Synthesis and biological activity of novel 1H-1,4-diazepines containing benzene sulfonyl piperazine moiety

Article abstract of DOI:10.1007/s00044-010-9430-2

The synthesis of biologically active 1H-1,4-diazepines 6a-e in good yield, from the heterocyclization reaction of [N⁴-(4-acetylamino) benzene sulfonyl) piperazinyl- N¹-propyl]-1,3-dialkyl/aryl propane-1,3-dione 5a-e and ethylenediamine (EDA) in the presence of silica sulphuric acid (SSA) is described. The novel β-diketones/β-ketoesters 5a-e were synthesized by the condensation reaction of [N4-(4- acetylamino) benzene sulfonyl) piperazinyl-N1-1-bromopropane with various β-diketones/β-ketoesters 4a-e.All structures of the newly synthesized compounds were elucidated by elemental analysis and spectral studies.The compounds 6a-e have been screened for antimicrobial, antifungal and anthelmintic activity. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9430-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:975–980
DOI 10.1007/s00044-010-9430-2
ORIGINAL RESEARCH
Synthesis and biological activity of novel 1H-1,4-diazepines
containing benzene sulfonyl piperazine moiety
•
Shalini Saingar Rajesh Kumar Yogesh Chandra Joshi
•
Received: 19 April 2010 / Accepted: 10 September 2010 / Published online: 25 September 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The synthesis of biologically active 1H-1,4-
diazepines 6a–e in good yield, from the heterocyclization
reaction of [N4-(4-acetylamino) benzene sulfonyl) piperaz-
inyl-N1-propyl]-1,3-dialkyl/aryl propane-1,3-dione 5a–e and
ethylenediamine (EDA) in the presence of silica sulphuric
acid (SSA) is described. The novel b-diketones/b-ketoesters
5a–e were synthesized by the condensation reaction of [N4-(4-
acetylamino) benzene sulfonyl) piperazinyl-N1-1-bromopro-
pane with various b-diketones/b-ketoesters 4a–e. All structures
of the newly synthesized compounds were elucidated by ele-
mental analysis and spectral studies. The compounds 6a–e have
been screened for antimicrobial, antifungal and anthelmintic
activity.
Gluckman, 1964), anticonvulsant (Fiakpui et al., 1993),
antihistaminic (Guryn et al., 1980), antiproliferative
(Ramajayam et al., 2007), anti-inflammatory (Stochla et al.,
1984), fungicidal and herbicidal (Tandon et al., 2009).
The anti-HIV activity of substituted 1H-1,4-diazepine and
their derivatives is comparable to that of zidovuline
(30-azidothymidine, AZT), the well known anti-HIV drug
¨
(Gorlitzer et al., 1995). They also exhibit platelet-activating
factor (PAF) antagonistic and serotoninergic S3 antagonistic
(Casals and Tenzel 1991; Fray et al., 1995) activities.
1H-1,4-diazepine nucleus has been proved as a versatile
system in medicinal chemistry. Furthermore, a number of
established drug molecules like Brotizolam, Bunazosin,
Dilazep, Etizolam, Homofenazine, Zometapine, Clotiaze-
pam, Clozapine and Dibenzepine are accessible starting
from the corresponding 1H-1,4-diazepines (Sternbach
et al., 1968). Research in this area is still very active and
is directed towards the synthesis of potential bioactive
1H-1,4-diazepine with enhanced pharmacology activity.
Various methods are reported in literature for the syn-
thesis 1H-1,4-diazepines (El-Kashef et al., 2007; Insuasty
et al., 2008; Lee and Kim, 2009; Mibu et al., 2003;
Raboisson et al., 2005). However, these methods are
associated with several drawbacks such as harsh reaction
conditions, complex and tedious experimental procedures
and low yields. In recent years, the use of organic–
inorganic hybrid-immobilized solid support reagents have
received great interest. Such reagents not only simplify the
purification process, but also provide help in preventing the
release of reaction residues into the environment (Wight
and Davis, 2002). Furthermore, from the synthetic point of
view, these reagents significantly reduce reaction time and
make the workup easier. Recently, silica and sulphuric acid
in dichloromethane have been reported for the oxathio-
acetalyzation of carbonyl compounds (Shirini et al., 2009).
