Synthesis of novel 3-chloro-1-(5H-dibenz[b,f]azepine-5yl) propan-1-one derivatives with antioxidant activity

Article abstract of DOI:10.1007/s00044-009-9292-7

A series of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one derivatives (2a-k) bearing different amino acids were synthesized by base condensation reaction. 3-Chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one(2) was obtained by N-acylation of 5H-dibenz[

Full text of DOI:10.1007/s00044-009-9292-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:101–108
DOI 10.1007/s00044-009-9292-7
ORIGINAL RESEARCH
Synthesis of novel 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)
propan-1-one derivatives with antioxidant activity
•
H. Vijay Kumar C. Kishor Kumar
•
Nagaraja Naik
Received: 9 August 2009 / Accepted: 10 December 2009 / Published online: 31 December 2009
Ó Springer Science+Business Media, LLC 2010
Abstract A series of 3-chloro-1-(5H-dibenz[b,f]azepine-
5yl)propan-1-one derivatives (2a–k) bearing different
amino acids were synthesized by base condensation reaction.
3-Chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one(2)
was obtained by N-acylation of 5H-dibenz[b,f]azepine (1).
All the synthesized compounds were evaluated for their
potential over antioxidant activities against inhibition of
lipid peroxidation by b-carotene and linoleic acid assay and
inhibition of human low-density lipoprotein (LDL) oxida-
tion assay. Typically, compound 2 showed weak antioxidant
activity, whereas coupling of different amino acids enhances
the antioxidant activities based on the presence of different
functional groups. Among the derivatives, compound 2d
showed significant antioxidant activities followed by 2h, 2i,
2j and 2k.
in medically useful antioxidants (Block, 1992; Rice-Evans
et al., 1996). Recent evidence (Yen and Chen, 1995) sug-
gests that free radicals, which are generated in many bio-
organic redox processes, may induce oxidative damage in
various components of the body (e.g. lipids, proteins and
nucleic acids) and may also be involved in processes
leading to the formation of mutations. Furthermore, radical
reactions play a significant role in the development of life-
limiting chronic diseases such as cancer, ageing, diabetes,
arteriosclerosis and others (Moskovitz et al., 2000).
It has been suggested that oxidative modification of low-
density lipoproteins (LDLs) may play a role in the develop-
ment of atherosclerosis (Jialal and Devaraj, 1996). The oxi-
dativemodificationdependsonacommoninitiatingstep—the
peroxidation of polyunsaturated fatty acid components in the
LDLs (Steinberg et al., 1989). Such modification of LDLs can
be inhibited by antioxidants (Frankel and Kanner, 1993).
In the literature, some tricyclic amines and their chemical
structure showed antioxidant neuroprotective activity in vitro
(Chirtian Beh and Moosmann, 2000). Nowadays, the free-
radical scavenging mechanism of aromatic amines (Ar2NHs)
has been discussed from the view of chemical kinetics
(Lucarini et al., 1999). 5H-dibenz[b,f]azepine, i.e. iminostil-
bene, is a common basic fused tricyclic amine. It is used as an
intermediate for the synthesis of the registered anticonvulsant
drug oxcarbazepine (Krichka and Ledwith, 1974), the struc-
tureofwhich has recentlybeenreported(Hempeletal., 2005).
Dibenz[b,f]azepine and its derivatives has been variously
reported as having antiallergic activity, specifically antihis-
taminic activity, spansmolytic, serotonin antagonistic, anti-
convulsive, antiemetic, antiepileptic, anti-inflammatory,
sedative and fungicidal action (Fouche and Leger, 1971).
The research on free radicals provides theoretical
information for the medicinal development and supplies
some in vitro methods for quick-optimizing drugs; it
Keywords 5H-dibenz[b,f]azepine ꢀ
3-Chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one ꢀ
Amino acid ꢀ Antioxidant activity
Introduction
Free radicals and active oxygen species have been related
with cardiovascular and inflammatory diseases and even
with a role in cancer and ageing (Beckman and Ames,
1998; Halliwel and Gutteridge, 1989). Efforts to counteract
the damage caused by these species are gaining acceptance
as a basis for novel therapeutic approaches, and the field of
preventive medicine is experiencing an upsurge of interest
H. V. Kumar ꢀ C. K. Kumar ꢀ N. Naik (&)
Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore, Karnataka 570 006, India
e-mail: drnaik_chem@yahoo.co.in
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Med Chem Res (2011) 20:101–108
attracts more scientific attention from bioorganic and
medicinal chemists. In addition to the traditional O–H bond
type antioxidant, tricyclic amines having N–H bond func-
tions as the antioxidant have attracted much research
attention, because aromatic amines (Ar2NHs) have always
been the central structure in many currently used drugs
(You-Zhi and Zai-Qun, 2007). Usually phenolic com-
pounds were found to have antioxidant and radical scav-
enging activities and they also inhibit LDL oxidation
(Vinson et al., 1995; Teissedre and Waterhouse, 2000).
