Synthesis of N-phenylsulfonamide derivatives and investigation of some esterase enzymes inhibiting properties

Article abstract of DOI:10.1016/j.bioorg.2020.104279

In this study, synthesis of nine N-phenylsulfonamide derivatives was designed by starting from aniline, which is the simplest aromatic amine. These compounds were obtained in yields between 69 and 95%. Inhibitory properties of synthesized compounds on car

Full text of DOI:10.1016/j.bioorg.2020.104279

BioorganicChemistry104(2020)104279
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Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis of N-phenylsulfonamide derivatives and investigation of some esterase enzymes
inhibiting properties
A R T I C L E I N F O
A B S T R A C T
Keywords:
In this study, synthesis of nine N-phenylsulfonamide derivatives was designed by starting from aniline, which is
the simplest aromatic amine. These compounds were obtained in yields between 69 and 95%. Inhibitory
properties of synthesized compounds on carbonic anhydrase I (CA I), CA II isoenzymes, acetylcholinesterase
(AChE) and butyrylcholinesterase (BChE) enzymes were investigated. Inhibitors of CA isoenzymes are important
therapeutic targets, particularly due to their preventive/activation potential in the treatment of diseases such as
edema, glaucoma, cancer and osteoporosis. Cholinesterase inhibitors are valuable compounds that can be used in
many different therapeutic applications, including Alzheimer's disease. The compound 8 for CA I, AChE and
4-Phenyl-sulfonamide
Carbonic anhydrase
Aniline
Cholinesterase
Enzyme inhibition
BChE, 2 for CA II showed a very active inhibition profile (KI 45.7
31.5 0.33 nM for AChE and 24.4 0.29 nM for BChE). The results indicate that these N-phenyl-sulfonamide
derivatives are potent CA and cholinesterases and new potential drugs.
0.46 for CA I, 33.5
0.38 nM for CA II,
1. Introduction
In the last 160 years, aniline has become one of the most used facial
building blocks in the chemical industry. Aniline is a raw material used
in several fields to produce functional products in many different ap-
plication areas, such as the production of rubber processing chemicals,
agrochemicals, paints and pigments and pharmaceuticals. In pharma-
ceutical chemistry, although it is a stable and small output molecule,
aniline is mainly used for the preparation of analgesics, antipyretics,
antiallergics and vitamins [22].
Carbonic anhydrases (EC 4.2.1.1, CAs) are a family of enzymes that
both have physiological hydratase and also esterase activity. CA iso-
enzymes are found in many tissues involved in many different im-
portant biological processes [1–5].
Sulfonamides are being used as CA inhibitors or activators and they
have broad biological activities such as anticancer, antifungal, anti-
obesity, antibacterial, antidiuretic, antiglaucoma, and antiepileptic
[2,6]. Generally, acetazolamide is used as an antiglaucoma agent, sul-
fadiazine is used as an antibiotic and sulfapyridine, a sulfonamide
consisting of pyridine, is used against bacterial infections [7]. The other
sulfonamide derivative is nimesulide, which has anticancer activity, is
mainly used for designing novel sulfonamide derivatives [8] (see
Fig. 1).
Sulfonamides, especially aromatic or heteroaromatic ones, are the
well known inhibitors of CA isoenzymes and numerous literature has
been reported in this area [23]. Nevertheless, sulfonamide derivatives
of aniline has not yet been investigated. In this paper we focused on N-
phenyl-sulfonamide derivatives that contain methanosulfonamide, 4-
methoxybenzenesulfonamide, 3-(trifluoromethyl) benzenesulfonamid,
4-fluorobenzenesulfonamide,
3-fluorobenzenesulfonamide,
3-pyr-
In some studies conducted recently by our group, we investigated
the inhibition of carbonic anhydrase isoenzymes obtained from dif-
ferent organisms with different substances. These inhibitors were sub-
stances such as sulfonamides, pyrazole derivatives, phthalocyanine
derivatives and some natural molecules [9–16].
idinesulfonamide, 8-quinolinesulfonamide, 2-naphthalenesulfonamide,
2-thiophenesulfonamide. Sulfonamides were synthesized in yields from
69 to 95% and spectral data was taken from 1H NMR. The 1H NMR
spectra of compounds was compatible with known molecular structures
[24–27].
Alzheimer's disease (AD) is defined as a neurodegenerative condi-
tion characterized by abnormal behaviours and intellectual reductions.
This disease has become one of the leading public health problems due
to the elderly increasing population especially in developed countries
[17–20]. Inhibition of AChE and BuChE enzymes that hydrolyze acet-
ylcholine (ACh) and butyrylcholine (BCh) neurotransmitters have be-
come a treatment option for AD [21].
