Synthesis and study of some new N-substituted imide derivatives as potential antibacterial agents

Article abstract of DOI:10.2478/s11696-010-0049-z

Dibenzobarrelene (I) was used as a starting compound for the synthesis of some new 3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-1H-benzo[f]isoindole-1,3(2H)-diones, N-substituted with: 4-toluenesulfonyloxy, III; butoxy, IV; 3-bromopropoxy, V; 3-(4-phenylpiperazi

Full text of DOI:10.2478/s11696-010-0049-z

Chemical Papers 64 (5) 637–644 (2010)
DOI: 10.2478/s11696-010-0049-z
ORIGINAL PAPER
Synthesis and study of some new -substituted imide derivatives
as potential antibacterial agents
Abd El-Galil M. Khalil, Moged A. Berghot, Moustafa A. Gouda*
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 35516 Egypt
Received 1 February 2010; Revised 16 April 2010; Accepted 20 April 2010
Dibenzobarrelene (I ) was used as a starting compound for the synthesis of some new
3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-1H-benzo[f ]isoindole-1,3(2H )-diones, N-substituted with: 4-
toluenesulfonyloxy, III; butoxy, IV; 3-bromopropoxy, V; 3-(4-phenylpiperazin-1-yl)propoxy, VI; 3-
chloro-3-oxopropyl, VIII; 3-(4-phenylpiperazin-1-yl)-3-oxopropyl, IXa; 3-(4-methylpiperazin-1-yl)-
3-oxopropyl, IXb; 3-oxo-3-(piperidin-1-yl)propyl, X; 3-morpholino-3-oxopropyl, XI; 3-phenylamino-
3-oxopropyl, XII; 2-acetylaminoethyl, XIV; 2-aminoethyl, XV, and 2-acetoxyethyl, XVI. Newly
synthesized compounds were characterized by IR, 1H and 13C NMR, and mass spectral data. Se-
lected products were tested for antimicrobial activity.
c
ꢀ 2010 Institute of Chemistry, Slovak Academy of Sciences
Keywords: dibenzobarellene, bromopropoxy, propionamide, isoindole, cyclic imides, antibacterial
agents
Introduction
Gallenkamp electric melting point apparatus. TLC
analyses were carried out on silica gel 60 F254 pre-
coated aluminum sheets (Sigma–Aldrich, Germany).
IR spectra were recorded using the wafer technique
on a MATSON 5000 FTIR spectrometer (Faculty of
Science, Mansoura University, Egypt). 1H NMR spec-
tra were determined on a Varian XL-200 (Faculty
of Science, Cairo University, Egypt), Bruker WP-300
(Georg-August University, Goettingen, Germany),
and a Bruker AC-300 (Eberhard-Karls University,
Tuebingen, Germany) instruments. 13C NMR spectra
were determined on a Bruker AC-300 (Eberhard-Karls
University, Tuebingen, Germany). For NMR measure-
ments, CDCl3 or DMSO-d6 as a solvent and TMS as
an internal standard were used. Mass spectra were
recorded on a Finnigan MAT 212 instrument. Elemen-
tal analyses (C, H, N) were carried out on an elemental
analyzer Vario EL III (Microanalytical Center, Cairo
University, Egypt).
Imides are a valuable group of bioactive com-
pounds showing androgen receptor antagonist activ-
ity, anti-inflammatory, anxiolytic, antiviral, antibac-
terial, and antitumor properties (Salvati et al., 2005;
Kossakowski & Jarocka, 2001; Jindal et al., 2005;
Légora Machado et al., 2005; Suzuki et al., 2005;
Bran˜a et al., 2002; Fernández Bran˜a et al., 1989).
Moreover, N-substituted cyclic imides bearing a 3-(4-
phenyl-piperazin-1-yl)propyl moiety show significant
antidepressive activity (Sieklucka-Dziuba et al., 1995;
Wiczyn´ska et al., 1989; Samant & Kulkarni, 1979;
Khadilkar & Samant, 1986, 1993; Desai & Samant,
2000; Cegꢀla et al., 1996; Wu et al., 1969). This moi-
ety also shows antihypertensive and hypotensive ac-
tivities (Khadilkar & Samant, 1986, 1993). Therefore,
some new cyclic imide derivatives were synthesized,
starting from dibenzobarellene (Clar, 1931), in order
to investigate their antibacterial activity.
The agar diffusion technique (Cruickshank et al.,
1973), using a solution of the tested compound in
DMSO (2 mg mL−1) and DMSO as a control, was ap-
plied for in vitro antibacterial activity testing against
Bacillus thuringiensis (as gram-positive bacteria) and
Experimental
Melting points (uncorrected) were measured on a
*Corresponding author, e-mail: dr mostafa chem@yahoo.com

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A. E.-G. M. Khalil et al./Chemical Papers 64 (5) 637–644 (2010)
Escherichia coli (as gram-negative bacteria). The bac-
teria were maintained on nutrient agar. DMSO showed
no inhibition zones. The agar media were incubated
with different microorganism cultures tested. After 24
h of incubation at 30◦C, diameter of the inhibition
zone (mm) was measured (Table 1). Ampicillin and
chloramphenicol (purchased from Egyptian market) in
DMSO were used as reference drugs.
