Synthesis, spectral analysis and biological evaluation of sulfonamides bearing piperidine nucleus

Article abstract of DOI:10.14233/ajchem.2013.15027

In the current study, two new series of N-alkyl-N-(piperidin-1-yl) benzenesulfonamide (3a-f) and N-aryl substitued 2-[(phenylsulfonyl)- (piperidin-1-yl)amino]acetamide (5a-c) were synthesized and enzyme inhibiting activity was screened for all these chemi

Full text of DOI:10.14233/ajchem.2013.15027

Asian Journal of Chemistry; Vol. 25, No. 17 (2013), 9468-9472
http://dx.doi.org/10.14233/ajchem.2013.15027
Synthesis, Spectral Analysis and Biological Evaluation of
Sulfonamides Bearing Piperidine Nucleus
1
1,*
1
2
HIRA KHALID , AZIZ-UR-REHMAN , MUHAMMAD ATHAR ABBASI , ABDUL MALIK ,
3
4
3
MUHAMMAD ASHRAF , IRSHAD AHMAD and TAYABA ISMAIL
1Department of Chemistry, Government College University, Lahore-54000, Pakistan
2HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
3Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur-63100, Pakistan
4Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur-63100, Pakistan
*Corresponding author: Tel: +92 42 111000010; Ext. 450; E-mail: azizryk@yahoo.com; hirachemist@gmail.com
(Received: 26 December 2012;
Accepted: 1 October 2013)
AJC-14207
In the current study, two new series of N-alkyl-N-(piperidin-1-yl)benzenesulfonamide (3a-f) and N-aryl substitued 2-[(phenylsulfonyl)-
(piperidin-1-yl)amino]acetamide (5a-c) were synthesized and enzyme inhibiting activity was screened for all these chemical entities. The
synthesis was carried out by the coupling of benzenesulfonyl chloride (a) with 1-amino piperidine (b) under dynamic pH control in
aqueous media to afford parent compound N-(piperidin-1-yl)benzenesulfonamide (1). The parent compound further on treatment with
different electrophiles 2a-f and 4a-c in the presence of sodium hydride (NaH) and N,N-dimethyl formamide furnished 3a-f and 3a-c
1
derivatives, respectively. The structures of all the synthesized compounds were confirmed based on IR, EIMS and H NMR data. The
synthesized compounds were screened against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX)
enzymes and almost all the compounds exhibited promising activity but some of the compounds remained inactive against lipoxygenase
enzymes.
Key Words: 1-Aminopiperidine, Sulfonamides, Enzyme inhibiting activity, EI-MS and 1H NMR.
enzyme system is responsible for the termination of acetyl-
choline at cholinergic synapses. These are key components of
cholinergic brain synapses and neuromuscular junctions. The
major function ofAChE and BChE is to catalyze the hydrolysis
of the neurotransmitter acetylcholine and termination of the
nerve impulse in cholinergic synapses8,9. It has been found
that BChE is present in significantly higher quantities in
Alzheimer's plaques than in the normal age related non-
dementia of brains. Antagonists of the histamine H1 and H2
receptors have been successful as blockbuster drugs for treating
allergic conditions and gastric ulcers, respectively. Cholinest-
erase inhibitors increase the amount of acetylcholine avail-
able for neuronal and neuromuscular transmission through
their ability to reversibly or irreversibly Hence, the search for
new cholinesterase inhibitors is considered an important and
ongoing strategy to introduce new drug candidates for the treat-
INTRODUCTION
The piperidine nucleus is a ubiquitous structural feature
of biologically active compounds and numerous secondary
metabolites, for example (S)-pipecolic acid a non-proteino-
genic amino acid associated with epilepsy1-4. Piperidine bearing
compounds have diverse applications in commercial and
medicinal area. Piperidine and pyrrolidine ring containing
compounds were evaluated for their effect on plasma glucose
level5, insulin normalization and treatment of cocaine abuse6.
Sulfonamides are famous for enzyme inhibition such as
carbonic anhydrase, cysteine protease, HIV protease and cyclo-
oxygenase7. Worldwide researchers are trying to synthesize
new drugs with better pharmacokinetic and dynamic properties
with less adverse effects.
