Synthesis, pharmacological, and biological screening of novel derivatives of benzodiazepines

Article abstract of DOI:10.1002/jhet.1722

A series of novel 4-(substituted phenyl)-2-(thiophen-2-yl)-2,3-dihydro-1H- benzo[b][1,4]diazepine have been synthesized from 3-(substituted phenyl)-1-(thiophen-2-yl)prop-2-en-1-one. 3-(Substituted phenyl)-1-(thiophen-2- yl)prop-2-en-1-one was prepared by

Full text of DOI:10.1002/jhet.1722

July 2014
Synthesis, Pharmacological, and Biological Screening of Novel
Derivatives of Benzodiazepines
1189
*
K. Ishwar Bhat, Manoj Kumar Singh Chauhan, Abhishek Kumar, and Pankaj Kumar
Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences of Nitte University, Paneer,
Deralakatte 575 018, Mangalore, Karnataka, India
*
E-mail: bhatishwar@yahoo.co.in
Received February 18, 2012
DOI 10.1002/jhet.1722
Published online 23 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 4-(substituted phenyl)-2-(thiophen-2-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine have been
synthesized from 3-(substituted phenyl)-1-(thiophen-2-yl)prop-2-en-1-one. 3-(Substituted phenyl)-1-(thiophen-
2-yl)prop-2-en-1-one was prepared by condensing 2-acetyl thiophene with various aromatic aldehydes in the
presence of 20% NaOH as base. Different 3-(substituted phenyl)-1-(thiophen-2-yl)prop-2-en-1-one on cycliza-
tion with o-phenylenediamine in the presence of NaOH as base resulted in 4-(substituted phenyl)-2-(thiophen-2-
yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine derivatives. The structures of synthesized compounds are confirmed
1
by IR, H NMR, mass spectra, and elemental analysis. All the compounds have been screened for their
antimicrobial, analgesic, and anti-inflammatory activities.
J. Heterocyclic Chem., 51, 1189 (2014).
INTRODUCTION
characteristic absorption band at 1640 cmÀ1 of >C═C<
group. The title compounds 4-(substituted phenyl)-2-
(thiophen-2-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepine [13]
were prepared by cyclization of chalcones by using
o-phenylenediamine in the presence of NaOH as base. The
infrared spectra of benzodiazepine showed characteristic
absorption band at 1584 and 3357cmÀ1 corresponding
to the C═N and NH group, which was absent in the
intermediate chalcones. Similarly, the 1H NMR of the
synthesized benzodiazepines showed one characteristic
signal at d 7.6–7.8 of the NH group and d 3.0, 3.4, 5.1
Benzodiazepine and its derivatives constitute an important
class of organic compounds with diverse biological activities
such as antimicrobial [1], hypnotic [2] and anticonvulsant
[3], analgesic [4], anti-inflammatory [5] and anticancer [6],
and neuroleptic [7,8]. Other than their biological importance,
benzodiazepines are valuable intermediates for the synthesis
of fused ring compounds such as triazolo, thiazolo, imidazo,
oxadiazolo, oxazino, furano, and pyrimido benzodiazepines.
The intermediate compounds used for the synthesis of
benzodiazepines are substituted chalcones known for their
antimicrobial [9], antitubercular [10], anticancer [11], and
anti-inflammatory activities.
Herein is reported the synthesis of some derivatives of
some title structure type containing thiophene moiety in an
attempt to significantly improve the biological spectrum of
benzodiazepines. All the novel compounds were evaluated
for their antimicrobial, analgesic, and anti-inflammatory
activities.
1
(d, 3H of benzodiazepine), which was absent in the H
NMR spectra of substituted chalcones. Hence, the formation
of the title compounds benzodiazepines was confirmed and
further established by mass spectra, which is in accordance
with molecular formula.
All the synthesized compounds were tested for their anti-
inflammatory activity using carrageenan-induced rat hind
paw edema method of Winter et al. [14]. Data of anti-
inflammatory activity were expressed as mean Æ SEM, and
the Student’s t-test was applied to determine the significance
of the difference between the control group and rats treated
with the test compounds. The anti-inflammatory activity of
the newly synthesized compounds (MB1–MB8) was
compared with the standard diclofenac sodium 10 mg/kg
body weight, showing 46.80% inhibition of rat paw edema,
whereas tested compounds showed inhibition ranging from
34.04 to 43.61% after 120min. Compounds MB1, MB2,
RESULTS AND DISCUSSION
Various substituted 3-(substituted phenyl)-1-(pyridin-2-yl)
prop-2-en-1-one were prepared [12] by the reaction of
2-acetyl thiophene and substituted aromatic aldehydes in the
presence of 20% NaOH as base. These compounds were char-
acterized by TLC, melting point, and IR spectra that showed
© 2014 HeteroCorporation

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K. I. Bhat, M. K. S. Chauhan, A. Kumar, and P. Kumar
Vol 51
and MB3 showed almost good activity compared with
standard drug. The presence of hydroxy and fluoro groups
in the phenyl ring enhanced the anti-inflammatory activity
(Table 1).