Keywords 1H-1,4-diazepines ꢀ b-Diketones/
b-ketoesters ꢀ Piperazine ꢀ Silica sulphuric acid ꢀ
Ethylenediamine ꢀ Biological activities
Introduction
The diverse biological activities of various derivatives of
1H-1,4-diazepine are well known. Some of the 1H-1,4-
diazepine derivatives show interesting biological activities
such as anticancer (Krezel et al., 1999), antibacterial
(Kumar and Joshi, 2009), psychotropics (Childress and
S. Saingar ꢀ Y. C. Joshi (&)
Department of Chemistry, University of Rajasthan,
Jaipur 302004, India
e-mail: rnunia@yahoo.com
R. Kumar
Defence Laboratory, Jodhpur 342011, India
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Med Chem Res (2011) 20:975–980
The efficiency of silica sulphuric acid (SSA), under oper-
ationally simple conditions, has prompted us to explore the
possibility of using this reagent for the synthesis of 1H-1,4-
diazepines from the reaction of b-diketones/b-ketoesters
and ethylenediamine (EDA).
Table 1 Physical and analytical data of compounds 5a–e
Compd. R1
R2
Melting point Yield
(%)
Molecular
formula
(°C)
5a
5b
5c
5d
5e
CH3
CH3
155
81.3
76.2
69.6
72.4
67.7
C20H29N3O5S
C30H33N3O5S
C25H31N3O5S
C21H31N3O6S
C22H33N3O7S
C6H5 C6H5 183
In continuation of our ongoing research program to
develop new reagents and synthetic procedure for the
synthesis of novel heterocyclic compounds (Kumar and
Joshi, 2007a, b, c, 2010), we report here a new convenient
method for the synthesis of N4-(4-acetylamino) benzene
sulfonyl) piperazinyl-N1-propyl containing 1H-1,4-diaze-
pines due to their importance in medicinal chemistry
(Lavecchia et al., 2005; Kerns et al., 2003a, b; Zhao et al.,
2006). To achieve this target, we had synthesized b-dike-
tones/b-ketoesters 5a–e which were condensed with EDA
in presence of SSA, to obtain the corresponding substituted
1H-1,4-diazepines 6a–e with high yields.
CH3
CH3
C6H5 159
OC2H5 146
OC2H5 OC2H5 152
Staphylococcus aureus and Klebsiella pneumoniae and
antifungal activity against Aspergillus niger and Candia
albicans by the cup-plate method (Saundane et al., 1998).
Ciprofloxin and ciclopiroxolamine were used as standards
for comparison of antibacterial and antifungal activities,
respectively. The results indicate that these compounds
were active against all the four organisms. The anthel-
mintic activity was carried out on earth worms Pherituma
posthuma, by a technique as described by Bagavant et al.
(1994) with slight modification. Piperazine citrate was used
as standard drug. The values of antimicrobial and anthel-
mintic activity are terms of mean SEM of results done in
triplicate, reported in Table 3. The compounds 6a–e were
exhibited normal antimicrobial and antifungal activities but
showed significant anthelmintic activity due to presence of
piperazine moiety.
Results and discussion
Acetanilide was sulfonated with chlorosulfonic acid, to
obtain 4-(acetylamino) benzene sulfonyl chloride 1. This
compound 1, on condensation with piperazine in presence of
pyridine and acetic anhydride yielded N-[4-(1-piperazinyl
sulfonyl) phenyl] acetamide 2. The condensation had an
important role in this reaction. Pyridine, a weak base when
used as a solvent for condensation was not sufficiently
strong enough to cause the removal of proton as HCl. On the
contrary when acetic anhydride and pyridine were used as
solvent mixture it formed (N-acetyl pyridinium) complex,
an electrophilic complex which facilitated the condensation
to give desired product by removal of HCl. This is because
acetate ion in this complex being a comparatively strong
base helped in the removal of proton easily than pyridine
alone. Then compound 2 on bromination with 1,3-dibro-
mopropane in presence of ethanol, afforded [N4-(4-acetyl-
amino) benzene sulfonyl) piperazinyl-N1-1-bromopropane
3. The condensation reaction of compound 3 with various
b-diketones/b-ketoesters 4a–e in the presence of sodium
methoxide yielded corresponding substituted b-diketones/
b-ketoesters 5a–e. The compounds 5a–e were characterized
by elemental analysis and spectral studies (Tables 1, 2).