Most of the drugs used for the treatment of Alzheimer’s
disease are acetylcholinesterase inhibitors. Acetylcholinest-
erase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE,
EC 3.1.1.8) comprise a family of enzymes which include serine
hydrolases. The different specificities for substrates and
inhibitors for these enzymes are due to the differences in amino
acid residues of the active sites of AChE and BChE. The
ment of Alzheimer's disease and other related diseases10,11
.
Pharmacological potential of the heterocyclic compounds
motivated chemists to synthesize piperidine derivatives with
improved biological activities. In continuation of our previous
work on sulfonamides as possible therapeutic entrants12, here

Vol. 25, No. 17 (2013)
Synthesis, Spectral Analysis and Biological Evaluation of Sulfonamides 9469
we report the synthesis of new sulfonamides bearing piperi-
dine moiety with enzyme inhibition activity.
conversion, the obtained solid was filtered, washed with distilled
water and dried to yield the corresponding electrophile N-alkyl-
substituted-2-bromoacetamide 4a-c.
EXPERIMENTAL
General procedure for synthesis of N-substituted-2-
[(phenylsulfonyl) (piperidin-1-yl)amino] acetamide (5a-c):
To a solution of compound 1 (0.1 g, 0.40 mmol) in DMF
(5 mL) was added sodium hydride (0.01 g, 0.40 mmol) in small
portions over 2-5 min at 0-5 ºC.After addition, the temperature
was maintained at room temperature and stirred for 15 min.
The corresponding N-substituted aryl/alkyl-2-bromoacetamide
(0.09 g, 0.40 mmol) was added into the reaction mixture slowly
and stirred for 10-15 min. The reaction mixture was then heated
to 50 ºC and stirred at this temperature 30-40 min; progress
was monitored by TLC. After completion of reaction, mixture
was cooled to room temperature and quenched with cold water
(50 mL). The acquired precipitation was filtered, washed with
water and dried to acquire the resultant derivatives. In some
cases, the solid precipitation was not formed in the flask then
compound was extracted through solvent extraction method
by chloroform/ethyl acetate to yield the corresponding N-
substituted 2-[(phenylsulfonyl)(piperidin-1-yl)amino]acetamide
(5a-c) derivatives.
Chemicals were purchased from Sigma Aldrich and Alfa
Aesar (Germany). By using open capillary tube method melting
points were taken on Griffin and George melting point apparatus.
Melting points were uncorrected. By using thin layer chroma-
tography and n-hexane and ethyl acetate as mobile phase
purity of the synthesized compounds was detected at 364 nm.
By using KBr, IR peaks were recorded on a Jasco-320-A
spectrophotometer. 1H NMR signals were recorded at 300 MHz
in CD3OD using Bruker spectrometers, chemical shift values
are mentioned in ppm unit. EIMS signals are recorded by
utilizing a JMS-HX-110 spectrometer.
Procedure for synthesis of N-(piperidin-1-yl)benzene-
sulfonamide in aqueous medium (1): 1-Amino piperidine
(a) (2.6 mL; 10 mmol) was suspended in 50 mL water and the
pH was maintained at 9 by adding basic aqueous solution of a
Na2CO3 at 0-5 ºC. Then, benzenesulfonyl chloride (b) (2.9
mL; 10.0 mmol) was added in the reaction mass slowly over
10-15 min. After completion of the addition, the temperature
of the reaction mixture was allowed to rise slowly to room
temperature. The reaction mixture was stirred and monitored
with TLC for the completion of reaction. Then conc. HCl
(around 2 mL) was added slowly to adjust the pH to 2. The
reaction mass was cooled to room temperature, filtered and the
solid washed with distilled water to afford the title compound
1 on drying.
Spectral characterization of synthesized compounds
N-(Piperidin-1-yl)benzenesulfonamide (1): IR (KBr,
νmax, cm-1): 3430 (N-H stretching), 3024 (C-H stretching of
aromatic ring), 1546 (C=C stretching of aromatic ring), 1341
(-SO2-stretching), 1H NMR (300 MHz, CD3OD, δ/ppm): 7.90
(dd, J = 8.7, 1.5 Hz, 2H, H-2' and H-6'), 7.65 (m, 2H, H-3' and
H-5'), 7.52 (m, 1H, H-4'), 2.96 (t, J = 5.4 Hz, 2H, Heq-2 and
Heq-6), 2.47 (t, J = 5.4 Hz, 2H, Hax-2 and Hax-6), 1.61 (m, 2H,
CH2-4), 1.44 (m, 4H, CH2-3 and CH2-5). EIMS m/z: 240 (24
%) [M]+, 176 (37 %), 156 (54 %), 141 (100 %).
General procedure for synthesis of compounds 3a-f:
To a solution of compound 1 (0.2 g, 8.33 mmol) in N,N-dimethyl
formamide (5 mL) was added sodium hydride (0.01 g, 0.40
mmol) at 0-5 ºC. After completion of the addition, the tempe-
rature of the reaction mass was raised to room temperature
and stirred for 15 min. The corresponding alkyl halide (8.33
mmol) was added into the reaction mixture and stirred for 30-
40 min. The reaction mass was then monitored by TLC. After
complete conversion, the reaction mass was cooled to room
temperature and quenched with cold water (200 mL). The
obtained solid was filtered, washed with water and dried to
yield the corresponding N-alkyl derivatives 3a-f.
N-Ethyl-N-(piperidin-1-yl)benzenesulfonamide (3a):
IR (KBr, νmax, cm-1): 2915 (-CH2-stretching), 3029 (C-H
stretching of aromatic ring), 1541 (C=C stretching of aromatic
1
ring), 1337 (-SO2-stretching), H NMR (300 MHz, CD3OD,
δ/ppm): 7.90 (dd, J = 8.4, 1.2 Hz, 2H, H-2' and H-6'), 7.65 (m,
2H, H-3' and H-5'), 7.52 (m, 1H, H-4'), 2.95 (t, J = 5.4 Hz, 2H,
Heq-2 and Heq-6), 2.47 (t, J = 5.4 Hz, 2H, Hax-2 and Hax-6),
1.61 (m, 2H, CH2-4), 1.44 (m, 4H, CH2-3 and CH2-5), 3.20 (q,
J = 7.5 Hz, 2H, CH2-1"), 1.20 (t, J = 7.5, 3H, CH3-2"). EIMS
m/z: 268 (19 %) [M]+, 204 (34 %), 184 (47 %), 127 (100 %).
N-Allyl-N-(piperidin-1-yl)benzenesulfonamide (3b): IR
(KBr, νmax, cm-1): 2919 (-CH2-stretching), 3035 (C-H stretching
of aromatic ring), 1543 (C=C stretching of aromatic ring), 1335
(-SO2-stretching), 1H NMR (300 MHz, CD3OD, δ/ppm): 7.90
(dd, J = 8.7, 1.5 Hz, 2H, H-2' and H-6'), 7.65 (m, 2H, H-3' and
H-5'), 7.52 (m, 1H, H-4'), 5.78 (m, 1H, H-2"), 5.03 (dd, J =1.6,
17.3 Hz, 1H, Hb-3"), 4.96 (dd, J =1.2, 10.0 Hz, 1H, Ha-3''),
4.47 (s, 2H, CH2-1''), 3.10 (t, J = 5.4 Hz, 2H, Heq-2 and Heq-6),
2.47 (t, J = 5.4 Hz, 2H, Hax-2 and Hax-6), 1.61 (m, 2H, CH2-4),
1.44 (m, 4H, CH2-3 and CH2-5). EIMS m/z: 280 (15 %) [M]+,
216 (35 %), 239 (22 %), 196 (55 %), 139 (100 %).
The corresponding alkyl halides used for the reactions
were ethyl iodide, allyl iodide, benzyl chloride, 4-bromobenzyl
bromide, 2-phenyl ethyl iodide and 3-phenyl propyl iodide.
General procedure for synthesis of compounds 4a-c:
The calculated amount of substituted aromatic amines/aromatic
alkyl amines (11 mmol) was taken in an iodine flask containing
10 mL of distilled water and 5 % Na2CO3 solution was added
to adjust the pH 8.0-9.0.After adjusting the pH, the temperature
of the reaction mass was maintained at 0-5 ºC and stirred for
0.5 h. The bromoacetyl bromide (1 mL; 11 mmol) was further
poured drop wise in the reaction mass in 2-5 min at 0-5 ºC.