is proportional to the diameter (mm) of the zone of inhibition.
The plates were incubated at 37ꢀC for 24 h and 25ꢀC for 48h
in the case of antibacterial and antifungal activity studies.
Most of the tested compounds showed good antibacterial
activity against the standard drug ampicillin, and majority
of the compounds showed good antifungal activity against
the standard drug griseofulvin (Table 3).
All the compounds were tested for their analgesic activity
by using the tail immersion method [15] and exhibited
percentage inhibition in the range of 19.46–105.34% after
120 min. Compounds MB4 and MB6 showed highly potent
analgesic activity compared with the standard drug pentazo-
cine, whereas the rest of the tested compounds did not show
significant analgesic activity in the model used (Table 2).
All synthesized compounds were evaluated for their
antimicrobial activity, namely antibacterial activity against
Bacillus subtilis, Staphylococcus aureus, Escherichia coli,
and Pseudomonas aeruginosa and antifungal activity against
Candida albicans and Aspergillus niger using the cup plate
method. The zone of inhibition was determined for all the
tested compounds. The fungicidal and antibacterial activity
EXPERIMENTAL
Thin layer chromatography was used to reach the completion of
the reaction and homogeneity of the compounds synthesized.
Melting points were determined by open capillary and are
uncorrected. IR spectra in KBr pellets were recorded on an FTIR
1
spectrophotometer. H NMR spectra were recorded on a Bruker
spectrometer (Germany; 400Mz) in CDCl3 using TMS as an inter-
nal standard. The mass spectra were recorded on Shimadzu LCMS
2010 (USA). The homogeneity of the compound was checked on
silica gel G coated plates by using petroleum ether: methanol
Table 1
Anti-inflammatory effect of substituted benzodiazepines on carrageenan-induced paw edema in rats.
Increase in paw volume (mL)
Dose
Treatment
(mg/kg)
1 h
0.46 Æ 0.01
2 h
3 h
4 h
Control
Diclofenac sodium
—
10
50
50
50
50
50
50
50
50
0.73 Æ 0.01
0.81 Æ 0.01
0.94 Æ 0.03
0.18 Æ 0.01* (58.1)
0.23 Æ 0.01* (50)
0.27 Æ 0.02* (41.3)
0.27 Æ 0.02* (41.3)
0.21 Æ 0.02* (54.34)
0.26 Æ 0.01 (39.5)
0.23 Æ 0.01* (50)
0.32 Æ 0.01 (30.4)
0.28 Æ 0.01* (39.13)
0.32 Æ 0.02* (56.16)
0.39 Æ 0.01* (46.5)
0.42 Æ 0.01* (42.4)
0.45 Æ 0.01* (38.35)
0.46 Æ 0.01* (36.98)
0.38 Æ 0.01* (47.94)
0.41 Æ 0.03* (43.8)
0.35 Æ 0.03* (52.05)
0.47 Æ 0.03 (35.61)
0.40 Æ 0.01* (50.61)
0.48 Æ 0.02* (40.74)
0.45 Æ 0.01* (44.44)
0.51 Æ 0.02* (37.03)
0.49 Æ 0.01* (39.50)
0.55 Æ 0.01 (32.09)
0.45 Æ 0.03* (44.44)
0.52 Æ 0.01* (35.80)
0.47 Æ 0.02* (41.97)
0.50 Æ 0.05* (46.80)
0.55 Æ 0.03* (41.48)
0.53 Æ 0.04* (43.61)
0.54 Æ 0.01* (42.55)
0.58 Æ 0.01* (38.29)
0.59 Æ 0.02 (37.23)
0.60 Æ 0.03* (36.17)
0.63 Æ 0.01 (32.9)
0.62 Æ 0.02* (34.04)
MB1
MB2
MB3
MB4
MB5
MB6
MB7
MB8
All values are expressed as mean Æ SEM (n = 6).