Compounds 5a–e on the reaction with EDA in the presence
of SSA underwent dehydrative annulation to afford novel
substituted 1H-1,4-diazepines 6a–e (Scheme 1). SSA was
prepared by reported method (Salehi et al., 2006).
From these results, it is apparent that attempts to intro-
duce functionality methyl/phenyl at position 5 and 7
resulted in significantly increased antibacterial and anti-
fungal activities due to its electron donating character but
steric hindrance also played a major important role. The
diazepine-5,7-dione showed more anthelmintic activity
than others due to more electronegativity of oxygen. This
result implies that the presence of electron withdrawing
groups at position 5 and 7 of diazepines can increase
anthelmintic activity.
Experimental section
General procedures
All the melting points were determined in open capillary
tubes and are uncorrected. The purity of the newly syn-
thesized compounds was checked by TLC on aluminium
oxide 60 F254 plates (Merck) and spots were visualized by
exposing the dry plates in iodine vapour. The IR spectra
were recorded on a Nicolet-Magna-FT-IR-550 spectrome-
1
ter in using KBr pellets. H NMR and 13C NMR spectra
Antimicrobial, antifungal and anthelmintic activities
of compounds 6a–e
were run on model DRX 300 at 300.13 and 75 MHz,
respectively in CDCl3 and mass spectra on a LCMS
instrument. The elemental analysis (C, H, N) of compounds
was performed on Carlo Erba-1108 element analyzer. Their
The newly synthesized diazepine compounds 6a–e have
been screened for the antibacterial activity against
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Med Chem Res (2011) 20:975–980
977
Table 2 Spectral data of synthesized compounds 5a–e
Compd. IR (kmax/cm-1
)
1HNMR (d/ppm)
13CNMR (d/ppm)
5a
5b
5c
5d
3350, 3025, 2918,
1730, 1682, 1370,
1155
1.09 (q, 2H), 1.37 (t, 2H), 1.86 (s, 6H), 2.15 (s, 3H), 17.5 (CH3), 19.3, 24.9, 49.7 (CH2–CH2–CH2–), 22.6
(CH3), 47.5, 53.8 (N–CH2–CH2–N), 68.5 (CH),
120–125 (Ar–C), 169.7 (CONH), 193.7 (C=O)
2.35 (t, 2H), 2.42–2.75 (complicate, 8H) 4.12 (m,
1H), 7.62–7.85 (m, 4H), 10. 38 (s, 1H)
3345, 3017, 2915,
1735, 1680, 1370,
1145
1.10 (q, 2H), 1.42 (t, 2H), 2.13 (s, 3H), 2.40 (t, 2H), 17.8 (CH3), 19.4, 24.9, 49.5 (CH2–CH2–CH2–), 47.4,
2.38–2.73 (complicate, 8H) 4.14 (m, 1H), 7.62–7.85 53.7 (N–CH2–CH2–N), 68.5 (CH), 120–129 (Ar–C),
(m, 14H), 10. 40 (s, 1H)
168.9 (CONH), 194.3 (C=O)
3350, 3020, 2915,
1736, 1680, 1370,
1155
1.13 (q, 2H), 1.38 (t, 2H), 1.95 (s, 3H), 2.18 (s, 3H), 18.3 (CH3), 19.3, 24.9, 49.8 (CH2-CH2-CH2-), 24.7
2.35 (t, 2H), 2.42-2.75 (Complicate, 8H) 4.13 (m,
1H), 7.60-7.83 (m, 9H), 10. 42 (s, 1H)
(CH3), 47.5, 53.8 (N-CH2-CH2-N), 169.7 (CONH),
68.3 (CH), 121-129 (Ar–C), 193.5 (C=O)
3350, 3025, 2907,
1730, 1680, 1370,
1150, 1105, 1245
1.15 (q, 2H), 1.36 (t, 3H), 1.49 (t, 2H), 2.07 (s, 3H), 17.5 (CH3), 19.3, 24.9, 49.7 (CH2–CH2–CH2–), 22.6
2.15 (s, 3H), 2.36 (t, 2H), 2.40-2.78 (complicate, 8H), (CH3), 47.5, 53.8 (N–CH2–CH2–N), 59.5 (O–CH2–),
4.05 (q, 2H), 4.15 (m, 1H), 7.62–7.85 (m, 4H), 10. 23 68.5(CH), 168.9 (CONH), 122–128 (Ar–C), 194.3
(s, 1H)
1.10 (q, 2H), 1.30 (t, 6H), 1.40 (t, 2H), 2.10 (s, 3H), 17.5 (CH3), 19.3, 24.9, 49.7 (CH2–CH2–CH2–), 47.5,
2.35 (t, 2H), 2.42–2.75 (complicate, 8H), 3.85 (q, 53.8 (N–CH2–CH2–N), 59.3 (O–CH2–), 68.5 (CH),
4H), 4.12 (m, 1H), 7.62-7.85 (m, 4H), 10. 38 (s, 1H) 169.4 (CONH), 124–129 (Ar–C), 194.8 (C=O)
(C=O)
5e
3350, 3020, 2915,
1780, 1660, 1370,
1150, 1120, 1245
results were found to be in good agreement with the cal-
culated values.
