Synthesis, characterization, antimicrobial and single crystal X-ray crystallographic studies of some new sulfonyl, 4-chloro phenoxy benzene and dibenzoazepine substituted benzamides

Article abstract of DOI:10.1016/j.ejmech.2006.05.011

A new class of benzamide derivatives 3a(I-VI) and 3b(I-VI), bearing different bioactive moieties were synthesized and evaluated for their efficacy as antimicrobials in vitro. Compounds 3bVI, 3aII, 3aV, 3bIII, 3aVI, 3bII showed significant antibacterial ac

Full text of DOI:10.1016/j.ejmech.2006.05.011

European Journal of Medicinal Chemistry 41 (2006) 1262–1270
http://france.elsevier.com/direct/ejmech
Original article
Synthesis, characterization, antimicrobial and single crystal X-ray
crystallographic studies of some new sulfonyl, 4-chloro
phenoxy benzene and dibenzoazepine substituted benzamides
B.S. Priya a, S. Nanjunda Swamy a, M.V. Tejesvi b, Basappa a, G. Sarala c, S.L. Gaonkar a,
S. Naveen c, J. Shashidhara Prasad c, K.S. Rangappa a,*
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570 006, Karnataka, India
b Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore-570 006, Karnataka, India
c Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore-570 006, Karnataka, India
Received in revised form 18 April 2006; accepted 29 May 2006
Available online 05 July 2006
Abstract
A new class of benzamide derivatives 3a(I–VI) and 3b(I–VI), bearing different bioactive moieties were synthesized and evaluated for their
efficacy as antimicrobials in vitro. Compounds 3bVI, 3aII, 3aV, 3bIII, 3aVI, 3bII showed significant antibacterial activity and 3bIII, 3bII,
3aIV, 3bV, 3bVI, 3aI exhibit significant antifungal activity. The title compounds are characterized by spectral and elemental analysis. Com-
pounds 2-methoxy-N-[4-(thiazol-2-yl-sulfamoyl)-phenyl]-benzamide 3aII and 2-(2-(2-ethoxybenzoylamino) phenethyl)-N-(2-ethoxybenzoyl)
benzenamine 3bV are characterized by the single crystal X-ray studies. Compound 3aII crystallizes in monoclinic space group P21 and 3bV
in triclinic space group P-1. Compounds 3aII and 3bV exhibit both inter and intra molecular hydrogen bonding.
© 2006 Elsevier Masson SAS. All rights reserved.
Keywords: Benzamide; Antibacterial; Antifungal; Monoclinic; Triclinic
1. Introduction
matory [4], antimicrobials [5] and in treatment of Alzheimer’s
diseases [6]. From the standpoint of elaborated complex natural
product and process chemistry, we have targeted in synthesiz-
ing novel amide derivatives, which plays an extremely impor-
tant role in therapeutic as well as in medicinal field. One of the
important categories of medicine is antibiotic, where sulfona-
mides are used for the treatment of bacterial infections [7], in
which the amide moiety may exert their effects by modifying
the metabolic activity of the invaded pathogenic microorgan-
isms. These categories of medicines on absorption into the sys-
tem interfere with microbe’s growth or kill them. Penicillin,
erythromycin, tetracycline, norfloxacin, etc. come under this
category for the treatment of antimicrobials. Our previous stu-
dies on the synthesis of heterocycles like isoxazolines, novel
isoxazolidines, 1,2-benzisoxazole substituted amides and chro-
man-2-carboxamides showed a wide spectrum of antimicrobial
activities [8–12]. In connection with our efforts, in synthesiz-
ing and identifying the various biological targets, herein we
The need for new antimicrobial agents is greater than ever
because of the emergence of multidrug resistance in common
pathogens, the rapid emergence of new infections, and the
potential for use of multidrug-resistant agents in bioweapons.
Solutions encouraging and facilitating the development of new
antimicrobial agents are needed [1]. Compound comprising of
an amide bond backbone have a wide range of biological activ-
ities. Thus among the natural and synthetic substituted amide
derivatives, there are compounds possessing anti-proliferative
[2], antiviral, antimalarial, general anesthetics [3], anti-inflam-
* Corresponding author.
E-mail addresses:
rangappaks@chemistry.uni-mysore.ac.in, rangappaks@yahoo.com
(K.S. Rangappa).
0223-5234/$ - see front matter © 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.05.011

B.S. Priya et al. / European Journal of Medicinal Chemistry 41 (2006) 1262–1270
1263
report the synthesis of new class of substituted benzamides and
their antimicrobial activity in vitro against different strains.
2. Chemistry
Amide moiety is versatile in organic compounds since all the
three atoms in the O–C–N chain are potentially reactive. Several
efficient methods have been exploited for the amidation using
specific dehydrating reagents under mild liquid-phase condition.
The synthesis of substituted amides began with the synthesis of
various acid chlorides, where the acid chloride undergoes con-
densation reaction with different amines in presence of triethyla-
mine as acid scavenger in dichloroethane as solvent. The physi-
cal data of newly synthesized molecules is shown in Table 1 and
the synthetic scheme shown in Schemes 1, 2 and 3.
Scheme 2.
Scheme 3.