*P < 0.05 significant compared with control.
Table 2
Analgesic effect of substituted benzodiazepines by tail immersion method in rats.
Reaction time in seconds at time (min)
Dose
Treatment
(mg/kg)
0 min
30 min
2.13 Æ 0.04
60 min
2.50 Æ 0.05
90 min
2.73 Æ 0.06
120 min
Control
Pentazocine
MB1
—
10
50
50
50
50
50
50
50
50
2.18 Æ 0.06
2.88 Æ 0.06
2.53 Æ 0.05
2.41 Æ 0.03
2.78 Æ 0.06
2.68 Æ 0.03
2.26 Æ 0.04
2.06 Æ 0.03
2.48 Æ 0.06
2.24 Æ 0.07
2.62 Æ 0.02
4.91 Æ 0.02* (130.5)
3.35 Æ 0.07* (57.27)
4.11 Æ 0.03* (93.28)
4.68 Æ 0.06* (199.27)
3.67 Æ 0.04* (72.15)
3.38 Æ 0.04* (58.82)
4.41 Æ 0.05* (107.04)
3.1 Æ 0.03* (45.50)
4.68 Æ 0.07* (119.71)
7.74 Æ 0.04* (209.6)
5.20 Æ 0.05* (108)
6.10 Æ 0.03 (144)
5.31 Æ 0.05* (112)
5.48 Æ 0.09* (119)
5.75 Æ 0.04* (130)
6.19 Æ 0.05* (147.60)
6.25 Æ 0.07* (150)
4.70 Æ 0.03* (88)
8.80 Æ 0.9* (222.34)
7.31 Æ 0.07* (167.76)
8.30 Æ 0.07* (204.63)
8.06 Æ 0.03* (193.04)
6.18 Æ 0.14* (126.37)
7.56 Æ 0.17* (176.92)
7.18 Æ 0.04* (163)
5.46 Æ 0.08* (108.39)
4.16 Æ 0.04* (58.77)
3.36 Æ 0.18* (28.24)
3.48 Æ 0.10* (32.82)
5.0 Æ 0.12 (94.84)
3.66 Æ 0.33* (39.69)
5.38 Æ 0.09* (105.34)
4.41 Æ 0.07* (56.87)
3.33 Æ 0.03* (19.46)
MB2
MB3
MB4
MB5
MB6
MB7
MB8
7.90 Æ 0.09* (189.37)
5.73 Æ 0.14* (109.89)
All values are expressed as mean Æ SEM (n = 6).
*P < 0.05 significant compared with control.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis, Pharmacological, and Biological Screening of Novel Benzodiazepine Derivatives
1191
Table 3
Antimicrobial activity of benzodiazepine derivatives.
Diameter of zone of inhibition (mm)
Sl.
no.
Compounds
number
Bacillus
subtilis
Staphylococcus
aureus
Escherichia
coli
Pseudomonas
aeruginosa
Candida
albicans
Aspergillus
niger
1
2
3
4
5
6
7
8
9
MB1
MB2
MB3
MB4
MB5
MB6
MB7
MB8
13
15
12
12
13
14
11
13
18
—
19
18
17
14
18
13
15
16
20
—
20
17
18
18
19
15
16
18
21
—
12
14
10
11
13
12
10
12
15
—
10
11
08
10
09
10
12
08
—
13
13
09
10
12
11
11
09
10
—
16
Ampicillin
Griseofulvin
10
(1:1) as the solvent and observed in UV light. All the synthesized
compounds gave satisfactory elemental analysis.
Synthesis of compounds MC1–MC8. General procedure: 3-
2% NaOH, and the reaction mixture was refluxed for about 10 h.
After completion of the reaction, the reaction mixture was poured
into crushed ice. The product obtained was filtered, washed with
water, and dried. The compounds were obtained as yellow,
brown, brownish yellow, red, and white crystals.
(substituted phenyl)-1-(thiophen-2-yl)prop-2-en-1-one.
A
solution of 2-acetyl thiophene (0.01 mol) and substituted
benzaldehyde (0.01mol) in 20mL of absolute ethanol was stirred
together for 24 h in the presence of 3–4 mL of 20% NaOH.
The mixture was poured into crushed ice and acidified with HCl.
The product obtained was filtered, washed with water, and
dried. The compounds were obtained as yellow, orange, brown,
red, and white crystals.