Recently, the antioxidant properties of 5H-dibenz[b,f]
azepine and some of its analogues were reported, and their
structure–activity relationships was established based on
the different substituents and positions (Vijay Kumar et al.,
2008).
series of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-
one derivatives as target compounds were synthesized.
Scheme 1 illustrates the way used for the preparation of
model compound 3-chloro-1-(5H-dibenz[b,f]aqepine-
5yl)propan-1-one, whereas Scheme 2 illustrates the way to
prepare the target compounds. The structure of the com-
pounds was elucidated by IR, 1H NMR, mass spectral data
and elemental analysis. In the IR spectra of 3-chloro-1-(5H-
dibenz[b,f]azepine-5yl)propan-1-one, C=O stretching band
was observed at about 1675.3 cm-1 and CH2 stretching
band was observed at 2971.0–3026.1 cm-1. Absence of N–
H band at 3360 cm-1 confirms the N-acylation reaction. An
absorption band at 3067.9–2700 cm-1 was observed due to
aromatic stretching. The structure of compound 2 was con-
firmed by the absence of signal at 3.5 ppm which corre-
sponds to N–H proton signal of seven-membered ring. The
signal due to seven-membered Ar–H protons was appeared
as singlet at around 6.9 ppm and two methylene protons was
appeared at 2.8 and 3.7 ppm as triplet, respectively. In the IR
spectra of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-
1-one derivatives, N–H absorption band was observed at
around 3315.5–3361.4 cm-1 region except in the case of
compounds 2f and 2j. The carboxylic –OH stretching was
observed at around 2467–3510 cm-1. The other prominent
absorption bands observed in the IR spectrum are at
1667.6–1679.0 cm-1 (C=O) and 3021.3–2896 cm-1 (Ar–
H). These data proved that coupling of amino acids to the
intermediate has been taken place. On the other hand, in 1H
NMR spectra of all the amino acid analogues, i.e. 2a–k, the
seven-membered two aromatic protons was appeared as
singlet at 6.9–7.0 ppm. Two methylene protons due to N-
acylation were observed at 2.3–3.3 ppm as triplet. N–H
proton was appeared as singlet at 1.9–2 ppm, whereas, but in
case of compounds 2f and 2j, N–H proton peak was disap-
peared at the same position. The acid proton was observed at
around 11.5–12.8 ppm as singlet. Typically, in the case of
compound 2k addition to N–H proton, the N–H proton
present in the imidazole ring of histidine was signalled as
singlet at 13.5 ppm. In the same way, N–H group present in
the indole ring of typtophan in compound 2i signalled as
singlet at 7.3 ppm. All the respective aromatic protons in all
analogues were observed at the expected region. Mass
spectra of all the synthesized analogues showed M? peaks in
agreement with their molecular formula.
Herein, we have reported the synthesis of new 3-chloro-
1-(5H-dibenz[b,f]azepine-5-yl)propan-1-one
analogues
obtainedbycouplingofdifferentaminoacids.Theantioxidant
properties of 3-chloro-1-(5H-dibenz[b,f]azepine-5-yl)pro-
pan-1-one derivatives obtained were evaluated by their inhi-
bition of lipid peroxidation using the b-carotene-linoleic
model system and inhibition of human LDL oxidation assay.
Results and discussion
Chemistry
In this study, the initial compound 5H-dibenz[b,f]azepine
(1) was obtained according to the literature method (Krichka
and Ledwith, 1974). The model compound 3-chloro-1-(5H-
dibenz[b,f]azepine-5-yl)propan-1-one (2) was prepared
from N-acylation of 5H-dibenz[b,f]azepine with 3-chloro
propionylchloride in the presence of triethylamine as base.
Further coupling of different amino acids was done by base
catalyzed condensation reaction to obtain a series of
3-chloro-1-(5H-dibenz[b,f]azepine-5-yl)propan-1-one deriv-
atives (2a–k) with good yield. Here, the amino acids like
glycine, alanine, threonine, cysteine, methionine, proline,
phenylalanine, tyrosine, hydroxyproline, histidine and
tryptophan were used. Selection of amino acids was done on
the basis of its chemical feasibility. The reaction sequences
are outlined in Schemes 1 and 2. In the present study, a
The synthesized compounds were evaluated for antioxi-
dant activity by b-carotene–linoleic acid model system. This
assay is described for rapid evaluation of antioxidant activ-
ity. The method is based on the determination of the coupled
oxidation of carotene and linoleic acid. The basic principle
involved here is linoleic acid, unsaturated fatty acids get
oxidized by reactive oxygen species (ROS) produced
by oxygenated water. The products formed initiate the
b-carotene oxidation, which leads to discoloration. Bleaching
O
Cl
Cl
HCl
+
N
triethylamine, C6H6
RT, 6hr
N
H
O
Cl
(1)
(2)
Scheme 1 Synthesis of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)pro-
pan-1-one (2)
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Med Chem Res (2011) 20:101–108
103
Scheme 2 Reaction sequence
to obtain 3-chloro-1-(5H-
dibenz[b,f]azepine-5yl)propan-
1-one derivatives
CH3OH, K2CO3
reflux, 6ꢀ8hr
HO
O
NH2
R
HCl
+
+
N
N
O
O
NH
Cl
HO
R
O
(2)
(2a-k)
Where,
Compound
2a
R
Compound
2g
R
H
2b
ꢀCH3
2h
OH
2c
ꢀCH3OH
ꢀCH2SH
2i
2j
N
H
OH
2d
N
N
2e
2f
CH2CH2SCH3
2k
N
H
N
of b-carotene, a free-radical mediated phenomenon resulting
from hyperoxides, formed from linoleic acid. b-carotene
looses its double bonds by oxidation, which results in lose of
its characteristic orange colour monitored spectrophoto-
metrically at 470 nm. Bleaching of b-carotene with respect
to time for synthesized compounds at different concentra-
tions is represented in Fig. 1.