3. Results and discussion
3.1. Chemistry
Series of benzamides using different acid chlorides and
amines were obtained in very good yield in the ratio of 70–
85% with a purity of 90–95%. IR spectrum of the synthesized
compounds showed N-H bond stretching in the region of
3300–3400 cm–1 and the C=O bond stretching in the region of
1600–1700 cm–1. Synthesized compounds were characterized
by spectral, elemental analysis and finally by single crystal
X-ray studies for the compounds 3aII and 3bV.
3.2. Crystal structure analysis of 3aII and 3bV
Figs. 1 and 2 represent the ORTEP of the molecules 3aII
and 3bV with thermal ellipsoids at 50% probability with
selected bond lengths and bond angles. Table 2 represents crys-
tal and experimental data of the molecules 3aII and 3bV.
Compound 3aII exhibits both intramolecular and intermolecu-
Scheme 1.
Table 1
Reaction condition and physical data of benzamide series
Amides
3a I
3a II
3a III
3a IV
3a V
Time (h)
Rf value
0.72
0.63
0.54
0.66
0.78
0.64
0.55
0.82
0.64
0.67
0.58
0.75
Eluent
Yield (%)
75
75
80
85
80
70
75
70
70
70
85
85
m.p. (°C)
Oily
179–182
Oily
Oily
Oily
4
4
5
6
4
4
4
5
6
4
4
4
Chloroform/methanol 9:1
Chloroform/methanol 9:1
Chloroform/methanol 9:1
Chloroform/methanol 9:1
Chloroform/methanol 9:1
Chloroform/methanol 9:1
Benzene/ethyl acetate 9:1
Benzene/ethyl acetate 9:1
Benzene/ethyl acetate 9:1
Benzene/ethyl acetate 9:1
Benzene/ethyl acetate 9:1
Chloroform/methanol 9:1
3a VI
3b I
Oily
130–133
205–210
215–217
224–228
117–120
98–102
3b II
3b III
3b IV
3b V
3b VI

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B.S. Priya et al. / European Journal of Medicinal Chemistry 41 (2006) 1262–1270
Fig. 1. ORTEP diagram of molecule 3aII at 50% Probability.
Bond length: S1A-C2A: 1.723(4) Å, C2A-C3A: 1.329(5) Å, C3A-N4A: 1.390(4) Å, N6A-S7A: 1.602(3) Å, S7A-O9A: 1.434(2) Å, C17A-O18A: 1.210(4) Å,
C19A-C24A: 1.407(5) Å, C22A-C23A: 1.390(7) Å.
Bond angles: O8A-S7A-N6A: 104.80(2)°, O9A-S7A-C10A: 107.61(2)°, N6A-S7A-C10A: 105.15(2)°, C17A-N16A-C13A: 129.0(3)°, O18A-C17A-N16A: 122.6
(3)°, O25A-C24A-C23A: 123.3(3)°, C24A-O25A-C26A: 119.5(3)°.
Fig. 2. ORTEP diagram of molecule 3bV at 50% Probability.
Bond length: C1A-C2A: 1.350(8) Å, O3A-C2A: 1.504(6) Å, C19A-C20A: 1.523(5) Å, N12A-C10A: 1.351(4) Å, C10A-O11A: 1.223(4) Å, N12A-C13A: 1.406(4)
Å, N27A-C28A: 1.374(5) Å, C22A-N27A: 1.409(5) Å.
Bond angles: C1A-C2A-O3A:103.5(6)°, C9A-C10A-O11A: 119.6(3)°, O11A-C10A-N12A: 122.3(3)°, N12A-C13A-C14A: 123.3(3)°, N12A-C13A-C18A: 117.8
(3)°, C18A-C19A-C20A: 111.0(3)°, N27A-C28A-O29A: 122.3(4)°, C22A-N27A-C28A: 126.9 (3)°.

