recommenda-
tions of Golbraikh et al.,29 who have recently reported
that the only way to estimate the true predictive power
of a model is to test their ability to predict accurately
the biological activities of compounds. The low residual
activity values observed justify the selection of the linear
regression models expressed by Eqs. 1–6. Further the
plot of linear regression predicted ꢀlog BS values
against the observed ꢀlog BS values also favors the
model expressed by Eq. 1 (Fig. 3).
Even though the sample size and the ‘Rule of Thumb’
allowed us to go for development of multi-parametric
model in multiple linear regression analysis, the high
interrelationship among the parameters restricted us
for mono-parametric model. The other statistically sig-
nificant models derived are presented in Table 7. The
multi-colinearity occurs when two independent variables
are correlated with each other that becomes a problem
for a theoretical statistician. One should note that the
change in signs of the coefficients, a change in the values
of previous coefficient, change of significant variable
into insignificant one or an increase in standard error
of the estimate on addition of an additional parameter
to the model are indications of high interrelationship
among descriptors.
1.7
1.6
1.5
1.4
1.3
1.2
1.1
2. Conclusions
From the results and discussion made above we con-
clude that the benzamides are effective against the
microbial species tested. The results obtained from pres-
ent investigation of in vitro antimicrobial activity studies
indicate that the N-(2-hydroxyphenyl)-3-methoxy-2-
nitrobenzamide (8i, entry 20) and N-(2-hydroxy-6-carb-
methoxyphenyl)-2-benzyloxybenzamide (9, entry 21) are
the most effective ones. Further, a general trend showed
that the presence of electron-withdrawing groups (NO2,
Cl) leads to increase in the activity in comparison to the
presence of electron releasing group. The topological
parameters especially, the valence molecular connectiv-
1.0
.9
.9
1.0
1.1
1.2
1.3
1.4
1.5
Observed log BS
Figure 3. Plot of predicted logBS activity values against the experi-
mental logBS values for the linear regression developed model by
Eq. 1.
2
ity indices and shape indices (2v, vv, and ja1) can be
used successfully for modeling antimicrobial activity of

4122
A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
Table 7. Regression analysis and quality of correlation for modeling antimicrobial activity of benzamides (r2CV > 0.5)
S.No.
QSAR Model
n
r
r2CV
F
s
B. subtilis (ꢀlogBS =)
1
2
0.015 MR + 0.066
0.080 0v + 0.041
28
28
28
28
28
28
28
28
28
28
28
28
0.848
0.905
0.841
0.899
0.822
0.840
0.870
0.762
0.850
0.831
0.860
0.937
0.656
0.757
0.608
0.738
0.611
0.659
0.689
0.503
0.645
0.485
0.704
0.820
66.59
0.096
0.077
0.098
0.080
0.103
0.098
0.089
0.118
0.095
0.107
0.093
0.064
117.95
62.95
109.60
54.49
62.78
81.32
36.16
67.72
57.90
74.04
90.58
3
0.103 0vv + 0.076
0.114 1v + 0.089
4
5
0.169 1vv + 0.149
0.252 2vv + 0.091
0.065 j1 + 0.159
6
7
8
0.106 j2 + 0.388
9
0.074 ja1 + 0.180
0.0004 W + 0.821
ꢀ0.0003 Te + 0.247
0.1412v ꢀ 0.067 IP + 0.559
10
11
12
S. aureus (ꢀlog SA =)
13
14
15
16
17
18
19
20
0.033 0v + 0.828
28
28
28
28
28
28
28
28
0.786
0.751
0.754
0.768
0.802
0.784
0.787
0.791
0.569
0.510
0.516
0.536
0.597
0.562
0.559
0.577
42.06
33.72
34.27
37.58
47.09
41.53
42.38
43.57
0.054
0.057
0.057
0.055
0.052
0.054
0.053
0.053
0.044 0vv + 0.829
0.046 1v + 0.862