anisole (BHA). Whereas in the case of compounds 2c and 2e,
average decrease in the absorbance was viewed. The control
(no additive) was decolorized within 150 min, indicating
that rapid oxidation occurred. The % antioxidant activity
for 3-chloro-1-(5H-dibenz[b,f]azepine-5-yl)propan-1-one
derivatives was measured on the basis of bleaching of
b-carotene is depicted in Table 1. The presence of antioxi-
dant compounds 2d, 2h, 2i, 2j and 2k binds the extent of
b-carotene bleaching by neutralizing the linoleate free rad-
ical; hence extent of decrease in discoloration indicates
higher antioxidant activity. The presence of free S–H group
in 2d analogues, phenolic group in compound 2h, hydroxyl
group attached to the pyrolidine ring in compound 2j and free
N–H group in case of 2i and 2k may donate the hydrogen
atom which decreases the extent of b-carotene bleaching by
neutralizing the linoleate free radical. The extent of decrease
in decoloration by these analogues possesses highest anti-
oxidant activity. The antioxidant activity throughout this
Figure 1 indicates that due to the oxidation of linoleic acid
which eventually attacks the highly unsaturated b-carotene
molecule undergo rapid discoloration. In our experimental
conditions, compounds 2, 2a, 2b, 2f and 2g in the suspension
loose its chromophore when it allowed for oxidation during
different time interval (0–180 min). Initially, the absorbance
of all the compounds was more and decreased drastically
with time allowed for oxidation, but in case of compounds
2d, 2h, 2i, 2j and 2k there is negligible decrease in the
absorbance and the same was also observed in the case of
standards like ascorbic acid (AA) and butylated hydroxy
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Med Chem Res (2011) 20:101–108
Fig. 1 Bleaching of b-carotene
with respect to time in the
presence of 3-chloro-1-(5H-
dibenz[b,f]azepine-5-yl)propan-
1-one derivatives at different
concentrations (a = 10 lM and
b = 25 lM). Each value
represents the mean SD
(n = 3)
(a)
0.45
0.4
0.35
0.3
0 min
30 min
60 min
90 min
120 min
150 min
180 min
0.25
0.2
0.15
0.1
0.05
0
2
2a
2b
2c
2d
2e
2f
2g 2h
2i
2j
2k AA BHA
Compound
(b)
0.45
0.4
0.35
0.3
0 min
30 min
60 min
90 min
120 min
150 min
180 min
0.25
0.2
0.15
0.1
0.05
0
2
2a
2b 2c
2d 2e
2f
2g 2h
2i
2j
2k
AA BHA
Compound
Table 1 Percentage of antioxidant activity of 3-chloro-1-(5H-
dibenz[b,f]azepine-5-yl)propan-1-one derivatives and standards by
b-carotene-linoleic acid mode
the following order: AA [ BHA [ 2h [ 2j [ 2k [ 2i
[ 2d [ 2c [ 2e [ 2b [ 2a [ 2g [ 2.
Antioxidant effects of 3-chloro-1-(5H-dibenz[b,f]aze-
pine-5-yl)propan-1-one derivatives having different con-
centrations were examined by inhibiting human LDL
oxidation in the presence of CuSO4 as an oxidation
inhibitor with different time intervals (2, 4 and 6 h,
respectively). The % inhibition of human LDL oxidation is
shown in the Table 2. From the graph, initially compound
(2) showed less inhibition on LDL oxidation but all its
amino acids derivatives showed enhanced in the inhibition
of LDL oxidation. All the synthesized compounds showed
inhibition of LDL in dose-dependent manner. Among the
analogues at 10 lM, compounds 2h, 2j, 2i and 2d showed
78.69, 75.76, 73.45 and 72.54% at the end of 6 h, whereas,
at 25 lM inhibited 83.54, 77.14, 75.23 and 75.85%,
respectively, showing significant activity. As oxidation
modified LDL may play a role in the pathogenesis of
atherosclerosis, the prevention of LDL oxidation may
reduces the risk of this disease. In this study, it had been
demonstrated that the polyunsaturated fatty acids in LDL
could be protected from oxidation by the 3-chloro-1-(5H-
dibenz[b,f]azepine-5-yl)propan-1-one derivatives. The pres-
ence of phenolic –OH, aromatic N–H and S–H groups
present in the respective amino acids might account for the
prevention of LDL oxidation.