B.S. Priya et al. / European Journal of Medicinal Chemistry 41 (2006) 1262–1270
1265
Table 2
Crystal data and structure refinement for 3aII and 3bV
Identification code
CCDC number
Empirical formula
Formula weight
Crystal size
3aII
293717
C17H15N3O4S2
389.44
0.3 × 0.25 × 0.25 mm
293(2) K
3bV
293718
C32H32N2O4
508.24
0.3 × 0.25 × 0.25 mm
293(2) K
Temperature
Reflections for cell determination
Wavelength
7270
0.71073 Å
4657
0.71073 Å
Crystal system
Monoclinic
Triclinic
Space group
P21
P 1
Cell dimensions
a = 10.717(5) Å, b = 10.914(8) Å,
c = 15.284(1) Å, α = 90°,
β = 90.802(4)°, γ = 90°
1787.5(2) Å3
a = 11.6580(10) Å, b = 14.079(2) Å,
c = 17.447(3) Å, α = 88.402(3) Å,
β = 75.728(8) Å, γ = 81.582(8) Å
2674.6(7) Å3
Volume
Z
4
4
Density (calculated)
Absorption coefficient
F000
1.447 mg m–3
0.326 mm–1
1.261 mg m–3
0.083 mm–1
1076
808
Theta range for data collection
Index ranges
2.29°–32.45°
–14 ≤ h ≤ 14
2.20°–32.47°
–11 ≤ h ≤ 11
–16 ≤ k ≤ 16
–20 ≤ k ≤ 19
–23 ≤ l ≤ 23
–23 ≤ l ≤ 26
Reflections collected
Independent reflections
Refinement method
10874
17274
10874 [R (int) = 0.0000]
Full-matrix least-squares on F2
10874/1/472
11695 [R (int) = 0.0375]
Full-matrix least-squares on F2
11695/0/690
Data/restraints/parameters
2
Goodness-of-fit on F
1.092
1.332
Final R indices [I > 2 σ (I)]
R indices (all data)
Extinction coefficient
R1 = 0.0532, ωR2 = 0.1360
R1 = 0.0862, ωR2 = 0.1707
0.0100(18)
R1 = 0.0962, ωR2 = 0.2465
R1 = 0.2013, ωR2 = 0.2965
0.0064(18)
Largest diff. peak and hole
0.516 eÅ–3 and –0.306 eÅ–3
0.396 eÅ–3 and –0.273 eÅ–3
lar hydrogen bonding. The intermolecular bonds are between
N6A-H6A—N4B with bond length 2.863(4) Å, bond angle
143° and symmetry {x, –1 + y, z}, the N6B-H6B—N4A with
bond length 2.926(4) Å, bond angle 144° and symmetry { x,
1 + y, z}, the C2A-H2A—O18A with bond length 3.047(5) Å,
bond angle 116° and symmetry {2 – x, –1/2 + y, –z} and
C15A-H15A—O9A with bond length 3.454(4) Å, bond angle
158° and symmetry {2 – x, –1/2 + y, –z}.
Compound 3bV exhibits both intramolecular and intermole-
cular hydrogen bonding. The intermolecular bonds are between
C2B-H2B—O11A with bond length 3.304(5) Å, bond angle
132° and symmetry {1 – x, 1 – y, 1 – z}, the C1A-H1A—
O11B with bond length 3.385(6) Å, bond angle 150° and sym-
metry {1 – x, 1 – y, – z}, and the C37B-H37B—O29A with
bond length 3.395(1) Å, bond angle 140° and symmetry {1 –
X, – Y, –Z}, respectively.
Table 3
Minimal inhibitory concentration (MIC) in μg ml–1 of compounds against tested bacterial strains by microdilution method
Compound
Minimal inhibitory concentration (MIC) in μg ml–1
Bacillus substilis
Escherichia coli
Pseudomonas fluorescens
Xanthomonas campestris pvs. Xanthomonas oryzae
3a I
3a II
32 1.2
28 1.2
25 1.1
24
5
12 0.3
13 0.4
6
8
1
0.2
25 1.1
0.3
15 0.6
16 0.7
8
23
0.32
1
7
0.3
6
0.2
8
3a III
3a IV
3a V
3a VI
3b I
20 0.8
17 0.7
16 0.7
17 0.72
25 0.9
0.35
9
8
0.3
7
0.21
12 0.4
26
0.2
0.3
1
9
0.31
12 0.5
24
11 0.95
30 1.2
18 0.8
10 0.4
22 0.9
10 0.4
29 1.2
15 0.6
1
23
1
3b II
13 0.40
11 0.4
14 0.6
15 0.62
10 0.36
0.22
14 0.5
10 0.3
16 0.6
15 0.42
3b III
3b IV
3b V
3b VI
Streptomycin
Tetracycline
a
9
0.3
7
18 0.7
19 0.75
13 0.5
12 0.4
3
24
6
1
0.2
5
0.2
4
0.13
0.1
6
0.2
23 0.9
–
18 0.8
–
15 0.6
–
–
–
12 0.42
16 0.6
Values are mean of three determinations, the ranges of which are less than 5% of the mean in all cases.

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B.S. Priya et al. / European Journal of Medicinal Chemistry 41 (2006) 1262–1270
3.3. Biology
both bearing sulfathiazole moiety, the presence of different
substituents at R1 makes 3aII active. Compounds 3aV and
3b III showed good activity bearing different moieties and
substituents at R1 and R2 position, respectively. Compounds
3bIV and 3aIV bearing sulfadiazine moiety at R2, ethoxy
and methoxy at R1, respectively, showed moderate potency.
Compounds 3aI and 3bI were not effective against any of the
strains tested. Antifungal activity of the compounds tested is
shown in Tables 5 and 6. From our results, compounds
3bIII, 3bII, 3aIV, 3bV, 3bVI and 3aI showed significant inhi-
bitory activity in the following order 3bIII > 3bII > 3aIV >
3bV > 3bVI > 3aI. Interestingly, we found compounds 3aII,
3aV and 3aVI showed significant inhibitory activity against
the fungal strains tested but they exhibited moderate potency
against bacterial strains. Compound 3aI showed good antifun-
gal activity but was ineffective against bacteria. Compounds
3aII, 3aVI, 3bIV and 3aIII exhibited moderate antifungal
activity. Compounds 3bI and 3aV were not effective against
any of the fungus tested.