After completion of the addition, the iodine flask was vigor-
ously shaken (manually) till the solid precipitates formed and
the temperature of the reaction was allowed to rise slowly to
room temperature. The solid precipitate was further stirred
for 45 min. The progress of reaction completion was moni-
tored by TLC (n-hexane:ethyl acetate: 70:30). After complete
N-Benzyl-N-(piperidin-1-yl)benzenesulfonamide (3c):
IR (KBr, νmax, cm-1): 2919 (-CH2-stretching), 3035 (C-H
stretching of aromatic ring), 1543 (C=C stretching of aromatic
1
ring), 1335 (-SO2-stretching), H NMR (300 MHz, CD3OD,
δ/ppm): 7.90 (dd, J = 8.7, 1.5 Hz, 2H, H-2' and H-6'), 7.65 (m,

9470 Khalid et al.
Asian J. Chem.
2H, H-3' and H-5'), 7.52 (m, 1H, H-4'), 7.48 (m, 2H, H-3" and
H-5"), 7.25 (m, 1H, H-4"), 7.11 (d, J = 7.00 Hz, 2H, H-2" and
H-6"), 4.47 (s, 2H, CH2-7"), 3.10 (t, J = 5.4 Hz, 2H, Heq-2 and
Heq-6), 2.47 (t, J = 5.4 Hz, 2H, Hax-2 and Hax-6), 1.61 (m, 2H,
CH2-4), 1.44 (m, 4H, CH2-3 and CH2-5), EIMS m/z: 330 (23
%) [M]+, 266 (44 %), 239 (25 %), 246 (65 %), 91 (100 %).
N-(4-Bromobenzyl)-N-(piperidin-1-yl)benzenesulfon-
amide (3d): IR (KBr, νmax, cm-1): 2923 (-CH2-stretching), 3029
(C-H stretching of aromatic ring), 1549 (C=C stretching of
7.61 (m, 2H, H-3' and H-5'), 6.95-6.99 (m, 4H, H-3'" to H-
6'"), 6.80 (m, 1H, H-4'), 3.90 (s, 3H, CH3-2"'), 4.09 (s, 2H,
CH2-2"), 2.96 (t, J = 5.4 Hz, 2H, Heq-2 and Heq-6), 2.47 (t, J =
5.4 Hz, 2H, Hax-2 and Hax-6), 1.71 (m, 2H, CH2-4), 1.61 (m,
4H, CH2-3 and CH2-5). EIMS m/z: 401 (13 %) [M]+, 372
(43 %), 281 (49 %), 239 (71 %), 141 (100 %).
N-(3-Methoxyphenyl)-2-[(phenylsulfonyl)(piperidin-1-
yl)amino]acetamide (5c): IR (KBr, νmax, cm-1): 3440 (N-H
stretching), 3021 (C-H stretching of aromatic ring), 2920
(-CH2-stretching), 1529 (C=C stretching of aromatic ring),
1323 (-SO2-stretching), 1H NMR (300 MHz, CD3OD, δ/ppm):
11.13 (s, 1H, N-H), 7.72 (dd, J = 6.6, 1.8 Hz, 2H, H-2' and
H-6'), 7.63 (m, 2H, H-3' and H-5'), 7.23 (m, 1H, H-4'), 7.11 (t,
J = 8.1 Hz, 1H, H-5'"), 7.09 (dd, J = 8.1, 1.2 Hz, 1H, H-6"'),
6.76 (d, J = 1.5 Hz, 1H, H-2"'), 6.52 (dd, J = 8.1, 1.2 Hz, 1H,
H-4"'), 4.15 (s, 2H, CH2-2"), 3.92 (s, 3H, CH3-3"?), 2.92 (t, J
= 5.4 Hz, 2H, Heq-2 and Heq-6), 2.43 (t, J = 5.4 Hz, 2H, Hax-2
and Hax-6), 1.73 (m, 2H, CH2-4), 1.60 (m, 4H, CH2-3 and CH2-
5). EIMS m/z: 401 (10 %) [M] +, 372 (32 %), 281 (54 %), 239
(61 %), 141 (100 %).
1
aromatic ring), 1329 (-SO2-stretching), H NMR (300 MHz,
CD3OD, δ/ppm): 7.68 (dd, J = 8.7, 1.5 Hz, 2H, H-2' and H-6'),
7.54 (m, 2H, H-3' and H-5'), 7.46 (d, J = 8.0 Hz, 2H, H-3" and
H-5"), 7.39 (m, 1H, H-4'), 7.02 (d, J = 8.0 Hz, 2H, H-2" and
H-6"), 4.47 (s, 2H, CH2-7"), 3.14 (t, J = 5.4 Hz, 2H, Heq-2 and
Heq-6), 2.47 (t, J = 5.4 Hz, 2H, Hax-2 and Hax-6), 1.71 (m, 2H,
CH2-4), 1.56 (m, 4H, CH2-3 and CH2-5). EIMS m/z: 409 (13
%) [M]+, 345 (29 %), 325 (33 %), 268 (49 %), 171 (100 %).
N-[(2-Phenylethyl)-N-(piperidin-1-yl)benzenesulfon-
amide (3e): IR (KBr, νmax, cm-1): 2921 (-CH2-stretching), 3034
(C-H stretching of aromatic ring), 1541 (C=C stretching of
1
aromatic ring), 1332 (-SO2-stretching), H NMR (300 MHz,
Enzyme inhibition essays
CD3OD, δ/ppm): 7.86 (dd, 2H, J = 7.2, 1.5 Hz, H-2' and H-6'),
7.69 (m, 2H, H-3' and H-5'), 7.61 (m, 1H, H-4'), 7.17-7.21
(m, 5H, H-2"' to H-6"'), 3.55 (t, J = 5.4 Hz, 2H, Heq-2 and Heq-
6), 3.15 ( t, J = 5.4 Hz, 2H, CH2-8"), 2.55 (t, J = 5.4 Hz, 2H,
Hax-2 and Hax-6), 2.66 (t, J = 5.4 Hz, 2H, CH2-7"), 1.61 (m,
2H, CH2-4), 1.44 (m, 4H, CH2-3 and CH2-5). EIMS m/z: 344
(16 %) [M]+, 280 (35 %), 239 (54 %), 260 (74 %), 105 (100 %).
N-(3-Phenylpropyl)-N-(piperidin-1-yl)benzenesulfon-
amide (3f): IR (KBr, νmax, cm-1): 2917 (-CH2 stretching), 3037
(C-H stretching of aromatic ring), 1543 (C=C stretching of
Cholinesterase assay: The AChE and BChE inhibition
activity was performed according to the reported method13 with
slight modifications. Total volume of the reaction mixture was
100 µL. It contained 60 µL Na2HPO4 buffer with concentration
of 50 mM and pH 7.7. Ten µL test compound (0.5 mM well-1)
was added, followed by the addition of 10 µL (0.005 unit well-1)
enzyme (Sigma, USA). The contents were mixed and pre-read
at 405 nm. Then contents were pre-incubated for 10 min at 37 ºC.
The reaction was initiated by the addition of 10 µL of 0.5 mM
well-1 substrate (acetylthiocholine iodide or butyrylthiocholine
chloride), followed by the addition of 10 µL DTNB (0.5 mM
well-1). After 15 min of incubation at 37 ºC absorbance was
measured at 405 nm using 96-well plate reader Synergy HT,
Biotek, USA. All experiments were carried out with their
respective controls in triplicate. Eserine (0.5 mM well-1) was
used as a positive control. The percent inhibition was calculated
by the help of following equation:
1
aromatic ring), 1323 (-SO2-stretching), H NMR (300 MHz,
CD3OD, δ/ppm): 7.86 (dd, J = 7.2, 1.5 Hz, 2H, H-2' and H-6'),
7.69 (m, 2H, H-3' and H-5'), 7.61 (m, 1H, H-4'), 7.17 (m, 5H,
H-2" to H-6"), 3.55 (t, J = 5.4 Hz, 2H, Heq-2 and Heq-6), 3.15
(t, J = 5.4 Hz, 2H, CH2-9"), 2.55 (t, J = 5.4 Hz, 2H, Hax-2 and
Hax-6), 2.66 (t, J = 5.4 Hz, 2H, CH2-7"), 1.93 (m, 2H, CH2-
8"), 1.61 (m, 2H, CH2-4), 1.44 (m, 4H, CH2-3 and CH2-5).
EIMS m/z: 358 (16 %) [M]+, 294 (35 %), 274 (54 %), 239
(74 %), 141 (100 %).
Control - Test
=
×100
Inhibition (%)
N-(2-Methylphenyl)-2-[(phenylsulfonyl)(piperidin-1-
yl)amino]acetamide (5a): IR (KBr, νmax, cm-1): 3450 (N-H
stretching), 3015 (C-H stretching of aromatic ring), 2912 (-
CH2-stretching), 1526 (C=C stretching of aromatic ring), 1337
(-SO2-stretching), 1H NMR (300 MHz, CD3OD, δ/ppm): 11.09
(s, 1H, N-H), 7.98 (dd, J = 8.7, 1.5 Hz, 2H, H-2' and H-6'),
7.73 (m, 2H, H-3' and H-5'), 7.61 (m, 1H, H-4'), 7.11-7.28
(m, 4H, H-3"' to H-6"'), 4.04 (s, 2H, CH2-2"), 3.14 (t, J = 5.4
Hz, 2H, Heq-2 and Heq-6), 2.47 (t, J = 5.4 Hz, 2H, Hax-2 and
Hax-6), 2.19 (s, 3H, CH3-2"'), 1.71 (m, 2H, CH2-4), 1.56 (m,
4H, CH2-3 and CH2-5). EIMS m/z: 387 (16 %) [M]+, 323 (35
%), 372 (54 %), 281 (74 %), 105 (100 %).
Control
IC50 values were calculated using EZ-Fit Enzyme kinetics soft-
ware (Perrella Scientific Inc. Amherst, USA).
Lipoxygenase assay: Lipoxygenase (LOX) activity was
assayed according to the reported method14-16 with slight
modifications. A total volume of 200 µL lipoxygenase assay
mixture contained 150 µL sodium phosphate buffer (100 mM,
pH 8.0), 10 µL test compound and 15 µL purified lipoxygenase
enzyme (600 units well-1, Sigma Inc.). The contents were mixed
and pre-read at 234 nm and preincubated for 10 min at 25 ºC.
The reaction was initiated by addition of 25 µL substrate
solution. The change in absorbance was observed after 6 min
at 234 nm using 96-well plate reader Synergy HT, Biotek,
USA. All reactions were performed in triplicates. The posi-
tive and negative controls were included in the assay. Baicalin
(0.5 mM well-1) was used as a positive control. The percen-
tage inhibition and IC50 values were calculated as mentioned
above.
N-(2-Methoxyphenyl)-2-[(phenylsulfonyl)(piperidin-1-
yl)amino]acetamide (5b): IR (KBr, νmax, cm-1): 3443 (N-H
stretching), 3019 (C-H stretching of aromatic ring), 2923
(-CH2-stretching), 1531 (C=C stretching of aromatic ring),
1325 (-SO2-stretching), 1H NMR (300 MHz, CD3OD, δ/ppm):
11.02 (s, 1H, N-H), 7.74 (dd, J = 6.6, 1.8 Hz, 2H, H-2', H-6'),

Vol. 25, No. 17 (2013)
Synthesis, Spectral Analysis and Biological Evaluation of Sulfonamides 9471
Statistical analysis: All the measurements were done in
triplicate and statistical analysis was performed by Microsoft
Excel 2003. Results are presented as mean sem.