In this research a number of sulphonamide derivatives were pre-
pared by reaction of aniline with aromatic and aliphatic sulphona-
mides. The reaction of aniline with a series of sulfonyl chloride afforded
the target compounds. Protocols for mesylation of amines offer sim-
plicity, short reaction time and mild conditions. The reaction transform
a broad range of substrates with excellent yield.
In this study, novel N-phenylsulfonamide derivatives were synthe-
sized in order to discover some novel inhibitors of the esterase enzyme
(both for CAs and cholinesterases). Two CA isoenzymes (hCA I and
hCAII) from human erythrocytes were purified and the inhibitory ef-
fects of the indicated substances on hCA I, II, AChE and BChE were
investigated.
Therefore, many researchers have tried to identify novel inhibitors
of these enzymes for the treatment of AD. The physiological activity of
the AChE enzyme is the hydrolysis of ACh. Increasing ACh concentra-
tion is a treatment strategy due to the loss of cholinergic neurons in
Alzheimer's patients. Drugs such as neostigmine, galantamine and riv-
astigmine are AChE enzyme inhibitors. These drugs act by increasing
the amount of ACh by preventing the hydrolysis of ACh [21].
https://doi.org/10.1016/j.bioorg.2020.104279
Received 13 March 2020; Received in revised form 11 August 2020; Accepted 11 September 2020
Availableonline17September2020
0045-2068/©2020ElsevierInc.Allrightsreserved.

BioorganicChemistry104(2020)104279
Fig. 1. Sulfonamides with extensive biological activity.
2. Experimental and methods
4-Fluoro-N-phenylbenzenesulfonamide (5): The above procedure
was followed with aniline and sulfonyl chloride (14) to yield 5 as a
1
2.1. Chemistry
white solid (70% yield) [24]. H NMR (400 MHz, CDCl3) δ 7.80–7.76
(m, 2H), 7.28–7.24 (m, 2H), 7.18–7.05 (m, 5H).
2.1.1. General information
3-Fluoro-N-phenylbenzenesulfonamide (6): The above procedure
was followed with aniline and sulfonyl chloride (15) to yield 6 as a
white solid (77% yield). 1H NMR (400 MHz, CDCl3) δ 7.63–7.55 (m,
1H), 7.55–7.48 (m, 1H), 7.48–7.41 (m, 1H), 7.31–7.22 (m, 3H),
7.20–7.13 (m, 1H), 7.14–7.07 (m, 2H).
Commercially available reagents utilized in this study were used
directly without any additional purification. The reactions were carried
out under a nitrogen atmosphere, unless otherwise stated. Anhydrous
solvents were distilled over appropriate drying agents prior to use.
1H NMR Spectra: Bruker 400 spectrometers. Melting points were
determined in open glass capillary using a Stuart melting point SMP30
apparatus. The chromatographic purifications were performed by
column chromatography employing silica gel (230–400 mesh,
40–63 μm), and eluting with hexane or hexane/EtOAc mixtures of in-
creasing polarity. The progress of the reactions was monitored by thin
layer chromatography. For detection of the spots, the TLC plates were
exposed to UV light (254 and 365 nm).
N-phenylpyridine-3-sulfonamide (7): The above procedure was
followed with aniline and sulfonyl chloride (16) to yield 7 as a white
solid (92% yield) [27]. 1H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 8.87
(d, J = 2.1 Hz, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.12 (ddd, J = 8.1, 2.3,
1.5 Hz, 1H), 7.60 (dd, J = 8.1, 4.8 Hz, 1H), 7.25 (t, J = 7.9 Hz, 2H),
7.15–7.02 (m, 3H).
N-phenylnaphthalene-2-sulfonamide (8): The above procedure
was followed with aniline and sulfonyl chloride (17) to yield 8 as a
white solid (83% yield) [24]. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H),
7.89 (dd, J = 9.3, 8.5 Hz, 3H), 7.80 (dd, J = 8.7, 1.6 Hz, 1H), 7.61
(dtd, J = 8.0, 6.9, 3.3 Hz, 2H), 7.30–7.18 (m, 2H), 7.18–7.06 (m, 4H).
N-phenylthiophene-2-sulfonamide (9): The above procedure was
followed with aniline and sulfonyl chloride (18) to yield 9 as a light
yellow solid (69% yield) [24]. 1H NMR (400 MHz, CDCl3) δ 7.54 (ddd,
J = 5.0, 4.4, 1.3 Hz, 1H), 7.33–7.26 (m, 3H), 7.18–7.12 (m, 3H), 7.02
(dd, J = 5.0, 3.8 Hz, 1H).
2.1.2. General procedure for preparation of compounds 1–9
Appropriate sulfonyl chloride derivative (1.1 eq) was added to a
stirred solution of the aniline (1 eq) in CH2Cl2 at room temperature. The
resulting mixture was cooled down to 0 °C before Et3N (2.17 eq) was
slowly added. The resulting mixture was warmed to room temperature
and stirred for 24 h before it was quenched with NH4Cl (sat. aq.). The
layers were separated and the organic layer was extracted with water
and CH2Cl2, dried over Na2SO4 and concentrated in vacuo. The re-
maining residue purified via column chromatography over silica gel
using gradient elution with EtOAc and hexanes to yield sulfonamides
1–9.
2.2. Purification of hCA I and II isozymes
Human CA I and CA II isoenzymes were purified from fresh human
erythrocytes using affinity chromatography. The purification method
used in this study was described in previous studies in detail [15–17].
N-phenylmethanesulfonamide (1): The above procedure was
followed with aniline and sulfonyl chloride (10) to yield 1 as a light
yellow solid (85% yield) [24].1H NMR (400 MHz, CDCl3) δ 7.36 (t,
J = 7.9 Hz, 2H), 7.26–7.17 (m, 3H), 6.89 (s, 1H), 3.02 (s, 3H).
4-Methoxy-N-phenylbenzenesulfonamide (2): The above proce-
dure was followed with aniline and sulfonyl chloride (11) to yield 2 as a
white solid (78% yield) [24]. 1H NMR (400 MHz, CDCl3) δ 7.75–7.70
(m, 2H), 7.29–7.20 (m, 2H), 7.15–6.95 (m, 3H), 6.92–6.80 (m, 2H),
3.82 (s, 3H)
2.3. Esterase activity test for carbonic anhydrase isoenzymes
Inhibition kinetics studies for CA I and CA II isoenzymes have been
performed with minor changes in the esterase method. In this part of
our study, the inhibition effects of N-phenylsulfonamide derivatives
1–9 were determined. All trials were examined three times. Trials in
different concentration ranges were performed for all inhibitors
[15,28]. In the absence of the inhibitor in the measuring medium, the
control cuvette activity was considered as 100%. KI values were found
by Lineweaver and Burk’s curves [12–17] (Table1).
N-phenyl-3-(trifluoromethyl)benzenesulfonamide
(3):
The
above procedure was followed with aniline and sulfonyl chloride (12)
to yield 3 as a white solid (84% yield) [25]. 1H NMR (400 MHz, CDCl3)
δ 8.04 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.58
(t, J = 7.9 Hz, 1H), 7.30–7.25 (m, 2H), 7.20–7.15 (m, 1H), 7.10–7.05
(m, 2H), 6.90 (s, 1H).
2.4. Activity test for cholinesterase enzymes
N-phenylquinoline-8-sulfonamide (4): The above procedure was
followed with aniline and sulfonyl chloride (13) to yield 4 as a white
solid (95% yield) [26]. 1H NMR (400 MHz, CDCl3) δ 9.20 (dd, J = 4.3,
1.6 Hz, 1H), 8.63 (s, 1H), 8.37–8.32 (m, 2H), 8.04 (dd, J = 8.2, 1.0 Hz,
1H), 7.65 (dd, J = 8.3, 4.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.15–7.08
(m, 2H), 7.07–6.98 (m, 3H).
Inhibition activities of N-phenylsulfonamide derivatives (1–9) on
cholinergic enzymes (AChE and BuChE) were determined using the
Ellman method [29]. For this analyze neostigmine drug, an AChE in-
hibitor, was used as a reference molecule. KI values obtained for N-
phenylsulfonamide derivatives (1–9) are summarized in Table 1.
2

BioorganicChemistry104(2020)104279
Table 1
(i) In inhibition studies of hCA I isoenzyme, N-phenylsulfonamide
derivatives 1–9 showed good inhibitor activities, with KI values in
the range of 45.7–103.1 nM, similar to structurally related com-
hCA I, hCA II, AChE and BChE inhibition data some compounds.
KI (nM)*
pounds
4-Amino-N-(pyridin-2-yl)
benzenesulfonamide
Inhibitor
hCA I
hCA II
0.97 83.3
AChE
BChE
(Sulfapyridine) (KI of 26.19 μM). Compounds 2, 3, 4, and 8 ex-
hibited much stronger hCA I inhibition effect compared to the
other synthesized compounds. It has been determined that natural
phenolic compounds, sulfonamides, uracil derivatives, pesticides
and many different chemicals was shown to provide similar results
with these compounds [6–12,36–41].