Compound
Percentage (%) antioxidant activitya
10 lM
25 lM
2
2.89
2.96
4.24
8.80
2a
2b
2c
2d
2e
2f
10.00
53.75
82.24
52.58
4.22
15.37
76.03
84.42
67.33
6.15
2g
2h
2i
5.39
8.30
86.79
83.59
85.36
84.96
87.16
86.76
89.07
85.90
88.44
86.76
90.43
89.75
2j
2k
AA
BHA
a
Each value represents the mean SD (n = 3)
assay increases with increase in the concentrations. The
increasing antioxidant activities of synthesized compounds
and the standards in the assays performed are showed in
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Med Chem Res (2011) 20:101–108
105
spectrometer; mass spectra were obtained by the Waters–
Q–TOF ultima spectrometer. Micro analytical data were
obtained by Elemental–Vario EL–III.
Table 2 Percentage of inhibition of human LDL oxidation by
3-chloro-1-(5H-dibenz[b,f]azepine-5-yl)propan-1-one derivatives and
standards at different concentration (a = 10 lM and b = 25 lM)
Compound
Percentage (%) human LDL inhibitiona
Antioxidant evaluation
2 h
4 h
6 h
a
b
a
b
a
b
Inhibition of lipid peroxidation by b-carotene and linoleic
acid assay
2
5.34
7.43
8.24
9.14
6.87
9.77
7.92
8.87
12.43
10.3
2a
2b
2c
2d
2e
2f
6.71
8.92
7.95
9.75
10.2
Each compound at final concentrations of 10 and 25 lM
was incorporated into b-carotene–linoleic acid model sys-
tem independently, and the activity was monitored spec-
trophotometrically at 470 nm (Miller, 1971).
10.14
59.65
73.41
59.78
14.12
16.35
79.58
73.25
75.55
70.12
85.19
82.71
11.01
56.98
72.54
59.67
15.38
13.53
78.69
73.45
75.76
68.53
84.39
83.53
12.13
61.58
75.85
61.59
17.35
18.72
83.54
75.23
77.14
72.69
92.19
90.89
53.54
67.33
54.56
11.93
9.98
56.23
70.48
55.01
13.65
13.14
73.56
71.24
73.65
68.28
79.16
75.71
55.45
69.78
57.86
13.56
11.21
75.45
70.78
73.54
65.73
81.29
79.96
Preparation of the suspension The substrate suspension
was prepared by addition of b-carotene (4 mg dissolved in
5 ml chloroform) into a covered round bottomed flask
containing Tween-40 (600 mg) followed by the addition of
linoleic acid (60 ll). The chloroform was removed com-
pletely under vacuum using rotavapour at 40°C. The
resulting solution was diluted with triple distilled water
(30 ml), and the emulsion was mixed well and diluted with
oxygenated water (120 ml).The aliquots (4 ml) were
transferred to different stopper test tubes containing com-
pound (50 and 100 lM/ml) in distilled ethanol. Control
was prepared with distilled ethanol (1 ml) and emulsion
(4 ml). BHA and ascorbic acid solution as internal stan-
dards of the same concentration were also analyzed for
comparison. Zero adjustment was done using distilled
water. Absorbance of the samples was measured at a
wavelength of 470 nm, immediately (t = 0) and subse-
quently after every 30 min for 3 h (t = 180). The tubes
were placed in a water bath at 50°C between the readings.
Antioxidant activity of each compound was evaluated in
triplicates in terms of photooxidation of b-carotene using
the following formula:
2g
2h
2i
70.45
67.87
69.73
56.34
74.29
70.72
2j
2k
AA
BHA
a
Each value represents the mean SD (n = 3)
Conclusion
In conclusion, we have reported a convenient protocol for
the synthesis of novel 3-chloro-1-(5H-dibenz[b,f]azepine-
5-yl)propan-1-one derivatives by base condensation reac-
tion. The antioxidant property was evaluated using differ-
ent in vitro models. Initially, compound 2 showed
negligible activity. Whereas, coupling of different amino
acids showed enhance in the antioxidant activity. Among
the derivatives, compounds 2d, 2g, 2h, 2i, 2j and 2k were
identified as potent antioxidants. It is conceivable from
these studies that coupling of amino acid to 3-chloro-1-
(5H-dibenz[b,f]azepine-5-yl)propan-1-one can exhibit
interesting antioxidant properties. These effects may be
useful in the treatment of pathologies in which free-radical
oxidation plays a fundamental role.
Â
À
ÁÃ
% Antioxidant activity ¼ 100 1 ꢁ Ao ꢁ At=A0o ꢁ Aot
;
where Ao is the initial absorbance of the sample, At
absorbance of the sample after time ‘t’, A0o initial absor-
bance of the control, Ato absorbance of control after
time ‘t’.