In continuation of our efforts in synthesizing new antimicro-
bials, we have developed new derivatives of benzamides and
tested for their efficacy as antimicrobials in vitro by disk diffu-
sion, microdilution and turbidometric methods against different
strains. Nystatin was used as positive control against fungi,
streptomycin and tetracycline against bacteria. The tests were
repeated thrice and the results are reported as mean of at least
three determinations. Antibacterial activity of the compounds
tested is shown in Tables 3 and 4. From our results, com-
pounds 3bVI, 3aII, 3aV, 3bIII, 3aVI and 3bII showed signif-
icant inhibitory activity in the following order 3bVI > 3aII >
3aV > 3bIII > 3aVI > 3bII. Compounds 3bVI and 3aVI bear-
ing the bioactive phenoxy moiety, difference in the activity
between 3bVI and 3aVI might be attributed to the presence
of ethoxy and methoxy group at R1 position, respectively.
Compound 3aII showed increased activity compared to 3bII
Table 4
Inhibitory zone (diameter) mm of compounds against tested bacterial strains by disk diffusion method
Compound
Inhibitory zone (diameter) mm
Pseudomonas fluorescens Xanthomonas campestris pvs. Xanthomonas oryzae
0.18 0.08 0.08
42 1.8
23
22 0.9
40 1.6
34 1.5
Bacillus substilis
0.2
30 1.1
14 0.52
15 0.59
28 1.2
Escherichia coli
0.06
3a I
3a II
6
2
5
2
3
38 1.7
19 0.7
20 0.8
36 1.5
30 1.3
28 1.2
18 0.8
15 0.65
25 1.1
21 0.9
32 1.2
16 0.5
17 0.7
30 1.1
25 0.9
3a III
3a IV
3a V
3a VI
3b I
1
25
4
1
0.1
3
0.09
7
0.28
5
0.18
4
0.17
20 0.8
27
3b II
22 0.9
27 1.1
16 0.7
17 0.6
32 1.2
15 0.5
–
25 1.1
32 1.5
17 0.52
18 0.8
40 1.3
19 0.7
–
30 1.2
36 1.5
20 0.8
21 0.82
45 2.1
22 0.9
–
19 0.8
22 0.9
16 0.6
17 0.62
30 1.1
–
3b III
3b IV
3b V
3b VI
Streptomycin
Tetracycline
1
14 0.6
15 0.62
35 1.23
–
16 0.61
a
15 0.52
Streptomycin sulfate (10 μg disc–1); Tetracycline (10 μg disc–1); Synthesized compounds (25 μg disc–1). Values are mean of three determinations, the ranges of
which are less than 5% of the mean in all cases.
Table 5
Minimal inhibitory concentration (MIC) in μM of compounds against tested fungal strains by Turbidometric method
Compound
Minimal inhibitory concentration (MIC) in μM
Aspergillus niger
26 1.1
30 1.2
31 1.22
17 0.65
42 1.5
Aspergillus flavus
30 1.3
34 1.3
36 1.4
20 0.8
47 1.4
35 1.5
50 2.1
15 0.6
17 0.6
36 1.4
22 0.9
25 0.98
35 1.4
Fusarium oxysporum
32 1.2
37 1.4
38 1.6
19 0.7
61 2.5
38 1.6
52 2.3
16 0.6
18 0.7
39 1.7
21 0.9
27 1.2
Trichoderma species
Fusarium moniliforme
27 1.15
33 1.4
35 1.3
18 0.7
47 1.9
34 1.4
51 2.1
14 0.5
16 0.62
35 1.5
23 1.1
25 1.5
33 1.5
3a I
25 1.05
30 1.2
29 1.2
17 0.7
44 1.9
29 1.2
49 1.9
13 0.5
15 0.55
31 1.3
20 0.8
22 0.9
29 0.75
3a II
3a III
3a IV
3a V
3a VI
3b I
3b II
3b III
3b IV
3b V
3b VI
Nystatin
a
31 1.1
48
2
15 0.6
13 0.5
29 1.2
19 0.67
22
1
30 1.2
37 1.5
Values are mean of three determinations, the ranges of which are less than 5% of the mean in all cases.

B.S. Priya et al. / European Journal of Medicinal Chemistry 41 (2006) 1262–1270
1267
Table 6
Inhibitory zone (diameter) mm of compounds against tested fungal strains by disk diffusion method
Compound
Inhibitory zone (diameter) mm
Aspergillus niger
16 0.6
13 0.45
11 0.4
Aspergillus flavus
17 0.71
14 0.58
16 0.7
22 0.9
Fusarium oxysporum
Trichoderma species
Fusarium moniliforme
21 0.9
20 0.8
17 0.67
28 1.2
3a I
3a II
19 0.7
17 0.65
15 0.6
21
1
18 0.8
17 0.65
25 1.1
3a III
3a IV
3a V
3a VI
3b I
3b II
3b III
3b IV
3b V
3b VI
Nystatin
20 0.8
24
8
1
0.31
4
0.14
14 0.6
0.21
21 0.9
24
5
0.2
2
0.08
19 0.84
0.19
1
0.02
19 0.0.8
0.28
15 0.6
18 0.78
6
4
24
0.11
1
2
26
0.09
1
5
7
27 1.2
31 1.3
20 0.87
30 1.2
34 1.4
18 0.78
25 1.2
23 1.1
18 0.7
1
27 1.1
29 1.2
16 0.68
22 0.95
20 0.9
17 0.74
12 0.5
19 0.8
17 0.7
13 0.55
15 0.59
20 0.89
18 0.72
15 0.62
23
1
21 0.9
19 0.8
a
Nystatin (10 μg disc–1); Synthesized compounds (25 μg disc–1). Values are mean of three determinations, the ranges of which are less than 5% of the mean in
all cases.