4-(4-Fluorophenyl)-2-(thiophen-2yl)-2,3-dihydro-1H-benzo[b]
[1,4]diazepine (MB1). This compound was obtained as brown
crystals (ethanol); mp 108–110ꢀC; yield 84%. IR (KBr): 1643
(Ar C═C str), 3085 (Ar C–H str), 3357 (N–H str of
1
benzodiazepine), 720 (Ar C–H bend) cmÀ1; H NMR: d 7.2–7.4
(m, 11H, Ar–H), 3.0, 3.4, 4.9 (d, 3H of benzodiazepine), 7.6
(s, 1H, NH); MS: m/z 322 (M+); Anal. Calcd for C19H14FN2S:
C, 70.71; H, 4.34; N, 8.68. Found: C, 70.63; H, 4.31; N, 8.62.
4-(4-Hydroxyphenyl)-2-(thiophen-2yl)-2,3-dihydro-1H-benzo
[b][1,4]diazepine (MB2) [16]. This compound was obtained as
brownish yellow crystals (ethanol); mp 118–120ꢀC; yield 53%. IR
(KBr): 1648 (Ar C═C str), 3085 (Ar C–H str), 3357 (N–H str
of benzodiazepine), 1587 (C═N str of benzodiazepine), 730
3-(4-Fluorophenyl)-1-(thiophen-2-yl)prop-2-en-1-one(PC1).
This compound was obtained as orange crystals (ethanol); mp
92–94ꢀC; yield 81%; IR (KBr): 1506 (aromatic C═C str), 3120
(aromatic C–H bending), 1105 (C–F str), 1690 (C═O str), 2900
1
(C–H aliphatic str) cmÀ1; H NMR: d 6.9 (d, 1H, CH═CH), 7.1
(d, 1H, CH═CH), 7.2–7.6 (m, 7H, Ar–H); MS: m/z 216 (M+).
3-(4-Hydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one(PC2).
This compound was obtained as yellow crystals (ethanol);
mp 68–70ꢀC; yield 46%.
(Ar C–H bend), 3610 (O–H str) cmÀ1 1H NMR: d 7.2–7.4
;
(m, 11H, Ar–H), 3.0, 3.5, 5.0 (d, 3H of benzodiazepine), 7.6
(s, 1H, NH); MS: m/z 320 (M+); Anal. Calcd for C19H15N2OS:
C, 71.15; H, 4.68; N, 8.73. Found: C, 71.10; H, 4.62; N, 8.76.
4-(3-Hydroxyphenyl)-2-(thiophen-2yl)-2,3-dihydro-1H-benzo
[b][1,4]diazepine (MB3) [17]. This compound was obtained as
yellow crystals (ethanol); mp 98–100ꢀC; yield 51%. IR (KBr):
1648 (Ar C═C str), 3085 (Ar C–H str), 3357 (N–H str
of benzodiazepine), 1587 (C═N str of benzodiazepine), 730
3-(3-Hydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (PC3).
This compound was obtained as yellow crystals (ethanol); mp
90–92ꢀC; yield 65%.
3-(2-Hydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (PC4).
This compound was obtained as yellow crystals (ethanol); mp
84–86ꢀC; yield 54%.
3-(3-Nitrophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (PC5).
This compound was obtained as brown crystals (ethanol); mp
104–106ꢀC; yield 66%.
3-(4-Methylphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (PC6).
This compound was obtained as greenish yellow (ethanol); mp
64–66ꢀC; yield 78%.
(Ar C–H bend), 3610 (O–H str) cmÀ1 1H NMR: d 7.2–7.4
;
(m, 11H, Ar–H), 3.0, 3.5, 5.0 (d, 3H of benzodiazepine), 7.6
(s, 1H, NH); MS: m/z 320 (M+); Anal. Calcd for C19H15N2OS:
C, 71.15; H, 4.68; N, 8.73. Found: C, 71.19; H, 4.71; N, 8.76.
4-(2-Hydroxyphenyl)-2-(thiophen-2yl)-2,3-dihydro-1H-benzo
3-(4-Chlorophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (PC7).
This compound was obtained as red crystals (ethanol); mp
67–69ꢀC; yield 69%.
3-(4-Dimethylaminophenyl)-1-(thiophen-2-yl)prop-2-en-1-one
(PC8). This compound was obtained as white crystals (ethanol);
mp 122–124ꢀC; yield 76%.
[b][1,4]diazepine (MB4) [18].