sulfonyl group), respectively. The EI-MS gave characteristic
peaks at m/z 176 and 156 which were attributed to the loss of
SO2 (sulfonyl) and 1-piperidinyl groups, respectively. In the
aromatic region of the 1H NMR spectrum signals appeared at
δ 7.90 (dd, J = 8.7, 1.5 Hz, 2H, H-2' and H-6'), 7.65 (m, 2H,
H-3' and H-5') and 7.52 (m, 1H, H-4') which were assigned to
the mono substituted benzenesulfonyl ring. In the aliphatic
region of the 1H NMR spectrum, signals appeared at 2.96 (t,
J = 5.4 Hz, 2H, Hax-2 and Hax-6), 2.47 (t, J = 5.4 Hz, 2H,
Heq-2 and Heq-6), 1.61 (m, 2H, CH2-4) and 1.44 (m, 4H, CH2-3
and CH2-5) which indicated the presence of piperidine nucleus
in the molecule. On the basis of above cumulative evidences,
the structure of 1 was assigned as N-(piperidin-1-yl)benzene-
sulfonamide. Similarly, the structure of other compounds was
RESULTS AND DISCUSSION
In the undertaken research, new series of heterocyclic
compounds containing piperidine nucleus was synthesized as
described in Scheme-I. The structures of all these compounds
were characterized by spectral data. The parent compound
N-(piperidin-1-yl)benzenesulfonamide (1), was prepared by
the coupling of benzenesulfonyl chloride (a) with 1-amino
piperidine (b) under the dynamic pH control of basic aqueous
media17. Further, the reaction of parent compound with diffe-
rent electrophiles yielded a series of N-alkyl substituted-N-
(piperidin-1yl)benzenesulfonamide (3a-f) and N-aryl
substitued 2-[(phenylsulfonyl)(piperidin-1-yl)amino]acetamide
(5a-c) derivatives as represented in Scheme-I. Synthesis of
all the derivatives 3a-f and 5a-c was performed in DMF using
sodium hydride which acts as a base. Complete conversion
was achieved within 30-70 min by stirring at room temperature.
The products were isolated by adding cold water in the reaction
mixture and filtering off the precipitated solid. In some cases,
compound was taken out through solvent extraction method
by chloroform/ ethyl acetate. Parent compound 1 was synthe-
sized as light yellow powder. The molecular formula
C18H17N3O3S was established by EI-MS and counting the
number of protons in the 1H NMR spectrum showing molecular
ion peak at m/z 240. The IR spectrum showed absorption bands
at 3430, 3024, 1546 and 1341 cm-1 which were assigned to,
SO2-N-H (stretching of sulfonamide), C-H (aromatic stretching),
C=C (stretching of aromatic ring) and -SO2 (stretching of
1
characterized by H NMR, IR and mass spectral data as
described in experimental section. The physical data of all the
synthesized compounds has been shown in Table-1.
Enzyme inhibition activity: The screening of these
synthesized compounds against acetylcholinesterase (AChE),
butyrylcholinesterase (BChE) and lipoxygenase (LOX) enzymes
revealed that these molecules exhibited good inhibitory
potential against acetylcholinesterase and butyrylcholinesterase
as it was evident from their IC50 values. It is obvious from
Table-2 that compounds N-allyl-N-(piperidin-1-yl)benzene-
sulfonamide (3b) and N-benzyl-N-(piperidin-1-yl)benzene-
sulfonamide (3c) were showed promising inhibitory potential
against butyrylcholinesterase enzyme having IC50 value of 4.4
0.03 and 4.21 0.11 µmol/L, respectively, relative to eserine,
a reference standard with IC50 value of 0.85 0.001 µmol/L,
probably due to the N-substitution of allyl and benzyl groups,
respectively in these molecules. Similarly, from a series of N-
O
O
3
1
N
H
2
S
5
DMF, NaH, Stirr at RT
4
6
N
R
H
3'
1'
H
R1
X
H
5'
1
2a-f
3a-f
O
O
O
O
H
H
H
H
Na2CO3 soln.
pH-9.0-10.0
S
N
H
N
S
H N
2
HN
+
H
Cl
O
H
H
Stirr at RT
O
O
3
1
N
H
1
2
R2
Br
S
5
b
N
H
CH2
6
4
N
H
a
3'
1'
4a-c
H
o
Stirr at 50 C
H
MF, NaH,
D
5'
2''
C
H
2
H
N
1''
R
2
O
5a-c
Compound
R1
Compound
R1
Compound
R2
7''
CH2
6'''
1''
CH2 CH3
2''
6''
3a
3d
5a
2'''
2''
4'''
4''
CH
Br
3
7''
CH2
H
Ha
6'''
8''
CH2
6''
C
C
3b
3c
3e
3f
5b
5c
1''
CH2
2'''
2''
4'''
4''
2'' 3'' Hb
OCH
3
9''
CH2
7''
CH2
7''
CH2 8''
CH2
6'''
6''
6''
2'''
4'''
2''
2''
4''
4''
CH
O
3
Scheme-I: Outline for the synthesis of sulfonamides bearing piperidine nucleus

9472 Khalid et al.
Asian J. Chem.