4. Conclusion
5.1.1. Substituted amides were synthesized by the reported
procedure [12]
In conclusion, we report the synthesis, antimicrobial studies
and crystal structure analysis of newer benzamide derivatives
bearing multifunctional moieties such as phenoxy, sulfathia-
zine, sulfamerazine, sulfadiazine, azepines, etc. Compounds
3bVI, 3aII, 3aV, 3bIII, 3aVI and 3bII showed significant
antibacterial activity and 3bIII, 3bII, 3aIV, 3bV, 3bVI and
3aI exhibited antifungal activity against all the strains tested
and found to be nonstrain dependent. The antimicrobial activ-
ity shown might be partly due to the delocalization of the π
electrons along the O–C–N chain. This produces partial dou-
ble-bond character in the C(O)–N bond. The versatility of the
amide group in forming partial bonds with itself and many
other functional groups is partly responsible for the structural
subtleties of the biologically important proton derivatives [13,
14]. The crystal data of the compounds 3aII and 3bV reveals
that it exhibits both intra and inter molecular hydrogen bond-
ing, which may play a pivotal role for its bioactivities. Modi-
fications to improve the potency of this series by diversifica-
tion of the position and type of amides are currently under
progress in our lab.
5.1.2. Synthesis of N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-
yl)-2-methoxy-benzamide 3aI
It was obtained from the reaction of 10,11-dihydro-5H-
dibenzo[b,f]azepin-3-yl-amine 2I (0.25 g, 1.190 mmol), 2-
methoxybenzoyl chloride (0.242 g, 1.428 mmol) and triethyla-
mine (0.722 g, 7.14 mmol). The product obtained was oily. IR
1
(cm–1 nujol): 3210.8, 1675.6, 1415.1, 1512. H NMR (CDCl3,
400 MHz) δ: 2.72 (s, 4H, -CH2); 3.12 (s, 3H, -O-CH3); 3.79 (s,
1H, NH-IDB); 6.78–7.05 (m, 9H, Ar-H); 7.42 (t, 1H, Ar-H);
7.78 (d, 1H, Ar-H), 10.04 (s, 1H, -NH). Anal. Calcd CHNS: C:
76.72, H: 5.85, N: 8.13. Found: C: 76.66, H: 5.75, N: 8.10.
5.1.3. Synthesis of 2-methoxy-N-[4-(thiazol-2-yl-sulfamoyl)-
phenyl]-benzamide 3aII
It was obtained from the reaction of 4-amino-N-thiazol-2-yl-
benzenesulfonamide 2II (0.25 g, 0.979 mmol), 2-methoxyben-
zoyl chloride (0.2 g, 1.176 mmol) and triethylamine (0.594 g,
5.87 mmol). The product obtained was pure white crystalline
solid. m.p. = 179–182 °C. IR (cm–1 nujol): 3345, 1700, 1478.5,
1
1512. H NMR (CDCl3, 400 MHz) δ: 3.1 (s, 3H, -O-CH3);
5. Experimental
6.61 (d, 1H, Th-H); 6.90–7.20 (m, 4H, Ar-H); 7.42–7.79 (m,
5H, Ar-H), 10.01 (s, 1H, -CO-NH); 10.40 (s, 1H, -SO2-NH).
Anal. Calcd CHNS: C: 52.43, H: 3.88, N: 10.79, S: 16.47.
Found: C: 52.36, H: 3.72, N: 10.71, S: 16.42.
5.1. Chemistry
The melting points were determined on SELACO-650 hot
stage apparatus and are uncorrected. IR (nujol) spectra were
measured on Shimadzu 8300 IR spectrophotometer, H NMR
were recorded on Shimadzu AMX 400-Bruker, 400 MHz spec-
trometer by using CDCl3 as solvent and TMS as an internal
standard (chemical shift in δ ppm). Elemental analyses were
obtained on a Vario-EL instrument. TLC was conducted on
0.25 mm silica gel plates (60F254, Merck) and Column by silica
gel BDH 60–120 mesh. All extracted solvents were dried over
Na2SO4, followed by evaporation in vacuo.
5.1.4. Synthesis of 2-methoxy-N-[4-(4-methyl-pyrimidin-2-yl-
sulfamoyl)-phenyl]-benzamide 3aIII
1
It was obtained from the reaction of 4-amino-N-(4-methyl-
pyrimidin-2-yl)-benzenesulfonamide 2III (0.25 g, 0.946
mmol), 2-methoxybenzoyl chloride (0.192 g, 1.129 mmol)
and triethylamine (0.574 g, 5.672 mmol). The product obtained
1
was oily. IR (cm–1 nujol): 3300.8, 1640, 1455.7, 1523. H
NMR (CDCl3, 400 MHz) δ: 2.50 (s, 3H, Ar-CH3); 3.21 (s,
3H, -O-CH3); 6.76 (d, 1H, Py-H); 6.91–7.01 (m, 2H, Ar-H);
7.45–7.95 (m, 6H, Ar-H); 8.12 (d, 1H, Py-H); 10.12 (s, 2H, -

1268
B.S. Priya et al. / European Journal of Medicinal Chemistry 41 (2006) 1262–1270
CO-NH); 10.35 (s, 2H, -SO2-NH). Anal. Calcd CHNS: C:
57.27, H: 4.55, N: 14.06, S: 8.05. Found: C: 57.12, H: 4.25,
N: 13.99, S: 7.85.