Experimental
Inhibition of human low-density lipoproteins (LDL)
oxidation assay
All the reagents were used as purchased from commercial
suppliers without further purification. Melting points were
determined by an open capillary method and are uncor-
rected. Thin layer chromatography (TLC) was performed
with aluminium sheets—Silica gel 60 F254 purchased from
Merck. The compounds were purified using column chro-
matography with silica gel (60–120 mesh), using chloro-
form: methanol: acetic acid, 65:30:05 as eluent. IR: Nicolet
5700 FT-IR spectrophotometer; 1H NMR: Bruker 250 MHz
Antioxidant effects of newly synthesized compounds were
examined by incubating human LDL in the presence of
CuSO4 as an oxidation initiator (Princen et al., 1992).
Fresh blood was obtained from fasting adult human
volunteers, and plasma was immediately separated by
centrifugation at 1500 rpm for 10 min at 4°C. LDL (0.1 mg
LDL protein/ml) was isolated from freshly separated
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Med Chem Res (2011) 20:101–108
plasma by preparative ultra centrifugation using a Beckman
L8-55 ultra centrifuge. The LDL was prepared from the
plasma, the isolated LDL was extensively dialyzed against
phosphate buffered saline (PBS) pH 7.4 and sterilized by
filtration (0.2 lm Millipore membrane system, USA) and
stored at 4°C under nitrogen. 1 ml of various concentrations
(10 and 25 lM) of compounds was taken in test tubes, 40 ll
of copper sulphate (2 mM) was added and the volume was
made up to 1.5 ml with phosphate buffer (50 mM, pH 7.4).
A tube without copper sulphate with compound served as a
positive control. All of the tubes were incubated at 37°C for
45 min. To the aliquots of 0.5 ml drawn at 2, 4 and 6 h
intervals from each tube, 0.25 ml of thiobarbutaric acid
(TBA, 1% in 50 mM NaOH) and 0.25 ml of trichloro acetic
acid (TCA, 2.8%) were added. The tubes were incubated
again at 95°C for 45 min and cooled to room temperature
and centrifuged at 2500 rpm for 15 min. A pink chromogen
was extracted after the mixture was cooled to room tem-
perature by further centrifugation at 2000 rpm for 10 min.
Thiobarbituric acid reactive species in the pink chromogen
were detected at 532 nm by a spectrophotometer against an
appropriate blank. Data were expressed in terms of mal-
ondialdehyde (MDA) equivalent, estimated by comparison
with standard graph drawn for 1,1,3,3-tetramethoxy-pro-
pane (which was used as standard) which give the amount
of oxidation and the results were expressed as protection per
unit of protein concentration (0.1 mg LDL protein/ml).
Using the amount of MDA, the percentage protection was
(ppm): d 2.8 (d, 2H, CH2–C=O), 3.7 (d, 2H, CH2Cl),
7.5–7.6 (m, 8H, Ar–H), 6.9 (d, 2H, Ar–H of seven-mem-
bered ring); Mass (m/z %): M? 284.56; Anal. Calcd. for
C17H14ClNO: C, 71.96; H, 4.97; Cl, 12.49; N, 4.94; O,
5.64%; Found: C, 71.97; H, 4.97; Cl, 12.48; N, 4.95; O,
5.65%.
General procedure for the synthesis of 3-chloro-1-(5H-di-
benz[b,f]azepine-5yl)propan-1-one derivatives (2a–k)
Amino acid (1.2 mM) in methanol (25 ml) was treated
with K2CO3 (600 mg) under N2 atmosphere. Later the
solution of 3-chloro-1-(5H-dibenz[b,f]azepine-5-yl)pro-
pan-1-one (1 mM) in methanol (50 ml) was added drop by
drop for 30 min. The reaction mixture was refluxed for
6–8 h. The progress of the reaction mixture was monitored
by TLC. The reaction mixture was then desolventized in
rotary evaporator, and the compound is extracted in ethyl
acetate. The ethyl acetate layer was washed with water and
dried over anhydrous Na2SO4. The light yellow solid was
obtained by further desolventation in rotary evaporator at
50°C.
The products were separated and purified by column
chromatography, using mixture of chloroform:metha-
nol:acetic acid = 85:12:3.
Compound 2a: 2-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxo-
propylamino)acetic acid [Glycine analogues] Light yel-
low solid, Yield (77%), M.p. 79–81°C, IR (KBr) mmax
(cm-1): 1669.7 (C=O), 3317.6 (N–H), 3428.5–2713.2
(OH–carboxylic acid), 3052.6–2748.1(Ar–H), 3022.2
calculated using the formula:
À
% Inhibition of LDL oxidation ¼ oxidation in control
Á
1
(CH2) cm-1; H NMR (250 MHz) (DMSO–d6) d (ppm):
ꢁ oxidation in experimental=oxidation in control
ꢂ 100:
7.3–7.7 (m, 8H, Ar–H), 7.0 (s, 2H, Ar–H of seven-mem-
bered ring), 3.5 (d, 2H, CH2 of glycine), 3.0 (t, 2H, CH2–
NH), 2.5 (t, 2H, CH2–C=O), 1.9 (s, 1H, NH), 12.8 (s, 1H,
OH of COOH). Mass (m/z %): M? 322; Anal. Calcd. for
C19H18N2O3: C, 70.79; H, 5.63; N, 8.69; O, 14.89%.