This compound was obtained
as brown crystals (ethanol); mp 136–138ꢀC; yield 46%. IR
(KBr): 1648 (Ar C═C str), 3085 (Ar C–H str), 3357 (N–H str
of benzodiazepine), 1587 (C═N str of benzodiazepine), 730
(Ar C–H bend), 3610 (O–H str) cmÀ1 1H NMR: d 7.2–7.4
;
(m, 11H, Ar–H), 3.0, 3.5, 5.0 (d, 3H of benzodiazepine), 7.6
(s, 1H, NH); MS: m/z 320 (M+); Anal. Calcd for C19H15N2OS:
C, 71.15; H, 4.68; N, 8.73. Found: C, 71.19; H, 4.72; N, 8.79.
4-(3-Nitrophenyl)-2-(thiophen-2yl)-2,3-dihydro-1H-benzo[b]
Synthesis of compounds MB1–MB8. General procedure:
4-(substituted phenyl)-2-(thiophen-2-yl)-2,3-dihydro-1H-benzo[b]
[1,4]diazepine.
Chalcones (0.01 mol) and hydroxyl amine
(0.01 mol) were dissolved in 30 mL methanol in the presence of
[1,4]diazepine (MB5).
This compound was obtained as dark
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1192
K. I. Bhat, M. K. S. Chauhan, A. Kumar, and P. Kumar
Vol 51
brown crystals (ethanol); mp 129–131ꢀC; yield 62%. IR (KBr):
1650 (Ar C═C str), 3080 (Ar C–H str), 3360 (N–H str
of benzodiazepine), 1590 (C═N str of benzodiazepine), 751
of the synthesized compounds showed potent anti-inflam-
matory, analgesic, antibacterial, and antifungal activities.
(Ar C–H bend), 1350 (N═O str of R–NO2) cmÀ1 1H NMR:
;
d
7.2–7.4 (m, 11H, Ar–H), 3.0, 3.5, 4.9 (d, 3H of
Acknowledgments. The authors are grateful to the Head, SAIF,
Punjab University, Chandigarh for 1H NMR and mass
spectroscopic analysis, and Mangalore University for elemental
analysis. The authors are highly grateful to Nitte University for
providing all the necessary research facilities and financial
assistance.
benzodiazepine), 7.7 (s, 1H, NH); MS: m/z 349 (M+); Anal.
Calcd for: C19H14N3O2S: C, 65.25; H, 4.01; N, 12.02. Found:
C, 65.63; H, 4.09; N, 12.09.
4-(4-Methylphenyl)-2-(thiophen-2yl)-2,3-dihydro-1H-benzo[b]
[1,4]diazepine (MB6).
This compound was obtained as
yellow crystals (ethanol); mp 153–155ꢀC; yield 77%. IR (KBr):
1660 (Ar C═C str), 3069 (Ar C–H str), 3374 (N–H str of
benzodiazepine), 1587 (C═N str of benzodiazepine), 742
(Ar C–H bend), 2850 (aliphatic C–H str ) 1440 (aliphatic C–H
REFERENCES AND NOTES
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(Ar C–H bend), 750 (C–Cl str ) cmÀ1 1H NMR: d 7.2–7.4
;
(m, 11H, Ar–H), 3.0, 3.5, 4.9 (d, 3H of benzodiazepine), 7.6
(s, 1H, NH),; MS: m/z 338 (M+); Anal. Calcd for: C19H14ClN2S:
C, 67.32; H, 4.13; N, 8.26. Found: C, 67.41; H, 4.19; N, 8.31.
4-(4-Dimethylaminophenyl)-2-(thiophen-2yl)-2,3-dihydro-1H-
benzo[b][1,4]diazepine (MB8).
This compound was obtained
as white crystals (ethanol); mp 148–150ꢀC; yield 79%. IR (KBr):
1665 (Ar C═C str), 3090 (Ar C–H str), 3365 (N–H str of
benzodiazepine), 1582 (C═N str of benzodiazepine), 749
(Ar C–H bend), 1310 (C–N str ), 2855 (aliphatic C–H str), 1455
(aliphatic C–H bend) cmÀ1; 1H NMR: d 7.2–7.5 (m, 11H, Ar–H),
3.1, 3.4, 4.7 (d, 3H of benzodiazepine), 7.7 (s, 1H, NH), 1.58
(s, 6H, CH3); MS: m/z 348 (M+); Anal. Calcd for C21H20N3S:
C, 72.52; H, 5.75; N, 12.08. Found: C, 72.63; H, 5.75; N, 12.08.
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CONCLUSION
This study reports the successful synthesis of substituted
benzodiazepine derivatives with moderate yields, and most
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet