Synthesis of novel sulphonamides and evaluation of their antibacterial efficacy

Article abstract of DOI:10.1080/10426500490459704

4-(4′-sulphanilyl)-1-phenyl pipearzine (2) has been prepared by ther reaction of N-acetyl sulphanilyl chloride (ASC) with 1-phenyl piperazine followed by the hydrolysis of the product by ethanolic HCl. The hydrolyze product on facile condensation reaction

Full text of DOI:10.1080/10426500490459704

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Phosphorus, Sulfur, and Silicon and the Related
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SYNTHESIS OF NOVEL SULPHONAMIDES AND
EVALUATION OF THEIR ANTIBACTERIAL EFFICACY
H. S. Patel a & H. J. Mistry a
a Sardar Patel University , Vallabh Vidyanagar, Gujarat, India
Published online: 16 Aug 2010.
To cite this article: H. S. Patel & H. J. Mistry (2004) SYNTHESIS OF NOVEL SULPHONAMIDES AND EVALUATION OF
THEIR ANTIBACTERIAL EFFICACY, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:6, 1085-1093, DOI:
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Phosphorus, Sulfur, and Silicon, 179:1085–1093, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490459704
SYNTHESIS OF NOVEL SULPHONAMIDES AND
EVALUATION OF THEIR ANTIBACTERIAL
EFFICACY
H. S. Patel and H. J. Mistry
Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
(Received August 26, 2003; accepted October 9, 2003)
4-(4ꢁ-sulphanilyl)-1-phenyl pipearzine (2) has been prepared by ther re-
action of N-acetyl sulphanilyl chloride (ASC) with 1-phenyl piperazine
followed by the hydrolysis of the product by ethanolic HCl. The hy-
drolyze product on facile condensation reaction with aromatic aldehy-
des yields Schiff bases/anils/azomethines (3a–h). These anils on cyclo
condensation reaction with chloro acetyl chloride and thio glycolic acid
(mercapto acetic acid) yields 2-azetidinones and 4-thiazolidinones re-
spectively. Biological screening of the prepared compounds have been
screened on some strains of bacteria.
Keywords: 2-Azetidinones; 4-thiazoidinones; cyclo-condensation
reaction; facile condensation; N-acetyl sulphanilyl chloride
The development of sulphonamides is one of the most fascinating and
informative fields in medicinal chemistry, highlighting the roles of
skillful planning and serendipity in drug research. The discovery of
sulphonamide marked the beginning of the chemotherapeutic era by
making possible a direct attack on microbial infections.1 Sulphonamide
antibacterials continued to be used because they are effective, inex-
pensive and free of super infection problems of the broad spectrum
antibiotics.2
As a part of surge of interest in heterocycles that have been
explored for developing pharmaceutically important molecules 4-
thiazolidinones3–5 and 2-azetidinones6–9 have played an important role
in medicinal chemistry. Moreover, they have been studied extensively
because of their ready accessibility, diverse chemical reactivity, and
broad spectrum of biological activities.
We thank Dr. R. M. Pael, head of the Department of Chemistry, for providing labora-
tory facilities.
Address correspondence to H. S. Patel, Department of Chemistry, Sardar Patel Uni-
versity, Vallabh Vidyanagar, 388 120, Gujarat, India. E-mail: dr hspatel@yahoo.co.in
1085

1086
H. S. Patel and H. J. Mistry
Also, piperazine derivatives plays pivotal role in medicinal chemistry
due to its application in the therapy of functional diseases.10 During
the past years considerable evidence has been accumulated to demon-
strate the efficiency of substituted 2-azetidinones, 4-thiazolidinones,
piperazine derivatives, and sulphonamides.11–13
Keeping in view of biological importance of these groups, we replace
them by piperazine moiety at N4-position of sulphanilamide and 2-
azetidinone/4-thiazolidinone at N1-position in sulphanilamide and our
approach clearly shows the biological importance of the coupled prod-
ucts. The research work is scanned in Scheme 1.
ANTIMICROBIAL ACTIVITY
Antibacterial Activity
Antibacterial activities of all the compounds were studied against Gram
positive bacteria (Bacillus subtillis and staphylococcus aureus) and
Gram negative bacteria (E. coli and Salmonella typhi) at a concentra-
tion of 50 µg/ml by agar cup plate method.14 Methanol system was used
as control in this method. Under similar conditions usinf penicillin and
sulphanilamide as a standard comparison carried out control experi-
ment. The area of inhibition of zone is measured in centimeters. Com-
pounds 4c, 4d, 4h, 5b, 5d, and 5f were found more active against the
above microbes. Other compounds found to be less or moderate active
than the standards (Tables I and II).
TABLE I Antibacterial Activity of Compounds 4a–h
Zone of Inhibition
Gram +ve
Staphyloccous
Gram −ve
Salmonella
Bacillus
subtillis
Compounds
aureus
typhi
E.coli.
4a
4b
4c
4d
4e
4f
4g
4h
54
45
70
82
45
65
68
80
85
78
60
67
78
72
65
60
55
70
65
75
43
52
78
68
43
62
68
74
75
82
65
69
62
78
75
49
58
67
73
69
Penicillin
Sulphanilamide

Novel Sulphonamides
1087
SCHEME 1
EXPERIMENTAL
Melting points were determined in open capillary tubes and are uncor-
rected. The IR spectra were recorded in KBr pellets on a Nicolet 400D
spectrometer and 1H NMR spectra in CDCl3 on Hitachi R-1500, 60 MHz
spectrometer using TMS as an internal standard. The required N-acetyl

1088
H. S. Patel and H. J. Mistry
TABLE II Antibacterial Activity of Compounds 5a–h
Zone of Inhibition
Gram +ve
Staphyloccous
Gram −ve
Bacillus
subtillis
Salmonella
typhi
Compounds
aureus
E.coli.
5a
5b
5c
5d
5e
5f
5g
5h
55
80
76
68
65
64
55
68
78
67
70
56
77
78
70
59
61
75
67
75
67
75
80
80
65
70
82
54
69
57
78
67
77
70
80
69
Sulphanilamide
sulphanilyl chloride (ASC) was prepared by reported method.15 All
chemicals used were of laboratory grade.
Preparation of 4-(4’-acetylaminobenzene
Sulphonyl)-1-phenyl Piperazine (1)
General Procedure
1-Phenyl piperazine (0.05 mmol) was dissolved in mixture of 40 ml
anhydrous acetone and 1 ml of dry pyridine in a 250 ml flask, and 11.67
g (0.05 mmol) of pure ASC slowly was added. Sodium bicarbonate was
added as an acid acceptor. The reaction mixture was set aside overnight
and almost pure 4-(4ꢁ-acetylaminobenzene sulphonyl)-1-phenyl piper-
azine (1) was filtered off, washed with cold water, and air dried. It was
then recrystallized from methylated spirit to give white product (1) in
70% yield.
Preparation of 4-(4’-sulphanilyl)-1-phenyl Piperazine (2)
General Procedure
4-(4ꢁ-Acetylaminobenzene sulphonyl)-1-phenyl piperazine (1) was
hydrolyzed by refluxing with 75 ml of ethanol containing 15 ml of con-
centrated HCl for 4–5 h. It was then poured into ice-cold water and
finally made just alkaline with liq. ammonia. The resultant product
4-(4ꢁ-sulphanilyl)-1-phenyl piperazine (2) was filtered off, washed with
water, and air dried. It was then recrystallizd from ethanol to give prod-
uct (2) in 65% yield.