Found: C, 70.76; H, 5.66; N, 8.68; O, 14.91%.
Synthesis of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)pro-
pan-1-one (2) To the well-stirred solution of 5H-di-
benz[b,f]azepine (2 mM) and triethylamine (2.2 mM) in
50 ml benzene, 3-chloro propionylchloride (2.2 mM) in
25 ml benzene was added drop by drop for about 30 min.
Then, the reaction mixture is stirred at room temperature
for about 6 h. Progress of the reaction was monitored by
TLC using 9:1 hexane:ethyl acetate mixture as mobile
phase. After the completion of reaction, the reaction mass
was quenched in ice cold water and extracted in diethyl
ether. The ether layer was washed twice with 5% NaHCO3
followed by distilled water. Finally, the ether layer is dried
with anhydrous Na2SO4. The light yellow solid product
was obtained by desolventation through rotary evaporator
at 35°C.
Compound 2b: 2-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxo-
propylamino)propanoic acid [L-Alanine analogues]
Light yellow solid, Yield (81%), M.p. 83–85°C, IR (KBr)
m
max (cm-1): 1669.3 (C=O), 3315.5 (N–H), 3489.1–2761.2
(OH–carboxylic acid), 3052.1–2748.0 (Ar–H), 3022.2
(CH2); 1H NMR (250 MHz) (DMSO–d6) d (ppm): 7.3–7.7
(m, 8H, Ar–H), 7.0 (s, 2H, Ar–H of seven-membered ring),
3.0 (t, 2H, CH2C=O), 2.4 (t, 2H, CH2–NH), 1.2 (d, 3H,
CH3 of alanine), 3.4 (q, 1H, CH of alanine), 2.0 (s, 1H, NH
of alanine), 12.0 (s, 1H, OH of COOH of alanine). Mass
(m/z %): M? 336.15; Anal. Calcd. for C20H20N2O3: C,
71.41; H, 5.99; N, 8.33; O, 14.27%. Found: C, 71.44; H,
5.98; N, 8.34; O, 14.29%.
Light yellow solid, Yield (85%), M.p. 109–110°C. IR
(KBr) mmax (cm-1): 3067.9–2700 (Ar C–H), 1675.3 (C=O),
2971.0–3026.1 (CH2); 1H NMR (250 mHz) (CDCl3) d
123

Med Chem Res (2011) 20:101–108
107
Compound 2c: 2-(3-(5H-dibenz[b,f]azepine-yl)-3-oxopro-
pyl amino)-3-hydroxy butanoic acid [L-Threonine ana-
logue] Light yellow solid, Yield (78%), M.p. 91–93°C,
IR (KBr) mmax (cm-1): 2617.6–3316.8 (OH–carboxylic
acid), 3022.2–2796.5 (Ar–H), 3361.4 (N–H), 1667.3
(C=O), 3022.2 (CH2); 1H NMR (250 mHz) (CDCl3) d
(ppm): d 2.12 (d, 2H, CH2CO), 2.6 (d, 2H, CH2N), 2.0 (s,
1H, NH), 3.5 (d, 1H, CH–N), 3.7 (t, 1H, CH–OH), 5.0 (s,
1H, OH), 1.25 (d, 3H, CH3), 11.5 (s, 1H, COOH),
7.35–7.81 (m, 8H, Ar–H), 7.0 (s, 2H, Ar–H of seven-
membered ring); Mass (m/z %): M? 366.; Anal. Calcd. for
C21H22N2O4: C, 68.84; H, 6.05; N, 7.65; O, 17.47%;
Found: C, 68.84; H, 6.05; N, 7.65; O, 17.46%.
CH2–C=O), 2.6 (d, 1H, CHN of pyrolidine ring), 1.8 (t, 1H,
CH2, C4a of pyrolidine ring), 1.6 (m, 3H, CH2, 2H of C3 and
1H of C4 of pyrolidine ring), 12.1 (s, 1H, OH of COOH of
pyrolidine). Mass (m/z %): M? 362.42; Anal. Calcd. for
C22H22N2O3: C, 72.91; H, 6.12; N, 7.73; O, 13.24%. Found:
C, 72.94; H, 6.11; N, 7.76; O, 13.26%.
Compound 2g: 2-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxo-
propylamino)-3-phenyl propanoicacid [L-Phenyl alanine
analogue] Light yellow solid, Yield (73%), M.p.