tetrahydro-4,9-[1,2]benzeno-1H-benzo[f]iso-
indole-1,3(2H)-dione (X), 2-(3-Morpholino-
3-oxopropyl)-3a,4,9,9a-tetrahydro-4,9-
[1,2]benzeno-1H-benzo[f]isoindole-1,3(2H)-
dione (XI), 3-(1,3-Dioxo-3a,4-dihydro-
4,9-[1,2]benzeno-1H-benzo[f]isoindol-
2(3H,9H,9aH)-yl)-N-phenylpropanamide
(XII)
1,3-Dioxo-3a,4-dihydro-4,9-[1,2]benzeno-1H-
benzo[f]isoindol-2(3H,9H,9aH)-yl 4-methyl-
benzenesulfonate (III), 2-Butoxy-3a,4,9,9a-
tetrahydro-4,9-[1,2]benzeno-1H-benzo[f]iso-
indole-1,3(2H)-dione (IV), 2-(3-Bromoprop-
oxy)-3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-
1H-benzo[f]isoindole-1,3(2H)-dione (V)
General procedure: A mixture of VIII (1.83 g,
5 mmol), triethylamine (0.5 cm3, 3.6 mmol), and
the corresponding amine (N-phenylpiperazine, N-
methylpiperazine, aniline, piperidine, or morpholine,
5 mmol) was heated under reflux in dichloromethane
(30 cm3) for 2 h. The solvent was evaporated under re-
duced pressure and the residue was washed with aque-
ous ethanol (20 cm3, 80 vol. %). The obtained solid
was crystallized from benzene (15 cm3) to give pure
product.
General procedure: Compound II (5.83 g, 0.02 mol)
was added portionwise to a mixture of the correspond-
ing halide (0.02 mol of p-toluenesulfonyl chloride or
0.025 mol of 1-bromobutane or 1,3-dibromopropane,
respectively) and triethylamine (2.5 cm3, 0.018 mol)
in DMF (20 cm3) and the mixture was heated at 85–
95◦C for 3–5 h. The reaction mixture was poured into
water (25 cm3), the precipitated solid was filtered off
and recrystallized from benzene/ethanol (ca. 20 cm3,
ϕr = 3 : 1 for III, ϕr = 1 : 1 for IV and V ) to give
pure products as white crystals.
2,2ꢀ-(Ethane-1,2-diyl)bis(3a,4,9,9a-tetrahydro-
4,9-[1,2]benzeno-1H-benzo[f]isoindole-
1,3(2H)-dione) (XIII)
This compound was prepared according to an al-
ready described method (Kitahonoki & Kido, 1975)
as follows: A mixture of I (0.64 g, 2.3 mmol) and
ethylenediamine (0.14 g, 2.3 mmol) in dioxane or pyri-
dine (15 cm3) was heated under reflux for 2 h. After
cooling, the obtained solid was filtered off and washed
with hot DMF (15 cm3) to afford XIII.
2-(3-(4-Phenylpiperazin-1-yl)propoxy)-
3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-1H-
benzo[f]isoindole-1,3(2H)-dione (VI)
N-(2-(1,3-Dioxo-3a,4-dihydro-4,9-[1,2]benzeno-
1H-benzo[f]isoindol-2(3H,9H,9aH)-
yl)ethyl)acetamide (XIV)
A mixture of V (2.06 g, 5 mmol), N-phenylpiper-
azine (0.81 g, 5 mmol), and triethylamine (1 cm3, 7
mmol) in DMF (10 cm3) was heated at 90◦C for 2 h.
The reaction mixture was poured into water (20 cm3)
and the obtained solid was crystallized from benzene
(20 cm3) to give VI as white crystals.
A mixture of I (0.64 g, 2.3 mmol), ethylenediamine
(0.14 g, 2.3 mmol), and fused sodium acetate (0.19 g,
2.3 mmol) in glacial acetic acid (15 cm3) was heated
under reflux for 3 h. After cooling to room temper-
3-(1,3-Dioxo-3a,4-dihydro-4,9-[1,2]benzeno-1H- ature, the separated product was filtered off, washed
benzo[f]isoindol-2(3H,9H,9aH)-yl)propanoyl
chloride (VIII)
with water, and crystallized from DMF/MeOH to af-
ford XIII as a white powder. The filtrate was poured
into water (20 cm3), the separated solid was filtered
off and crystallized from ethanol/benzene (20 cm3, ϕr
= 3 : 1) to give XIV as white crystals.
Compound VII (13.89 g, 0.04 mole) was treated
with thionyl chloride (75 cm3, 1.03 mol) and the reac-
tion mixture was heated under reflux for 6 h. The ex-
cess of thionyl chloride was distilled off and the residue
was crystallized from benzene (15 cm3) to give VIII
as a white powder.