presence of SSA (0.01 M) was stirred 50°C for 2 h. The
progress of reaction was monitored by TLC using 7:2:1
(benzene:ethanol:ammonia) upper layer as mobile phase.
Upon completion of reaction, the mixture was extracted
with ethyl acetate (2 9 25 ml), and the solvent was
removed. The crude product was washed with dry ether and
recrystallized from pet ether:ethyl acetate (1:1). The
product was purified by column chromatography over silica
gel using pet ether:ethyl acetate (40:60) as eluent.
Synthesis of [N4-(4-acetylamino) benzene sulfonyl)
piperazinyl-N1-propyl]-1,3-dimethyl/1-methyl-3-
phenyl/1,3-diphenyl/1-methyl-3-ethoxy/1,3-diethoxy
propane-1,3-dione 5a–e
Sodium methoxide (0.54 g, 0.01 mol) and b-diketones/
b-ketoester (0.01 mol) were placed in a dried round-bottom
flask and stirred for 1 h on a magnetic stirrer at 50°C, after
which a creamy mass was obtained. The N4-(4-acetyl-
amino) benzene sulfonyl) piperazinyl-N1-1-bromopropane
3 (3.9 g, 0.01 mol) was taken in dry toluene and added
drop by drop in above said reaction mass. The reaction
mixture was heated for 7 h at 80°C with stirring. The
progress of the reaction was monitored by TLC. After
completion of the reaction, the mixture was cooled and
toluene was removed. The reaction mixture was extracted
using chloroform and washed with water.
6-[N4-(4-Acetylamino) benzene sulfonyl) piperazinyl-N1-
propyl]-5,7-dimethyl-2,3-dihydro-1H-1,4-diazepine 6a
M.p. 145°C, yield 75%; IR (KBr): 3315 (N–H), 3010
(Ar–H), 2930 (C–H), 1700 (C=O), 1570 (C=N), 1345, 1140
(-SO2) cm-1
;
1H NMR (CDCl3): d 1.09 (quintet,
J = 7.46, 2H, CH2CH2CH2), 1.15 (triplet, J = 7.50, 2H,
CH2CH2CH2), 2.07 (s, 6H,CH3–C=N), 2.16 (s, 3H, CH3),
2.30 (triplet, J = 7.45, 2H, CH2CH2CH2–N), 3.14 (com-
plicated s, 4H,N–CH2–CH2–N), 3.45 (s, 1H, =CH–),
7.65–7.80 (m, 4H, Ar–H), 8.50 (s,1H, N–H); 13C NMR
(CDCl3): d 10.45, 16.45, 17.63, 28.20, 47.30, 48.55, 53.40,
124–128, 134.90, 164.60, 168.20; MS (m/z): 448
(M ? H?); Anal. Calcd for C22H33N5O3S: C, 59.06; H,
7.38; N, 15.66. Found: C 58.95, H 7.13, N, 15.45.
The chloroform layer was dried using anhydrous sodium
sulphate and distilled to yields the solid compound. The
product was purified by column chromatography over silica
gel using pet ether:ethyl acetate (50:50) as eluent. It was
purified by recrystallization from chloroform and ethyl
acetate. Purity of the compound was checked by TLC on
aluminium oxide 60 F254 plates (Merck) in a 7:2:1 (ben-
zene:ethanol:ammonia) upper layer using as a mobile
phase (Table 2).