0.054 2v + 0.843
0.029 j1 + 0.851
0.052 j2 + 0.914
0.065 ja2 + 0.920
ꢀ0.0001 Te + 0.891
E. coli (ꢀlog EC =)
21
0.054 2v ꢀ 0.075 IP + 1.446
28
28
0.785
0.710
0.534
0.455
23.65
26.43
0.047
0.064
A. ficcum (ꢀlog AF =)
22
0.074 1vv + 1.149
A. parasiticus (ꢀlog AP =)
23
24
25
26
27
28
29
30
31
32
33
34
0.016 MR + 0.266
28
28
28
28
28
28
28
28
28
28
28
28
0.867
0.884
0.844
0.829
0.807
0.822
0.869
0.825
0.848
0.792
0.838
0.820
0.698
0.732
0.629
0.632
0.774
0.633
0.698
0.600
0.653
0.539
0.520
0.638
78.92
93.91
64.65
57.08
109.62
54.29
80.21
55.45
66.34
43.97
61.70
53.68
0.097
0.091
0.105
0.109
0.085
0.111
0.097
0.110
0.103
0.119
0.106
0.111
0.084 0v + 0.293
0.111 0vv + 0.299
0.184 1vv + 0.374
0.141 2v + 0.289
0.266 2vv + 0.345
0.069 j1 + 0.394
0.123 j2 + 0.573
0.079 ja1 + 0.419
0.147 ja2 + 0.624
0.0004 W + 1.102
ꢀ0.0002 Te + 0.532
benzamides against the microbial species included in the
present study. Contribution of topological descriptors in
describing the antimicrobial activity of benzamides was
further evidenced by the results of our previous stud-
ies.12,13,15 The low residual activity and high cross-vali-
dated r2values (rc2vÞ observed indicated the predictive
ability of the developed QSAR models.
100 MHz NMR Spectrometer, respectively, in CDCl3–
DMSO-d6 and are expressed as ppm with respect to
TMS. Elemental analysis was carried out on Perkin-
Elmer 2400 instrument.
All the synthesized benzamides are new compounds ex-
cept 7a (no data were reported),31 8d,32 and 9.17
3.1. General procedure
3. Experimental
Carbonyldiimidazole (CDI) (4.86 g, 30 mmol) was dis-
solved in 30 mL dry THF with stirring at room temper-
ature under nitrogen atmosphere and appropriate
benzoic acid/naphthoic acid/cinnamic acid (30 mmol)
was added carefully. The reaction mixture was further
stirred for 10 min and then after the evolution of CO2
ceased, substituted aniline (20 mmol) was added. The
stirring was continued for additional 10 min at room
temperature and then refluxed for 12–18 h. After com-
Melting points were determined in open capillaries and
are uncorrected. Carbonyldiimidazole (CDI) was pur-
chased from Aldrich and used without further purifica-
tion. THF was distilled from sodium/benzophenone
prior to use. FTIR spectra were obtained in KBr on Per-
kin-Elmer Spectrum RX1 instruments and are reported
in cmꢀ1. Unless otherwise noted 1H and 13C NMR spec-
tra were determined on Bruker Avance II 400 and

A. Kumar et al. / Bioorg. Med. Chem. 15 (2007) 4113–4124
4123
pletion of the reaction, monitored by TLC, reaction
Acknowledgments
mixture was concentrated to obtain crude product.
The crude product was purified by column chromatog-
raphy using either hexane or 10–20% EtOAc in hexane.
The authors thank University Grants Commission, New
Delhi, for financial help and the Chairman, Department
of Chemistry, GJUST, Hisar, for discussion and help in
recording the data.
3.2. Biological studies
Using serial dilution technique in double strength nutri-
ent broth-I.P. and Sabouraud dextrose broth-I.P. as a
medium, the in vitro antibacterial and antifungal activ-
ity studies of the synthesized compounds against S. aur-
eus, B. subtilis, E. coli, A. ficcum, and A. parasiticus were
carried out. The benzamides were dissolved in DMSO to
give a concentration of 10 lg/mL (stock solution).
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4124
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