2-(2-Aminoethyl)-3a,4,9,9a-tetrahydro-4,9-
[1,2]benzeno-1H-benzo[f]isoindole-1,3(2H)-
dione (XV)
2-(3-(4-Phenylpiperazin-1-yl)-3-oxopropyl)-
3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-1H-
benzo[f]isoindole-1,3(2H)-dione (IXa), 2-
(3-(4-Methylpiperazin-1-yl)-3-oxopropyl)-
3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-1H-
benzo[f]isoindole-1,3(2H)-dione (IXb), 2-
(3-Oxo-3-(piperidin-1-yl)propyl)-3a,4,9,9a-
A solution of I (1.24 g, 4.5 mmol) and ethylene-
diamine (0.28 g, 4.6 mmol) in DMF (15 cm3) was
refluxed for 3 h and then left at room temperature
overnight. The separated product was filtered off and
crystallized from DMF/MeOH (20 cm3, ϕr = 2 : 1) to
give XIII. The filtrate was poured into water (20 cm3)
and the obtained solid was filtered off and crystallized

A. E.-G. M. Khalil et al./Chemical Papers 64 (5) 637–644 (2010)
639
2
1
O
3
O
10
11
12
ii
4
O
5
N
O
OSO2C6H4CH3-p
9
I
6
6
O
8
7
III
i
7
8
O
O
1
9
iii
iv
CH3
5
N
O
O
N
O
OH
4
3
IV
II
O
O
v
Br
N
N
O
O
N
O
N
Ph
O
VI
V
Fig. 1. Synthesis and reactions of 2-hydroxy-3a,4,9,9a-tetrahydro-4,9-[1,2]benzeno-1H-benzo[f ]isoindole-1,3(2H )-dione (II). Re-
action conditions: i) hydroxylamine hydrochloride, pyridine, HCl; ii) 4-toluenesulfonyl chloride, DMF, Et3N; iii) 1-
bromobutane, DMF, Et3N; iv) 1,3-dibromopropane, DMF, Et3N; v) N-phenylpiperazine, DMF, Et3N.
O
O
O
O
O
i
ii
O
N
OH
N
Cl
O
O
O
I
VII
VIII
O
O
O
O
O
v
iii
N
N
N
N
O
N
R
O
O
X I
VIII
IXa, R = Ph; IX b, R = CH3
O
O
O
vi
iv
N
O
N
N
O
NHPh
X II
X
Fig. 2. Synthesis and reactions of 3-(1,3-dioxo-3a,4-dihydro-4,9-[1,2]benzeno-1H-benzo[f ]isoindol-2(3H,9H,9aH )-yl)propanoyl chlo-
ride (VIII). Reaction conditions: i) 3-aminopropanoic acid, dioxane, Na2CO3; ii) thionyl chloride; iii) N-phenylpiperazine
or N-methylpiperazine, CH2Cl2, Et3N; iv) piperidine, CH2Cl2, Et3N; v) morpholine, CH2Cl2, Et3N; vi) aniline, CH2Cl2,
Et3N.
from ethanol/benzene (25 cm3, ϕr = 4 : 1) to give XV
as white crystals.
poured into water (25 cm3) and the obtained solid
was filtered off and recrystallized from methanol to
give XVI as white crystals.
2-(1,3-Dioxo-3a,4-dihydro-4,9-[1,2]benzeno-
1H-benzo[f]isoindol-2(3H,9H,9aH)-yl)ethyl
acetate (XVI)
2-(2-Hydroxyethyl)-3a,4,9,9a-tetrahydro-4,9-
[1,2]benzeno-1H-benzo[f]isoindole-1,3(2H)-
dione (XVII)
A mixture of I (1.38 g, 5 mmol) and ethanolamine
(0.31 g, 5 mmol) in glacial acetic acid (15 cm3) was
heated under reflux for 4 h. The reaction mixture was
The above given procedure applying dioxane/pyri-
dine (20 cm3, ϕr = 3 : 1) or DMF (20 cm3) instead

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A. E.-G. M. Khalil et al./Chemical Papers 64 (5) 637–644 (2010)
O
i
O
N
N
O
X III
O
O
O
ii
N
+ H2NCH2CH2NH2
O
NHCOCH3
O
O
X IV
I
O
iii
N
NH2
O
X V
Fig. 3. Reaction of dibenzobarrelene (I) with ethylenediamine in different solvents: i) dioxane/pyridine; ii) AcOH, AcONa; iii)
DMF.
O
i
N
OCOCH3
O
O
X VI
O
O
+ H2NCH2CH2OH
O
I
ii
N
OH
O
X VII
Fig. 4. Reaction of dibenzobarrelene (I) with ethanolamine in different solvents: i) AcOH, AcONa; ii) DMF or dioxane/pyridine.
of acetic acid and heating for 3 h was used. The ob-
tained solid was recrystallized from acetone to afford
XVII (82 % or 87 % yield for the reaction in diox-
ane/pyridine or DMF, respectively; m.p. = 220◦C, lit.:
218◦C (Weber et al., 1991)).
and 76.8 characteristic of CH3, (CH2)2, and OCH2
carbon atoms, respectively. Mass spectrum of V ex-
hibited molecular ion peaks M+ (0.6 %) and [M+
+
2] (0.6 %) at m/z 411 and 413, respectively.