6-[N4-(4-Acetylamino) benzene sulfonyl) piperazinyl-N1-
propyl]-5,7-diphenyl-2,3-dihydro-1H-1,4-diazepine 6b
M.p. 167°C, yield 73%; IR (KBr): 3325 (N–H), 3010 (Ar–
H), 2915 (C–H), 1705 (C=O), 1580 (C=N), 1355, 1145
(-SO2) cm-1; 1H NMR (CDCl3): d 1.10(quintet, J = 7.03,
2H, CH2CH2CH2), 1.13 (triplet, J = 7.25, 2H,
CH2CH2CH2), 2.15 (s, 3H, CH3), 2.32 (triplet, J = 6.85,
2H, CH2CH2CH2–N), 3.15 (complicated s, 4H,N–CH2–
Synthesis of 1H-1,4-diazepine derivatives 6a–e: general
procedure
An equimolar ratio of b-diketones/b-ketoesters (0.01 M)
5a–e, and EDA (0.01 M) in ethyl acetate (50 ml) in the
123

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Med Chem Res (2011) 20:975–980
Scheme 1 Synthesis of 1H-1,
4-diazepines 6a–e
NHCOCH3
NHCOCH3
NHCOCH3
NH
HN
HOSO2Cl
Pyridine/Acetic anhydride
SO2Cl
SO2
NH
N
1
2
BrCH2CH2CH2Br
ethanol
R1
NHCOCH3
NHCOCH3
O
(4a-e)
O
R2
R1
N CH2CH2CH2
O
O
SO2
CH3ONa
N
SO2
N
N CH2CH2CH2Br
R2
5a-e
3
H2N
H2N
SSA
R1
O
H
N
H
N
O
O
N
N
NHCOCH3
R
or
R
or
R
N
N
H
R1
R2
R=
6e
6a-c
6a : R1 = R2 = CH3
6d
6d : R1 = CH3
SO2
N CH2CH2CH2
N
6b : R1 = R2 = C6H5
6c : R1 = CH3 R2 = C6H5
CH2–N), 3.43 (s, 1H, =CH–), 7.65–7.80 (m, 14H, Ar–H),
8.52 (s, 1H, N–H); 13C NMR (CDCl3): d 10.65, 17.05,
17.79, 29.10, 47.35, 48.50, 52.93, 124–128, 134.96,
166.73, 168.85; MS (m/z): 572 (M ? H?); Anal. Calcd for
C32H37N5O3S: C, 67.22; H, 6.52; N, 12.25. Found: C,
67.14; H, 6.50; N, 12.30.
2.30 (triplet, J = 6.85, 2H, CH2CH2CH2–N), 3.13 (com-
plicated s, 4H, N–CH2–CH2–N), 3.44 (s, 1H, =CH–),
7.61–7.80 (m, 9H, Ar–H), 8.55 (s, 1H, N–H); 13C NMR
(CDCl3): d 11.37, 17.85, 18.53, 28.55, 46.85, 49.05, 55.60,
123–129, 135.70, 169.45, 168.20; MS (m/z):
510(M ? H?); Anal. Calcd for C27H35N5O3S: C, 63.63; H,
6.92; N, 13.74. Found: C, 63.65; H, 6.87; N, 13.70.
6-[N4-(4-acetylamino) benzene sulfonyl) piperazinyl-N1-
propyl]-5-methyl-7-phenyl-2,3-dihydro-1H-1,4-diazepine
6c
6-[N4-(4-acetylamino) benzene sulfonyl) piperazinyl-N1-
propyl]-7-methyl-2,3,4,6-tetrahydro-1H-1,4-diazepine-5-
one 6d
M.p. 147°C, yield 69%; IR (KBr): 3320 (N–H), 3010
(Ar–H), 2935 (C–H), 1709 (C=O), 1585 (C=N), 1345, 1125
M.p. 155°C, yield 72%; IR (KBr): 3325 (N–H), 3028 (Ar–
H), 2895 (C–H), 1735 (C=O), 1585 (C=N), 1335, 1120
;
(-SO2) cm-1 1H NMR (CDCl3): d 1.09 (quintet,
J = 6.46, 2H, CH2CH2CH2), 1.12 (triplet, J = 6.46, 2H,
(-SO2) cm-1
;
1H NMR (CDCl3): d 1.09 (quintet,
J = 6.86, 2H, CH2CH2CH2), 1.12 (triplet, J = 7.05, 2H,
CH2CH2CH2), 2.07 (s, 3H, CH3–C=N), 2.10 (s, 3H, CH3),
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Med Chem Res (2011) 20:975–980
979
Table 3 Antimicrobial, antifungal and anthelmintic activities of compounds 6a–e
Compd.