TABLE-1
PHYSICAL DATA OF THE SYNTHESIZED COMPOUNDS
Samples
1
Appearance
m.p. (ºC)
Molecular formula
Yield (%)
Light yellow powder
Brownish orange sticky liquid
Brown sticky solid
55-57
C11H16N2O2S
C13H20N2O2S
C14H20N2O2S
C18H22N2O2S
C18H21BrN2O2S
C19H24N2O2S
C20H26N2O2S
C20H25N3O3S
C20H25N3O4S
C20H25N3O4S
90
79
83
80
72
81
75
85
77
87
–
–
–
–
–
–
–
–
–
3a
3b
3c
Mustard sticky solid
Light yellow sticky solid
Greenish black sticky solid
Mustard sticky solid
Dark Brown sticky solid
Rust sticky solid
3d
3e
3f
5a
5b
5c
Rust sticky solid
TABLE-2
BIOACTIVITY STUDIES OF THE SYNTHESIZED SULFONAMIDES BEARING PIPERIDINE NUCLEUS
BChE AChE LOX
Compound No.
Inhibition (%)
at 0.5 mM
Inhibition (%)
at 0.5 mM
Inhibition (%)
at 0.5 mM
IC50 (µM)
IC50 (µM)
IC50 (µM)
30.74 0.42
80.67 0.11
95.68 0.41
95.19 0.32
80.33 0.31
95.53 0.64
94.09 0.34
96.35 0.04
91.47 0.82
89.79 0.45
Eserine
–
39.49 0.21
85.98 0.32
83.90 0.14
75.09 0.54
67.85 0.25
78.69 0.42
82.01 0.73
86.74 0.19
86.46 0.94
82.01 0.43
Eserine
–
57.96 0.22
50.06 0.63
42.17 0.31
48.51 0.98
40.69 0.34
42.95 0.26
49.42 0.63
67.73 0.11
66.11 0.37
48.90 0.69
Baicalein
329.31 0.08
1
3a
87.51 0.04
4.4 0.03
39.21 0.04
23.21 0.17
60.41 0.31
185.21 0.39
69.71 0.36
147.51 0.35
32.71 0.05
190.52 0.52
35.31 0.24
0.04 0.001
> 400
–
3b
4.21 0.11
89.21 0.014
16.21 0.54
17.42 0.08
18.11 0.24
34.41 0.52
137.24 0.05
0.85 0.001
–
3c
–
3d
-
3e
-
3f
339.11 0.18
181.31 0.09
-
5a
5b
5c
Control
22.4 1.3
Note: IC50 values (concentration at which there is 50 % enzyme inhibition) of compounds were calculated using EZ-Fit enzyme kinetics software
(Perella Scientific Inc. Amherst, USA). LOX = Lipoxygenase. AChE = Acetyl cholinesterase. BChE = Butyryl cholinesterase.
substituted 2-[(phenylsulfonyl)(piperidin-1-yl)amino]acetamide
(5a-c), the compound which showed talented inhibitory activity
was N-(2-methylphenyl)-2-[(phenylsulfonyl)(piperidin-1-
yl)amino]acetamide (5a) having IC50 value of 18.11 0.24
µmol/L as compared to reference standard. The enhanced
activity might be due to the substitution of N-(2-methylphenyl)-
acetamide which is probably more complimentary for the
inhibition of butyrylcholinesterase enzyme. The screening
against acetylcholinesterase enzyme depicted that the four
compounds 3b, 5a, 5c and 3a exhibited good inhibitory
potential but all other synthesized compounds showed moderate
activity as compared to relative eserine, a reference standard
with IC50 value of 0.04 0.001 µmol/L. However, only few
compounds (Table-2) showed very weak inhibition against
lipoxygenase enzyme but all other compounds remained
inactive.
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ACKNOWLEDGEMENTS
The authors are thankful to Higher Education Commission
of Pakistan for financial support.