Treatment of V with N-phenylpiperazine in DMF
afforded the corresponding 3-(4-phenylpiperazin-1-
yl)propyl derivative VI. The presence of piperazine
ring in VI was confirmed by a triplet at δ 2.55 and a
Results and discussion
1
The target compounds were synthesized as out-
lined in Figs. 1–3. Starting compound I reacted with
hydroxylamine as reported by Saikia et al. (1988)
to give N-hydroxyl derivative II. Subsequent reaction
of II with p-toluenesulfonyl chloride, 1-bromobutane
or 1,3-dibromopropane furnished the corresponding
cyclic imides, III–V, respectively (Fig. 1). Their struc-
ture was confirmed on the basis of analytical and spec-
multiplet at δ 3.1–3.3 in the H NMR spectra.
An attempt was also made to introduce a 3-
oxypropyl linker between the nitrogen atoms of the
imide group and piperazine ring, respectively. There-
fore, the 2-propanoic acid derivative VII was prepared
according to a previously reported method (Weber
et al., 1991). Reaction of VII with thionyl chloride
gave the acyl chloride derivative VIII which, on treat-
ment with N-phenyl- or N-methylpiperazine in methy-
lene chloride containing a catalytic amount of triethy-
lamine, gave corresponding amides IXa or IXb, respec-
tively.
1
tral data (Tables 2 and 3). H NMR spectrum of III
displayed a singlet at δ 2.4 corresponding to protons
of a CH3 group. Signal of the carbon atom of this
group was observed at δ 21.8. 13C NMR spectrum of
IV revealed characteristic signals at δ 13.4, 18.5, 29.5,
The IR spectrum of VIII showed the absence of

A. E.-G. M. Khalil et al./Chemical Papers 64 (5) 637–644 (2010)
641
Table 1. Inhibition zone (diameter of inhibition in mm) as a
criterion of antibacterial activities of newly synthe-
sized compounds
trum of IXa displayed multiplets overlapping in the
range of δ 3.0–3.1 and δ 3.3–3.5, respectively, due to
eight methylene protons of the piperazine ring. 13C
NMR spectrum of IXa exhibited signals at δ 29.9, 34.2,
41.2, 45.0, 46.6, and 167.9 characteristics of NCH2CH2
(piperazine) and CH2CH2CO carbon atoms, respec-
tively. 13C NMR spectrum of IXb revealed signals of
analogous carbon atoms at δ 30.0, 37.9, 41.4, 46.7,
54.6, 55.0, and 169.9 and an additional signal at δ
22.8 characteristic of the CH3 group.
Similarly, imides X–XII were obtained by the reac-
tion of VIII with morpholine, piperidine, and aniline,
respectively. 13C NMR spectrum of X revealed sig-
nals at δ 24.3, 25.5, 29.8, 34.3, and 42.3 characteris-
tic of the piperidine methylene carbon atoms and the
NCH2CH2CO moiety, respectively. In addition, sig-
nals at δ 33.4, 33.8, and 167.4, corresponding to the
COCH2CH2 moiety were observed.
Inhibition zone/mm
Compound
Bacillus thuringiensis Escherichia coli
III
IV
V
VI
VII
IXa
IXb
X
XI
21
17
21
20
16
16
15
16
16
16
18
23
15
15
14
13
13
–
–
–
–
–
XII
Ampicillin
Chloramphenicol
19
20
The study was also extended to the reactions of
I with ethylenediamine and ethanolamine in different
solvents to furnish new derivatives of cyclic imides.
Thus, treating I with ethylenediamine in acetic acid
afforded a mixture of the N,Nꢀ-ethylenebis-imide XIII
the band of the hydroxyl group and instead, bands of
carbonyl were observed, which were assigned to acid
chloride (1794 cm−1) and cyclic imide groups (1765
1
cm−1, 1705 cm−1), respectively. The H NMR spec-
Table 2. Characterization data of newly prepared compounds
wi(calc.)/%
wi(found)/%
Yield
M.p.
Compound
Formula
Mr
C
H
N
%
73
93
87
80
90
75
72
68
65
92
◦C
245
III
IV
C25H19NO5S
C22H21NO3
C21H18BrNO3
C31H31N3O3
C21H16ClNO3
C31H29N3O3
C26H27N3O3
C26H26N2O3
C25H24N2O4
C27H22N2O3
C38H28N2O4
C22H20N2O3
C20H18N2O2
C22H19NO4
445.49
347.41
412.28
493.60
365.81
491.58
429.51
414.50
416.47
422.48
576.64
360.41
318.37
361.39
67.40
67.48
76.06
76.13
61.18
61.14
75.43
75.52
68.95
69.02
75.74
75.81
72.71
72.85
75.34
75.43
72.10
72.23
76.76
76.71
79.15
79.24
73.32
73.44
75.45
75.53
73.12
73.24
4.30
4.41
6.09
6.14
4.40
4.38
6.33
6.40
4.41
4.48
5.95
6.02
6.34
6.41
6.32
6.39
5.81
5.90
5.25
5.21
4.89
4.95
5.59
5.68
5.70
5.86
5.30
5.38
3.14
3.23
4.03
4.16
3.40
3.37
8.51
8.59
3.83
3.90
8.55
8.67
9.78
9.89
6.76
6.83
6.73
6.82
6.63
6.61
4.86
4.93
7.77
7.86
8.80
8.94
3.88
3.97
187
V
190
VI
156
VIII
IXa
IXb
X
183–185
243–244
221–222
234
XI
245
XII
XIII
XIV
XV
XVI
249
14a
30b
24
> 325
208
66
83
220
149
a) Using glacial acetic acid and fused sodium acetate as a reaction solvent; b) using DMF.