Antibacterial activity zone of inhibition in
mm*
Antifungal activity zone of inhibition in
mm*
Anthelmintic activity in min.*
S. aureus
K. pneumoniae
A. niger
C. albicans
Paralysis
Death
6a
19 0.57
17 0.48
20 0.65
16 0.75
13 0.58
24 0.57
–
21 0.65
19 0.57
19 0.85
17 0.54
15 0.59
26 0.24
–
19 0.58
18 0.54
20 0.57
17 0.55
15 0.57
–
21 0.58
19 0.57
20 0.54
16 0.48
13 0.80
–
92 0.65
93 0.69
91 0.57
102 0.85
103 0.56
–
103 0.48
110 0.57
111 0.54
119 0.48
122 0.65
–
6b
6c
6d
6e
Ciprofloxin
Ciclopirox
Olamine
Piperazine citrate
22 0.44
–
24 0.74
–
–
–
–
–
100 0.57
125 0.57
* Values are in terms of mean SEM of results done in triplicate
CH2CH2CH2), 2.32 (triplet, J = 6.46, 2H, CH2CH2CH2–
N), 2.15 (s, 3H, CH3), 2.07 (s, 3H, CH3–C=N), 3.14
(complicated s, 4H, N–CH2–CH2–N), 3.43 (s, 1H, =CH–),
7.61–7.83 (m, 4H, Ar–H), 8.76 (s, 1H, N–H), 10.23 (s, 1H,
N–H); 13C NMR (CDCl3): d 10.55, 17.13, 18.75, 29.15,
46.83, 49.55, 57.60, 121–127, 135.68, 164.55, 169.10,
193.80; MS (m/z): 450 (M ? H?); Anal. Calcd for
C21H31N5O4S: C, 56.10; H, 6.95; N, 15.58. Found: C,
56.15; H, 6.95; N, 15.60.
synthesized compounds evaluated (6a–e), compounds
6a–c exhibited antimicrobial and antifungal activities in
comparison the standard drug, but compounds 6d and 6e
showed significant anthelmintic activity. More extensive
study is needed to confirm the preliminary results and
mode of action studies are required to be able to optimize
the effectiveness of this series of compounds 6a–e.
Acknowledgments The authors are thankful to Head, Department
of Chemistry, University of Rajasthan, Jaipur for providing laboratory
facilities. They are also thankful to Central Drug Research Institute,
Lucknow for providing spectral data.
6-[N4-(4-acetylamino) benzene sulfonyl) piperazinyl-N1-
propyl]-7-methyl-2,3,4,6-tetrahydro-1H-1,4-diazepine-5,
7-dione 6e
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J = 6.76, 2H, CH2CH2CH2), 1.12 (triplet, J = 7.33, 2H,
CH2CH2CH2), 2.13 (s, 3H, CH3), 2.32 (triplet, J = 8.45,
2H, CH2CH2CH2–N), 3.15 (complicated s, 4H, N–CH2–
CH2–N), 3.44 (s, 1H, =CH–), 7.50–7.75 (m, 4H, Ar–H),
8.53 (s, 1H, N–H), 10.71 (s, 2H, N–H); 13C NMR (CDCl3):
d 10.55, 15.95, 18.33, 28.15, 47.20, 48.65, 53.40, 125–128,
134.70, 164.45, 168.20, 198.10; MS (m/z): 452 (M ? H?);
Anal. Calcd for C20H29N5O5S: C, 53.20; H, 6.47; N, 15.51.
Found: C, 53.15; H, 6.50; N, 15.50.
Conclusion
¨
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