5.1.9. Synthesis of 2-ethoxy-N-[4-(thiazol-2-yl-sulfamoyl)-
phenyl]-benzamide 3bII
It was obtained from the reaction of 4-amino-N- thiazol-2-
yl-benzenesulfonamide 2II (0.25 g, 0.979 mmol), 2-ethoxy-
benzoyl chloride (0.216 g, 1.176 mmol) and triethylamine
(0.594 g, 5.87 mmol). The product obtained was pure white
solid. m.p. = 205–210 °C. IR (cm–1 nujol): 3320.8, 1632.5,
5.1.5. Synthesis of 2-methoxy-N-[4-(pyrimidin-2-yl-sulfamoyl)-
phenyl]-benzamide 3aIV
It was obtained from the reaction of 4-amino-N-pyrimidin-
2-yl-benzenesulfonamide 2IV (0.25 g, 0.998 mmol), 2-methox-
ybenzoyl chloride (0.203 g, 1.194 mmol) and triethylamine
(0.605 g, 5.988 mmol). The product obtained was oily. IR
(cm–1 nujol): 3260, 1620, 1428, 1534.5. 1H NMR (CDCl3,
400 MHz) δ: 3.16 (s, 3H, -O-CH3); 6.76 (d, 1H, Py-H);
6.95–7.05 (m, 2H, Ar-H); 7.45–7.95 (m, 6H, Ar-H); 8.12 (t,
2H, Py-H); 10.05 (s, 2H, -CO-NH); 10.29 (s, 2H, -SO2-NH).
Anal. Calcd CHNS: C: 56.24, H: 4.20, N: 14.57, S: 8.34.
Found: C: 56.12, H: 4.17, N: 14.92, S: 8.31.
1
1455.6, 1457.8. H NMR (CDCl3, 400 MHz) δ: 1.42 (t, 3H, -
CH3); 3.19 (q, 2H, -O-CH2-); 6.66 (d, 1H, Th-H); 6.94–7.16
(m, 4H, Ar-H); 7.38–7.75 (m, 5H, Ar-H), 10.16 (s, 2H, -CO-
NH); 10.53 (s, 2H, -SO2-NH). Anal. Calcd CHNS: C: 53.58,
H: 4.25, N: 10.41, S: 15.89. Found: C: 53.46, H: 4.17, N:
10.33, S: 15.72.
5.1.10. Synthesis of 2-ethoxy-N-[4-(4-methyl-pyrimidin-2-yl-
sulfamoyl)-phenyl]-benzamide 3bIII
It was obtained from the reaction of 4-amino-N-(4-methyl-
pyrimidin-2-yl)-benzenesulfonamide 2III (0.25 g, 0.946
mmol), 2-ethoxybenzoyl chloride (0.209 g, 1.132 mmol) and
triethylamine (0.574 g, 5.672 mmol). The product obtained
was pure white solid. m.p. = 215–217 °C. IR (cm–1 nujol):
5.1.6. Synthesis of 2-(2-(2-methoxybenzoylamino) phenethyl)-
N-(2-methoxybenzoyl) benzenamine 3aV
It was obtained from the reaction of diamino dibenzyl 2V
(0.25 g, 1.179 mmol), 2-methoxybenzoyl chloride (0.4 g, 2.353
mmol) and triethylamine (0.713 g, 7.075 mmol). The product
obtained was oily. IR (cm–1 nujol): 3340, 1620, 1432, 1512.6.
1H NMR (CDCl3, 400 MHz) δ: 2.71 (s, 6H, -O-CH3); 3.06 (s,
4H, -CH2-Ar); 6.92–7.10 (m, 10H, Ar-H); 7.38 (t, 2H, Ar-H);
7.51 (d, 2H, Ar-H), 7.79 (d, 2H, Ar-H); 10.15 (s, 2H, -CO-
NH). Anal. Calcd CHNS: C: 74.50, H: 5.82, N: 5.99. Found:
C: 74.425, H: 5.801, N: 5.899.
1
3365, 1620, 1425, 1523. H NMR (CDCl3, 400 MHz) δ: 1.39
(t, 3H, -CH3); 2.51 (s, 3H, Ar-CH3); 3.09 (q, 2H, -O-CH2-);
6.69 (d, 1H, Py-H); 6.96–7.04 (m, 2H, Ar-H); 7.44–7.91 (m,
6H, Ar-H); 8.05 (d, 1H, Py-H); 10.05 (s, 1H, -CO-NH); 10.56
(s, 1H, -SO2-NH). Anal. Calcd CHNS: C: 58.24, H: 4.89, N:
13.58, S: 7.77. Found: C: 58.14, H: 4.75, N: 13.42, S: 7.65.