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A. E.-G. M. Khalil et al./Chemical Papers 64 (5) 637–644 (2010)
Table 3. Spectral data of newly prepared compounds
Compound
Spectral data
IR, ν˜/cm−1: 2985 (aliphatic C—H), 1768, 1710 (2C O)
—
III
IV
—
1H NMR (CDCl3), δ: 2.4 (s, 3H, CH3), 3.3 (s, 2H, H-11, H-12), 4.8 (s, 2H, H-9, H-10), 7.3–7.7 (m, 12H, Haryl
)
13C NMR (CDCl3), δ: 168.7, 146.8, 140.9, 138.0, 131.1, 129.8, 129.3, 127.5, 127.0, 125.2, 124.2, 44.9, 43.8, 21.8
IR, ν˜/cm−1: 2960, 2933 (aliphatic C—H), 1770, 1717 (2C O), 1222 (N—O)
1H NMR (CDCl3), δ: 0.8–0.9 (t, 3H, CH3), 1.3–1.5 (m, 4H, 2CH2), 3.1–3.4 (m, 4H, OCH2, H-11, H-12), 4.8 (s, 2H,
—
—
H-9, H-10), 7.2–7.7 (m, 8H, Haryl
)
13C NMR (CDCl3), δ: 171.4, 140.0, 138.5, 127.0, 126.8, 125.1, 124.2, 76.8, 45.2, 43.5, 29.5, 18.5, 13.4
MS, m/z (Ir/%): 347 (1.3) (M+), 275 (0.4), 202 (10), 178 (100), 152 (5.3), 96 (2.0), 57 (17.4)
IR, ν˜/cm−1: 2963 (aliphatic C—H), 1771, 1718 (2C O), 1221 (N—O), 662 (C—Br)
—
V
—
1H NMR (CDCl3), δ: 1.8 (m, 2H, CH2), 3.1 (s, 2H, H-11, H-12), 3.3–3.5 (m, 4H, CH2Br, CH2O), 4.8 (s, 2H, H-9,
H-10), 7.2–7.6 (m, 8H, Haryl
)
13C NMR (CDCl3), δ: 171.3, 140.8, 138.5, 127.2, 126.9, 125.2, 124.2, 74.8, 45.2, 43.6, 30.8, 28.9
MS, m/z (Ir/%): 413 (0.6) (M+ + 2), 411 (0.6) (M+), 363 (0.5), 233 (1.4), 202 (17.4), 178 (100.0), 96 (3.3), 70 (9.4)
IR, ν˜/cm−1: 2939 (aliphatic C—H), 1772, 1722 (2C O), 1231 (N—O)
—
VI
—
1H NMR (CDCl3), δ: 1.5–1.7 (m, 2H, CH2), 2.35 (t, 2H, CH2N), 2.55 (t, 4H, NCH2CH2), 3.1–3.3 (m, 8H, H-11,
H-12, OCH2, NCH2CH2), 4.9 (s, 2H, H-9, H-10), 6.8–7.4 (m, 13H, Haryl
)
MS, m/z (Ir/%): 493 (12) (M+), 202 (20), 178 (100), 132 (12), 105 (14.6)
−1
—
IR, ν˜/cm : 2918 (aliphatic C—H), 1794, 1765, 1705 (3C O), 765 (C—Cl)
—
VIII
IXa
IR, ν˜/cm−1: 2924, 2827 (aliphatic C—H), 1762, 1669, 1645 (3C O)
—
—
1H NMR (CDCl3), δ: 1.7 (t, 2H, CH2CO), 3.0–3.1 (m, 4H, CH2CH2NPh), 3.2 (s, 2H, H-11, H-12), 3.3–3.5 (m, 4H,
CH2CH2NCO), 3.7 (t, 2H, (CO)2NCH2), 4.8 (s, 2H, H-9, H-10), 6.7–7.5 (m, 13H, Haryl
)
13C NMR (CDCl3), δ: 176.5, 167.9, 150.8, 141.1, 139.2, 129.2, 128.3, 126.8, 126.5, 125.2, 124.2, 120.6, 116.7, 49.6,
49.2, 46.6, 45.0, 41.2, 34.2, 29.9
—
IXb
X
IR, ν˜/cm−1: 2880 (aliphatic C—H), 1765, 1693, 1640 (3C O)
—
1H NMR (CDCl3), δ: 1.8 (t, 2H, CH2CO), 2.3 (s, 3H, CH3), 2.4 (m, 4H, NCH2CH2), 3.2–3.3 (m, 6H, H-11, H-12,
CH2CH2NCO), 3.6 (t, 2H, (CO)2NCH2), 4.8 (s, 2H, H-9, H-10), 7.0–7.5 (m, 8H, Haryl
13C NMR (CDCl3), δ: 176.8, 169.9, 141.4, 138.8, 126.8, 126.6, 124.8, 124.1, 55.0, 54.6, 46.7, 45.4, 45.1, 41.4, 37.9,
)
30.0, 22.8
IR, ν˜/cm−1: 2947, 2858 (aliphatic C—H), 1771, 1700, 1630 (3C O)
1H NMR (CDCl3), δ: 1.4–1.8 (m, 8H, 4CH2), 3.1–3.5 (m, 8H, H-11, H-12, NCH2CH2, (CO)2NCH2), 4.8 (s, 2H,
—
—
H-9, H-10), 7.2–7.6 (m, 8H, Haryl
)
13C NMR (CDCl3), δ: 176.4, 167.6, 141.1, 139.0, 127.1, 126.7, 126.4, 125.1, 124.1, 46.5, 45.5, 42.3, 34.3, 29.8, 25.5,