84–86°C, IR (KBr) mmax (cm-1): 2572.6–3191.5 (OH–
carboxylic acid), 3021.9–2800.1 (Ar–H), 3317.8 (N–H),
1678.9 (C=O), 2884.7–2918.0 (CH2); 1H NMR (250 mHz)
(CDCl3) d (ppm): d 2.12 (d, 2H, CH2–CO), 2.58 (d, 2H,
CH2–N), 3.2–3.5 (m, 2H, benzylic CH2 & t, 1H, CH–N),
7.0 (s, 2H, Ar–H of seven-membered ring), 7.35–7.45 (m,
8H, Ar–H), 7.5 (m, 5H, Ar–H of phenyl alanine), 11.5 (s,
1H, carboxylic OH), 2.0 (s, 1H, NH); Mass (m/z %): M?
409.14; Anal. Calcd. for C26H24N2O3: C, 75.71; H, 5.86;
N, 6.79; O, 11.64%; Found: C, 75.74; H, 5.88; N, 6.78; O,
11.65%.
Compound 2d: 2-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxo-
propylamino)-3-mercapto propanoic acid [L-Cysteine
analogue] Light yellow solid, Yield (79%), M.p.
77–79°C, IR (KBr) mmax (cm-1): 1669.6 (C=O), 3317.7 (N–
H), 3457.4–2661 (OH–carboxylic acid), 3052.6–2748.7
1
(Ar–H), 3022.2 (CH2); H NMR (250 MHz) (DMS–d6) d
(ppm): 7.1–7.8 (m, 8H, Ar–H), 7.0 (s, 2H, Ar–H of seven-
membered ring), 1.6 (s, 1H, SH), 2.0 (s, 1H, NH), 2.6 (t,
2H, CH2C=O), 3.2 (m, 2H, CH2–NH), 3.6 (m, 2H, CH2 of
cysteine), 3.8 (t, 1H, CH of cysteine), 12.5(s, 1H, OH of
COOH of cysteine). Mass (m/z %): M? 368.45; Anal.
Calcd. for C20H20N2O3S: C, 65.20; H, 5.47; N, 7.60; O,
13.03; S, 8.70%. Found: C, 65.21; H, 5.49; N, 7.63; O,
13.07; S, 8.70%.
Compound 2h: Synthesis of 3-(4-hydroxyphenyl)-2-(3-(5H-
dibenz[b,f]
azepine-5-yl)-3-oxopropylamino)propanoic
acid [L-Tyrosine analogue] Light yellow solid, Yield
(72%), M.p. 91–93°C, IR (KBr) mmax (cm-1): 2467.0–
3390.2 (OH–carboxylic acid), 3023.1–2896.0 (Ar–H),
1
3316.5 (N–H), 1679.0 (C=O), 2812.0–2836.0 (CH2); H
NMR (250 mHz) (CDCl3) d (ppm): d 2.12 (d, 2H, CH2–
CO), 2.58 (d, 2H, CH2–N), 3.2–3.5 (m, 2H, benzylic CH2
& t, 1H, CH–N), 6.8 (s, 2H, Ar–H, ortho to OH of tyro-
sine), 7.0 (s, 2H, Ar–H of seven-membered ring), 7.1 (s,
2H, Ar–H, para to OH of tyrosine), 7.35–7.54 (m, 8H,
Ar–H), 9.5 (s, 1H, OH of tyrosine), 11.5 (s, 1H, carboxylic
OH), 2.0 (s, 1H, NH); Mass (m/z %): M? 427.84. Anal.
Calcd. for C26H24N2O4: C, 72.88; H, 5.65; N, 6.54; O,
14.94%; Found: C, 72.88; H, 5.64; N, 6.55; O, 14.93%.
Compound 2e: 2-(3-(5H-dibenzo[b,f]azepin-5-yl)-3-oxo-
propylamino)-4-(methylthio) butanoic acid [L-Methionine
analogue] Light yellow solid, Yield (73%), M.p.
79–81°C, IR (KBr) mmax (cm-1): 1668.2 (C=O), 3320.5 (N–
H), 3433.2–2513.2 (OH–carboxylic acid), 3052.7–2747.6
(Ar–H), 3022.2 (CH2); 1H NMR (250 MHz) (DMSO–d6) d
(ppm): 7.1–7.8 (m, 8H, Ar–H), 7.0 (s, 2H, Ar–H of seven-
membered ring), 2.0(s, 1H, NH), 1.9 (t, 2H, CH2 of
methionine), 2.4 (s, 3H, CH3 of methionine), 2.5 (t, 2H,
CH2C=O), 2.6 (t, 2H, CH2 of methionine), 3.0 (t, 2H, CH2–
NH), 3.4 (t, 1H, CH of methionine), 12.2 (s, 1H, OH of
COOH of methionine). Mass (m/z %): M? 396.50; Anal.
Calcd. for C22H24N2O3S: C, 66.64; H, 6.10; N, 7.07; O,
12.11; S, 8.09%. Found: C, 66.66; H, 6.12; N, 7.05; O,
12.13; S, 8.08%.