5.1.11. Synthesis of 2-ethoxy-N-[4-(pyrimidin-2-yl-sulfamoyl)-
phenyl]-benzamide 3bIV
5.1.7. Synthesis of 2-(2-(2-methoxybenzoylamino)-4-
It was obtained from the reaction of 4-amino-N-pyrimidin-
2-yl-benzenesulfonamide 2IV (0.25 g, 0.998 mmol), 2-ethoxy-
benzoyl chloride (0.221 g, 1.197 mmol) and triethylamine
(0.605 g, 5.988 mmol). The product obtained was pure white
crystalline solid. m.p. = 224–228 °C. IR (cm–1 nujol): 3300,
chlorophenoxy)-N-(2-methoxybenzoyl)benzamine 3aVI
It was obtained from the reaction of 2-(2-amino-4-chloro-
phenoxy) benzenamine 2VI (0.25 g, 1.21 mmol), 2-methoxy-
benzoyl chloride (0.288 g, 1.694 mmol) and triethylamine
(0.734 g, 7.26 mmol). The product obtained was oily. IR
(cm–1 nujol): 3320, 1645, 1422, 1499.5. 1H NMR (CDCl3,
400 MHz) δ: 3.06 (s, 6H, -O-CH3); 6.86–6.96 (m, 5H, Ar-H);
7.05–7.24 (m, 4H, Ar-H); 7.39 (t, 2H, Ar-H); 7.79–7.88 (d,
4H, Ar-H); 10.44 (s, 2H, -NH). Anal. Calcd CHNS: C:
66.87, H: 4.61, N: 5.57. Found: C: 66.77, H: 4.55, N: 5.32.
1
1640, 1456, 1546. H NMR (CDCl3, 400 MHz) δ: 1.39 (t,
3H, -CH3); 2.29 (q, 2H, -O-CH2-); 6.74 (t, 1H, Py-H), 6.98–
7.10 (m, 2H, Ar-H); 7.34 (t, 1H, Ar-H); 7.88–7.94 (m, 5H, Ar-
H); 8.23 (dd, 2H, Py-H), 10.16 (s, 2H, -CO-NH); 10.48 (s, 2H,
-SO2-NH). Anal. Calcd CHNS: C: 57.27, H: 4.55, N: 14.06, S:
8.05. Found: C: 57.22, H: 4.47, N: 14.00, S: 7.95.
5.1.8. Synthesis of N-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-
5.1.12. Synthesis of 2-(2-(2-ethoxybenzoylamino)phenethyl)-N-
yl)-2-ethoxy-benzamide 3bI
(2-ethoxybenzoyl) benzenamine 3bV
It was obtained from the reaction of 10, 11-dihydro-5H-
dibenzo[b,f]azepin-3-yl-amine 2I (0.25 g, 1.190 mmol), 2-
ethoxybenzoyl chloride (0.263 g, 1.424 mmol) and triethyla-
mine (0.722 g, 7.14 mmol). The product obtained was pale
brown solid. m.p. = 130–133 °C. IR (cm–1 nujol): 3410,
It was obtained from the reaction of diamino dibenzyl 2V
(0.25 g, 1.179 mmol), 2-ethoxybenzoyl chloride (0.435 g,
2.358 mmol) and triethylamine (0.713 g, 7.075 mmol). The
product obtained was pale brown crystalline solid. m.p. =
1
117–120 °C. IR (cm–1 nujol): 3384, 1645, 1475, 1532. H
1
1650.4, 1455.9, 1489.5. H NMR (CDCl3, 400 MHz) δ: 1.28
NMR (CDCl3, 400 MHz) δ: 1.24 (t, 6H, -CH3); 3.15 (s, 4H, -
CH2-Ar); 3.55 (q, 4H, -O-CH2); 6.95–7.14 (m, 10H, Ar-H);
7.42 (t, 2H, Ar-H); 7.54 (d, 2H, Ar-H), 7.76 (d, 2H, Ar-H);
10.45 (s, 2H, -CO-NH). Anal. Calcd CHNS: C: 75.57, H:
6.34, N: 5.51. Found: C: 75.54, H: 6.72, N: 5.42.
(t, 3H, -CH3); 2.79 (s, 4H, -CH2); 3.08 (q, 2H, -O-CH2-); 3.82
(s, 1H, NH-IDB); 6.82–7.06 (m, 9H, Ar-H); 7.44 (t, 1H, Ar-H);
7.75 (d, 1H, Ar-H), 10.02 (s, 1H, -NH). Anal. Calcd CHNS: C:
77.07, H: 6.19, N: 7.82. Found: C: 76.86, H: 6.11, N: 7.71.

B.S. Priya et al. / European Journal of Medicinal Chemistry 41 (2006) 1262–1270
1269
5.1.13. Synthesis of 2-(2-(2-ethoxybenzoylamino)-4-
chlorophenoxy)-N-(2-ethoxybenzoyl) benzamine 3bVI
compounds. Plates were first kept at 4 °C for at least 2 hours to
allow the diffusion of chemicals and then incubated at 28 °C.