24.3
MS, m/z (Ir/%): 414 (8.8) (M+), 258 (13.2), 231 (4.4), 202 (8.8), 178 (100), 152 (14.2), 110 (8.3), 84 (47)
XI
XII
IR, ν˜/cm−1: 2968, 2858 (aliphatic C—H), 1772, 1698, 1643 (3C O)
—
—
IR, ν˜/cm−1: 3350 (NH), 2955 (aliphatic C—H), 1768, 1692, 1645 (3C O)
—
—
1H NMR (CDCl3/DMSO-d6), δ: 1.8 (t, 2H, CH2), 3.2–3.6 (m, 4H, CH2, H-11, H-12), 4.8 (s, 2H, H-9, H-10), 7.0–7.7
(m, 13H, Haryl), 9.8 (d, 1H, NH)
13C NMR (CDCl3/DMSO-d6), δ: 175.9, 167.4, 141.3, 138.7, 128.1, 126.2, 126.0, 124.4, 123.9, 122.9, 121.2, 119.1,
46.1, 44.6, 33.8, 33.4
−1
—
IR, ν˜/cm : 2950, (aliphatic C—H), 1771 (2C O), 1713 (2C O)
—
—
—
XIII
XIV
IR, ν˜/cm−1: 3404, 3372 (NH2), 1771, 1702 (2C O)
—
—
1H NMR (CDCl3), δ: 2.8 (t, 2H, NCH2), 3.2 (s, 2H, H-11, H-12), 3.4 (t, 2H, (CO)2NCH2), 4.8 (s, 2H, H-9, H-10),
7.0–7.4 (m, 8H, Haryl), 7.9 (s, 2H, NH2)
13C NMR (CDCl3), δ: 176.4, 160.9, 141.0, 139.4, 126.9, 126.8, 125.7, 124.3, 46.6, 45.4, 37.9, 36.1
IR, ν˜/cm−1: 3271, (NH), 2946 (aliphatic C—H), 1773, 1707, 1652 (3C O)
—
XV
—
1H NMR (CDCl3), δ: 1.9 (s, 3H, CH3), 2.9 (t, 2H, CH2N), 3.2 (s, 2H, H-11, H-12), 3.4 (t, 2H, (CO)2NCH2), 4.8 (s,
2H, H-9, H-10), 7.1–7.4 (m, 8H, Haryl), 10.8 (s, 1H, NH)
13C NMR (CDCl3), δ: 176.9, 170.0, 141.0, 139.4, 126.9, 126.0, 124.3, 46.7, 45.4, 38.3, 38.1, 23.0
IR, ν˜/cm−1: 2961 (aliphatic C—H), 1773, 1734, 1704 (3C O)
—
XVI
—
1H NMR (CDCl3), δ: 1.9 (s, 3H, CH3), 3.1 (s, 2H, H-11, H-12), 3.3 (m, 2H, CH2N), 3.4 (m, 2H, CH2O), 4.7 (s, 2H,
H-9, H-10), 7.2–7.4 (m, 8H, Haryl
)
13C NMR (CDCl3), δ: 176.5, 170.5, 141.3, 138.3, 127.0, 126.7, 124.9, 124.2, 60.6, 46.8, 45.4, 37.0, 20.8
(Kitahonoki & Kido, 1975, 1970; Kitamogi & Kido,
1967; Staniek & Stoll, 1995) and the acetamide deriva-
tive XIV while a mixture of XIII and the 2-aminoethyl
(monoimide) derivative XV was obtained when the
reaction was carried out in DMF instead of acetic
acid. On the other hand, only compound XIII was ob-
tained when the reaction was carried out in dioxane.
Compound XIV was also obtained by usual acetyla-
tion (acetic anhydride, pyridine) of the 2-aminoethyl
derivative XV (Goldfarb, 2009).
1H NMR spectrum of XIV displayed signals at δ
2.8, 3.4, and 7.9 attributed to CH2N, (CO)2 NCH2,

A. E.-G. M. Khalil et al./Chemical Papers 64 (5) 637–644 (2010)
643
and NH2 protons, respectively. The signals at δ 1.9,
2.9, 3.4, and 10.8 observed in the H NMR spectrum
tetrahydro-β-carboline ring system. Synthesis and prelimi-
nary in vivo studies. Die Pharmazie, 51, 932–936.
1
Clar, E. (1931). Zur Kenntnis mehrkerniger aromatischer
Kohlenwasserstoffe und ihrer Abk¨ommlinge, XI. Mitteil.:
of XV were assigned to CH3, CH2N, (CO)2NCH2,
and NH protons, respectively. 13C NMR spectra of
compounds XIV and XV exhibited signals at δ 36.1,
37.9 and 38.1, 38.3, respectively, characteristic of the
(NCH2CH2N) moiety.