Novel Sulphonamides
1089
Preparation of Schiff Bases (3a–h)
General Procedure
A mixture of equimolar amount (0.01 mmol) of 4-(4ꢁ-sulphanilyl)-
1-phenyl piperazine (2) and the substituted benzaldehydes in ethanol
(40 ml) and piperidine (0.3 ml) was refluxed for 5 h in a water bath.
The reaction mixture was concentrated, cooled, and poured into water;
the solid obtained was filtered and recrystallized from ethanol to give
white Schiff base (3a–h). It was obtained in 60–65% yield.
Preparation of 2-Azetidinones (4a–h)
General Procedure
A mixture of Schiff base (3a–h) (0.002 mmol) and triethyl amine
(TEA) (0.004 mmol) was dissolved in 1,4-dioxane (50 ml), cooled,
and stirred. To this well-stirred cooled solution chloro acetyl chloride
(0.004 mmol) was added drop wise within a period of 20 min. The
reaction mixture was then stirred for an additional 3 h and left at
room temperature for 48 h. The resultant mixture was concentrated,
cooled, poured into ice cold water, then air dried. The product thus ob-
tained was purified by column chromatography over silica gel using 30%
ethyl acetate: 70% benzene as eluent. Recrystallization from ether/n-
hexane gave 2-azetidinones (4a–h), which were obtained in 55–60%
yield.
Preparation of 4-Thiazolidinones (5a–h)
General Procedure
A mixture of Schiff bases (3a–h) (0.01 mmol) in THF (30 ml) and
mercapto acetic acid (0.01 mmol) with a pinch of anhydrous ZnCl2 was
refluxed for 12 h in an oil bath. The solvent was then removed to get a
residue, which was dissolved in benzene and passed through a column
of silica gel using benzene: chloroform (8:2, v/v) mixture as eluent. The
eluate was concentrated and the product crystallized from alcohol (50–
60% yield).
All the compounds [(4a–h) and (5a–h)] were characterized by analyt-
ical and spectral data (Tables III and IV) of the compounds is assigned
in Scheme 1.
RESULTS AND DISCUSSION
N-acetyl sulphanilyl chloride (ASC) was reacted with 1-phenyl piper-
azine to give 4-(4ꢁ-acetylaminobenzene sulphonyl)-1-phenyl piperazine

1090

1091

1092
H. S. Patel and H. J. Mistry
(1) by the reported method.16 It can be hydrolyzed to 4-(4ꢁ-sulphanilyl)-
1-phenyl piperazine (2) by ethanolic HCl.17 It was characterized by el-
emental analysis, IR spectral studies, and NMR spectral studies. The
IR spectra of the compound (2) show the bands at 3390 and 3410 cm−1
for-NH2 group.
This hydrolyzed product (2) was dissolved in ethanol and was reacted
with aromatic aldehydes in the presence of piperidine to yield Schiff
bases (3a–h). These Schiff bases (3a–h) were then characterized by the
elemental analysis, IR spectral studies, and NMR spectral studies. The
IR spectra of Schiff bases show the prominent band at 1630 cm−1 for
the azomethine group.18
These Schiff bases on cyclo-condensation reaction with chloro acetyl
chloride afford 2-azetidinone (4a–h) and with thio-glycolic acid afford
4-thiazolidinone (5a–h) respectively. The structures of both these com-
pounds (4a–h) and (5a–h), respectively, have been confirmed by ele-
mental analysis, IR spectral studies, and NMR spectral studies. These
compounds shows the band at 1690 cm−1 for cyclic >C O group.18 All
the compounds show the NMR signals for different kinds of protons at
their respective positions. The data are shown in Tables III and IV.
The antibacterial activity of both the series (4a–h) and (5a–h), re-
spectively, have been carried out against some strain of bacteria. The
results show that the prepared compounds are toxic against the bac-
teria. The comparison of the antibacterial activity of these compounds
with penicillin and sulphanilamide shows that these compounds have
almost similar activity.
The C,H,N,S analysis of all the compounds of the series are presented
in Tables III and IV. The values are consistent with their predicted
structure (Scheme 1).
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1093
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