Inhibition zones were measured after 24 hours of incubation
for bacteria and after 48 hours of incubation for fungi. The
microdilution method [20] was followed to determine the mini-
mum inhibitory concentration (MIC) of all the compounds
against bacterial strains. The nutrient liquid medium was used
as test media. Tests were performed in 96-well round bottom
sterile culture plates. The wells of the microdilution plate were
inoculated with 180 μl of the culture medium containing a final
inoculum of 0.5 × 2.5 × 103 CFU ml–1 [21]. All the com-
pounds previously solubilized in DMSO were serially diluted
twofolds in the liquid medium and had concentration 640–0.
1 μg ml–1. Twenty microliter of each concentration was
added to each well containing the culture suspension except
the growth control well. The final concentration ranged from
64 to 0.01 μg ml–1. Plates were incubated at 35 °C for
48 hours. Growth was assessed at 494 nm by measuring the
optical density in each well using an enzyme immunoassay
multiwell reader (Sigma Diagnostic). Turbidometric method
[22,23] was used to check antifungal activity of the compounds
at different concentrations using nystatin as the positive control
and DMSO as the negative control. To the culture tubes con-
taining 1.9 ml of sterile media, 0.1 ml of the test compound
was added at sterile conditions. Fresh inoculum was added to
all the tubes including standard and controls with a spore con-
centration adjusted to 1 × 106 spores ml–1. After incubating all
tubes at 37 °C for 48 hours, absorbance was recorded at
610 nm. Percentage of inhibition was calculated according to
the formula
It was obtained from the reaction of 2-(2-amino-4-chloro-
phenoxy)benzenamine 2VI (0.25 g, 1.21 mmol), 2-ethoxyben-
zoyl chloride (0.312 g, 1.694 mmol) and triethylamine
(0.734 g, 7.26 mmol). The product obtained was pale brown
crystalline solid. m.p. = 98–102 °C. IR (cm–1 nujol): 3360,
1
1660, 1480, 1210. H NMR (CDCl3, 400 MHz) δ: 1.54 (t,
6H, -CH3), 4.29 (q, 4H, -O-CH2-), 6.79–6.92 (m, 5H, Ar-H);
7.01–7.19 (m, 4H, Ar-H); 7.41 (t, 2H, Ar-H); 7.74–7.85 (d,
4H, Ar-H); 10.45 (s, 2H, -NH). Anal. Calcd CHNS: C:
66.60, H: 4.99, N: 5.55. Found: C: 66.52, H: 4.65, N: 5.42.
5.2. Crystal structure analysis of 3aII and 3bV
Single crystals of 3aII and 3bV suitable for X-ray diffrac-
tion studies were mounted on a glass fiber. The measurements
were made on a DIPLabo Imaging Plate system with graphite
monochromated MoKα radiation. Thirty-six frames of data
were collected using oscillation method. Image processing
and data reduction were done using Denzo [15]. The structure
was solved using maXus [16]. All the non-hydrogen atoms
were revealed in the first map itself [17]. Initially, the full-
matrix least squares refinement for 7270 reflections for 3aII
and 4657 reflections for 3bV with isotropic temperature factors
for all the non-hydrogen atoms was carried out [18]. The R1
value of 3aII is 0.0862. The R1 value of 3bV is 0.0938.
5.3. Antimicrobial activity
% Inhibition ¼ 100ðP ꢀ QÞ=P
Bacteria and fungal species used were obtained from
Department of Studies in Biotechnology, University of
Mysore, India, namely, Bacillus substilis, Escherichia coli,
Pseudomonas fluorescens, Xanthomonas campestris pvs,
Xanthomonas oryzae, Aspergillus niger, Aspergillus flavus,
Fusarium oxysporum, Trichoderma species and Fusarium mon-
iliforme. The bacterial strains were maintained on LB agar
medium and the filamentous fungi were maintained on potato
dextrose agar (PDA) medium at 28 °C. The disk diffusion
method [19] was used to determine antibacterial and antifungal
activity of the synthesized compounds. Paper discs with
DMSO were used as negative controls. The bacteria were
grown in LB broth, centrifuged at 10,000 rpm for 5 min, pellet
was dissolved in double distilled and used to inoculate the
plates. The inoculum was prepared with the spores derived
from 5 to 15 days culture on PDA medium for the filamentous
fungi. The mycelia were covered with 10 ml of distilled water
and the conidia were scraped using a sterile pipette. The spores
were recovered after filtration on sterile absorbent cotton and
were resuspended in sterile distilled water. The cell density of
each inoculum was adjusted with hemocytometer in order to
obtain a final concentration of approximately 104 CFU ml–1
and 106 spores ml–1 for the bacteria and filamentous fungi,
respectively. Nystatin (Himedia) was used as a positive control
for fungi and streptomycin and tetracycline for bacteria. Each
disk contained 10 μg of standard drugs and 25 μg synthesized
where P = absorbance without test sample and Q = absorbance
with test sample. Then the MIC was recorded in μM. All deter-
minant tests were performed duplicate and the results were
reported as mean of these values.
Acknowledgements
The authors are grateful to CSIR, DST-FIST and UGC-SAP
(Phase I) DRS Programme, New Delhi, Government of India
for financial assistance under the projects no: 01(1904)/03/
EMR-I, DV6/15/DST/2005-06, SP/I2/FOO/93 and DV4/375/
2004-05. We are thankful to NMR Research Institute, Banga-
lore, for NMR spectral analysis.
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