¨
Uber die Konstitution des Anthracens, II.: Bemerkungen zu
einer Arbeit von Otto Diels und Kurt Alder. Berichte der
Deutschen Chemischen Gesellschaft, 64, 2194–2200. DOI:
10.1002/cber.19310640854.
Cruickshank, R., Duguid, J. P., Marmion, B. P., & Swain, R.
H. A. (Eds.) (1973). Medical Microbiology (12th ed., vol. 2,
pp. 196–202). Edinburgh, UK: Churchill Livingstone.
Desai, R. A., & Samant, S. D. (2000). Preparation of N-[ω-(4-
aryl-1-piperazinyl)ethyl/propyl]-3-hydroxyphthalimides. In-
dian Journal of Chemistry, 39B, 455–457.
Fernández Bran˜a, M., Fernández, A., Garrido, M., López-
Rodríguez, M. L., Morcillo, M. J., & Sanz, A. M. (1989).
Synthesis, structure and cytostatic activity of a series of N-
substituted 3,4-diphenyl-1H-pyrrole-2,5-diones. Chemical &
Pharmaceutical Bulletin, 37, 2710–2712.
Goldfarb, D. S. (2009). Method for altering the lifespan of eu-
karyotic organisms. U.S. Patent Application Publication No.
US 2009/0163545 A1. Alexandria, VA, USA: United States
Patent and Trademark Office.
Jindal, D. P., Bedi, V., Jit, B., Karkra, N., Guleria, S., Bansal,
R., Palusczak, A., & Hartmann, R. W. (2005). Synthesis
and study of some new N-substituted imide derivatives as
potential anticancer agents. Il Farmaco, 60, 283–290. DOI:
10.1016/j.farmac.2005.01.011.
Similarly, treatment of I with ethanolamine in
refluxing acetic acid gave isoindol-2-yl-ethyl acetate
derivative XVI (Wehner et al., 1981), while the 2-(2-
hydroxyethyl)isoindole derivative XVII was obtained
when the reaction was carried out in pyridine/dioxane
or DMF instead of acetic acid. Reaction of I with
ethanolamine affording compound XVII (Wehner et
al., 1981) was previously studied by Weber et al.
(1991). In the 13C NMR spectrum, compound XVI
exhibited signals at δ 20.8, 37.0, 60.6, and 170.5 char-
acteristic of CH3, NCH2, CH2O, and CO carbons, re-
spectively.
Ten compounds were screened in vitro for their an-
timicrobial activities against two strains of bacteria
Bacillus thuringiensis and Escherichia coli. Measured
inhibition zones are given in Table 1.
The results shown in Table 1 revealed that com-
pounds III, V, and VI exhibited high activity against
Bacillus thuringiensis and moderate activity against
Escherichia coli. Compounds IX–XII showed mod-
erate activity against Bacillus thuringiensis and no
activity against Escherichia coli. Compounds XIII–
XVII were inactive against both bacteria. It is
worth to mention that linking N-cyclic imide with 3-
oxopropyl chain shows certain selectivity in its activ-
ity against Bacillus thuringiensis in comparison with
Escherichia coli.
Khadilkar, B. M., & Samant, S. D. (1993). Synthesis and phar-
macology of 2-[3-(4-aryl-1-piperazinyl)-2-hydroxypropyl/3-
oxopropyl/propoxy]-1H-isoindole-1,3(2H)-diones.
Journal of Chemistry, 32B, 1137–1142.
Indian
Khadilkar, B. M., & Samant, S. D. (1986). Synthesis and
pharmacology of some 2-[3-(4-aryl-1-piperazinyl)propyl]-1H-
benz[d]isoquinoline-1,3-(2H)-diones/2,5-pyrrolidones. Jour-
nal of Indian Chemical Society, 63, 529–530.
Kitahonoki, K., & Kido, R. (1975). N,Nꢀ-Alkylen-bis-dibenzo-
bicyclo-octanopyrrolidin-Verbindungen und ihre Herstellung.
German Patent No. DE 1695796. Munich, Germany: German
Patent and Trademark Office.
Kitahonoki, K., & Kido, R. (1970). N,Nꢀ-alkylene-bis-dibenzo-
bicyclooctanopyrrolidine compounds and production thereof.
U.S. Patent No. 3,513,174. Arlington, VA, USA: U.S. Patent
Office.
In general, as concluding remarks, we can affirm
that the above results from the in vitro screening
of antibacterial activity of the compounds tested can
serve as a guide to their possible chemotherapeutic po-
tential. It requires further confirmatory evidence form
in vivo studies in animals to ascertain their margin of
safety and freedom from undesirable toxic effects on
vital functions.
Kitamogi, K.,
&
Kido, R. (1967). N,Nꢀ-Alkylidenebis(acid
imides). Japan Patent No. JP 9574. Tokyo, Japan: Japan
Patent Office.
Kossakowski, J.,
& Jarocka, M. (2001). Synthesis of new
N-substituted cyclic imides with an expected anxiolytic
activity. XVII. Derivatives of 1-ethoxybicyclo[2.2.2]-oct-
5-one-2,3-dicarboximide. Il Farmaco, 56, 785–789. DOI:
10.1016/S0014-827X(01)01144-2.