Compound 2i: 2-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxo-
propylamino)-3-(1H-indol-3-yl)propanoic acid [L-Trypto-
phan analogue] Light yellow solid, Yield (73%), M.p.
96–98°C, IR (KBr) mmax (cm-1): 1668.3 (C=O), 3317.2 (N–
H), 3487.7–2716.2 (OH–carboxylic acid), 3095.6–2747.3
(Ar–H), 3022.2 (CH2); 1H NMR (250 MHz) (DMSO–d6) d
(ppm): 7.2–7.7 (m, 8H, Ar–H), 7.0 (s, 2H, Ar–H of seven-
membered ring), 2.0 (s, 1H, NH, CH2NH), 2.4 (t, 2H,
CH2C=O), 3.0 (t, 2H, CH2–NH), 3.2 (t, 2H, CH2 of tryp-
tophan), 3.7 (t, 1H, CH of tryptophan), 10.2 (s, 1H, NH of
indole ring), 7.3 (m, 1H, CH–NH of indole ring of tryp-
tophan), 7.4–7.7 (m, 4H, Ar–H of tryptophan), 12.1 (s, 1H,
OH of COOH of tryptophan); Mass (m/z %): M? 451.19;
Anal. Calcd. for C28H25N3O3: C, 74.48; H, 5.58; N, 9.31;
O, 10.63%. Found: C, 74.47; H, 5.59; N, 9.33; O, 10.65%.
Compound 2f: 1-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxopropyl)
pyrrolidine-2-carboxylic acid [L-Proline analogue] Light
yellow solid, Yield (79%), M.p. 75–77°C, IR (KBr) mmax
(cm-1): 1669.2 (C=O), 3484.8 (OH–carboxylic acid),
3052.1–3748.2 (Ar–H), 3022.2 (CH2); 1H NMR (250 MHz)
(DMSO–d6) d (ppm): 7.3–7.7 (m, 8H, Ar–H), 7.0 (s, 2H,
Ar–H of seven-membered ring), 3.4 (t, 1H, CH of pyroli-
dine group of proline), 3.3 (t, 2H, CH2–NH), 2.4 (m, 2H,
123

108
Med Chem Res (2011) 20:101–108
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Halliwel B, Gutteridge JMC (1989) Free radical in biology and
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Compound 2j: 1-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxo-
propyl)-3-hydroxy Pyrolidine-2-carboxylic acid [L-
Hydroxy proline analogue] Light yellow solid, Yield
(74%), M.p. 82–84°C, IR (KBr) mmax (cm-1):
2572.0–3261.6 (OH–carboxylic acid), 3021.3–2769.0 (Ar–
H), 1669.9 (C=O), 2895.9(CH2); 1H NMR (250 mHz)
(CDCl3) d (ppm): d 2.0–2.5 (t, 2H, CH2CO, and m, 2H,
CH2NH), 2.58 (d, 2H, CH2–N of pyrolidine), 1.7 (d, 2H,
CH2 of pyrolidine), 4.80 (s, 1H, OH of pyrolidine), 3.8 (m,
1H, CH-OH), 3.1 (d, 1H, CH to carboxylic acid), 11.5 (s,
1H, carboxylic OH), 7.35–7.54 (m, 8H, Ar–H), 7.0 (s, 2H,
Ar–H of seven-membered ring); Mass (m/z %): M?
378.23; Anal. Calcd. for C22H22N2O4: C, 69.83; H, 5.86;
N, 7.40; O, 16.91%; Found: C, 69.83; H, 5.86; N, 7.38; O,
16.89%.
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antioxidants. J Am Oil Chem Soc 48:91
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Compound 2k: 2-(3-(5H-dibenz[b,f]azepine-5-yl)-3-oxo-
propylamino)-3-(1H-imidazole-4-yl)propanoic acid [L-
Histidine analogue] Light yellow solid, Yield (74%),
M.p. 78–80°C, IR (KBr) mmax (cm-1): 1667.6 (C=O),
3322.8 (N–H), 3510.0–2480 (OH–carboxylic acid),
3052.2–2747.6 (Ar–H), 3022.2 (CH2); 1H NMR
(250 MHz) (DMSO–d6) d (ppm): 7.1–7.8 (m, 8H, Ar–H),
6.9 (s, 2H, Ar–H of seven-membered ring), 1.95 (s, 1H,
NH, CH2NH), 2.5 (t, 2H, CH2C=O), 3.2 (d, 2H, CH2 of
histidine), 3.3 (t, 2H, CH2–NH), 3.9 (t, 1H, CH–NH of
histidine), 7.3 (m, 1H, CH of imidazole ring of histidine),
8.6 (m, 1H, Ar–CH, N=CHNH of histidine), 12.3 (s, 1H,
OH of COOH of tryptophan), 13.5 (s, 1H,NH of imidazole
ring). Mass (m/z %): M? 402.45; Anal. Calcd. for
C23H22N4O3: C, 68.64; H, 5.51; N, 13.92; O, 11.93%.
Found: C, 68.66; H, 5.52; N, 13.91; O, 11.95%.
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