Légora Machado, A., Moreira Lima, L., Araújo, J. X., Jr., Fraga,
C. A. M., Gon¸calves Koatz, V. L., & Barreiro, E. J. (2005).
Design, synthesis and antiinflammatory activity of novel ph-
thalimide derivatives, structurally related to thalidomide.
Bioorganic & Medicinal Chemistry Letters, 15, 1169–1172.
DOI: 10.1016/j.bmcl.2004.12.012.
Saikia, R., Singh, A. K., & Bhattacharjee, G. (1988). N-
(Sulfony1oxy)phthalimides and analogues are potent inacti-
vators. Indian Journal of Chemistry, 27A, 790–793.
Salvati, M. E., Balog, A., Shan, W., Wei, D. D., Pickering,
D., Attar, R. M., Geng, J., Rizzo, C. A., Gottardis, M. M.,
Weinmann, R., Krystek, S. R., Sack, J., An, Y., & Kish, K.
(2005). Structure based approach to the design of bicyclic-
1H-isoindole-1,3(2H )-dione based androgen receptor antag-
onists. Bioorganic & Medicinal Chemistry Letters, 15, 271–
276. DOI: 10.1016/j.bmcl.2004.10.085.
Acknowledgements. The authors thank Dr. S. Bondock and
Dr. E. Abd El-Latif, Chemistry Department, Faculty of Sci-
ence, Mansoura University, Egypt, for spectral measurements,
and Dr. A. Mohamadin and Dr. A. El-Morsey, Botany De-
partment, Faculty of Science, Mansoura University, Egypt, for
microbiological screening.
References
Bran˜a, M. F., Domínguez, G., Sáez, B., Romerdahl, C., Robin-
son, S., & Barlozzari, T. (2002). Synthesis and antitu-
mour activity of new dendritic polyamines–(imide–DNA-
intercalator) conjugates: potent Lck inhibitors. European
Journal of Medicinal Chemistry, 37, 541–551. DOI: 10.1016/
S0223-5234(02)01362-4.
Cegꢀla, M. T., Boksa, J., Chojnacka-Wójcik, E., & Misztal,
S. (1996). 4-Aryl-1-piperazinylalkyl derivatives of 1,2,3,4-

644
A. E.-G. M. Khalil et al./Chemical Papers 64 (5) 637–644 (2010)
Samant, S. D., & Kulkarni, R. A. (1979). Synthesis and pharma-
cology of N-(N4-aryl-N1-piprazinylalkyl)phthalimides: CNS
depressants. Journal of Indian Chemical Society, 56, 1002.
Wehner, W., Michaelis, K. P., & Schneider, R. (1981). Alkanol-
amid-beta-ketocarbonsäureester und ihre Verwendung zur
Stabilisierung von chlorhaltigen Thermoplasten. European
Patent Application No. EP 0022749. Munich, Germany: Eu-
ropean Patent Office.
Wiczyn´ska, B., Chojnacka-Wójcik, E., Rokosz-Pelc, A., Mazela,
H., & Przegalin´ski, E. (1989). Antiserotonin activity of 9-
methyl-2-[3-(4-phenyl-1-piperazinylpropyl)]-1,2,3,4-tetra-
hydro-β-carbolin-1-one (B-193). Polish Journal of Pharma-
cology and Pharmacy, 41, 169–181.
Sieklucka-Dziuba, M., Rajtar, G.,
& Kleinrok, Z. (1995).
Some pharmacological properties and cumulative, subchronic
and chronic toxicity of 9-methyl-2-[3-(4-phenyl-1-piperazinyl-
propyl)]-1,2,3,4-tetrahydro-β-carbolin-1-one (B-193). Polish
Journal of Pharmacology, 47, 305–311.
Staniek, P., & Stoll, K. (1995). Imide nucleating agents for poly-
mers. German Patent Application No. DE 19520262. Munich,
Germany: German Patent Office.
Suzuki, K., Nagasawa, H., Uto, Y., Sugimoto, Y., Noguchi, K.,
Wakida, M., Wierzba, K., Terada, T., Asao, T., Yamada,
Y., Kitazato, K., & Hori, H. (2005). Napthalimidobenza-
mide DB-51630: a novel DNA binding agent inducing p300
gene expression and exerting a potent anti-cancer activity.
Bioorganic & Medicinal Chemistry, 13, 4014–4021. DOI:
10.1016/j.bmc.2005.03.053.
Wu, Y.-H., Smith, K. R., Rayburn, J. W., & Kissel, J. W. (1969).
Psychosedative agents. N-(4-phenyl-1-piperazinylalkyl)-sub-
stituted cyclic imides. Journal of Medicinal Chemistry, 12,
876–881. DOI: 10.1021/jm00305a037.
Weber, E., Finge, S., & Csoeregh, I. (1991). Modular design of
hosts involving a rigid succinimide framework and N-bonded
lateral groups. Crystalline inclusion properties and crystal
structures of inclusion compounds with dioxane, MeOH, and
DMF. Journal of Organic Chemistry, 56, 7281–7288. DOI:
10.1021/jo00026a018.