1
103.1
49.5
47.3
46.4
69.1
61.2
78.4
45.7
65.3
487.3
–
0.78
0.38
0.36
0.37
0.45
0.43
0.57
0.36
0.49
41.0
40.3
61.9
35.7
54.2
36.9
72.3
31.5
52.5
–
0.42 37.9
0.38 33.2
0.57 38.7
0.34 46.7
0.46 43.1
0.37 34.5
0.69 39.3
0.33 24.4
0.56 35.8
–
0.41
0.38
0.40
0.49
0.45
0.38
0.40
0.29
0.36
2
0.55
0.53
0.52
0.73
0.63
0.69
0.46
0.67
33.5
38.1
36.3
57.6
44.2
61.8
35.5
48.4
3
4
5
6
(ii) N-phenylsulfonamide derivatives 1–9 were found to inhibit the
hCA II isoenzyme more strongly than the hCA I isoenzyme
(Table 1). The structure–activity relationship (SAR) analyze for
1–9 compounds is as follows: The bulky group containing com-
pounds 2, 3, 4, 6, and 8 are more effective than other derivatives.
The best hCA II inhibitor among the derivatives 1–9 is the number
2, containing the p-methoxybenzene group, with the KI value of
33.5 nM. For hCA II isoenzyme, 3, 4, 6, and 8 yielded very close to
each other with a range between 35.5 and 44.2 nM.
7
8
9
AZA**
3.92 224.9
–
2.33
Neostigmine***
55.5
0.46 33.3
0.32
* Mean from at least three determinations.
** Acetazolamide (AZA) was used as a control for CA I and CA II.
*** Neostigmine was used as a control for AChE and BChE.
(iii) Compound 7 (KI = 72.3 nM) showed the weakest inhibitory effect
among the agents 1–9 against the AChE enzyme. However, number
8 (31.5 nM), which is the only derivative having naphthalene
group, showed a better inhibitory profile than other eight N-phe-
nylsulfonamide derivatives. The most obvious difference between
other compounds and this derivative is the larger volume of the
derivative number 8. Compared to others, the derivative 4 pro-
vided the closest result to derivative 8. The fact that derivatives 4
and 8 bearing this two-ring sterically bulky functional group have
stronger inhibition profiles may indicate that, geometry of these
two compounds make them stronger to be able to interact with the
active site of the AChE enzyme. According to the observed results
for derivatives 1–9 and AChE, the presence of electronegative
groups in functional groups may indicate a significant effect on the
inhibition value. In addition, it can be concluded that hydrophobic
and sterically larger molecules are more effective. The derivative
7, which is determined to be the weakest inhibitor, contains pyr-
idine as the functional group. Although the position of the F atom
changes only in derivatives 5 and 6, 1.47 times of activity variation
was detected between them. In addition, the values obtained for
the AChE enzyme in this study (31.5–72.3 nM) were compared
with the reference molecule neostigmine (55.5 nM). While four of
these synthesized derivatives showed approximate values to
neostigmine, the other five molecules exhibited better results.
(iv) In inhibition studies of BChE enzyme with derivatives 1–9, deri-
vative 4 (KI = 46.7 nM) was found to have the weakest inhibitory
effect. Among the N-phenylsulfonamide derivatives we tested, the
most effective BChE inhibitor was determined to be the naphtha-
lene-containing derivative 8 (KI = 24.4 nM). In addition, KI values
obtained for the BChE enzyme (24.4–46.7 nM) were compared
with the reference molecule neostigmine (33.3 nM). According to
these values, eight of these synthesized derivatives showed ap-
proximate values to neostigmine, while one molecule (8) provided
better results.
Stock solutions of derivatives 1–9 used in this study were prepared
by dissolving them in dimethyl sulfoxide to the concentration of 1 mg /
mL. The prepared stock solution was then diluted ten thousand times
with distilled water. In order to determine the inhibition activities of
derivatives 1–9 with these enzymes, measurements were performed in
seven different concentrations. The method used in this study has been
explained in previous studies in detail [17,30,31].
3. Results
3.1. Chemistry
In this research, a number of N-phenylsulfonamide derivatives were
synthesized by using a facile and efficient sulfonation method of
amines. Compounds were prepared by the reaction of aniline with
aromatic and aliphatic sulphonamides. The reaction of aniline with a
number of sulfonyl chlorides afforded the target compounds. Protocols
for mesylation of amines offer simplicity, short reaction time and mild
conditions. The reaction transformed a broad range of substrates in
excellent yield.
The reaction has been performed in DCM as the solvent, in the
presence of Et3N as base, in accordance with the procedure previously
reported by our group [6b]. Compounds 1–9 were characterized by
standard chemical and physical methods that confirm their structure
and were assayed for the inhibition of these esterase enzymes.
3.2. Biochemical studies
In this study, N-phenylsulfonamide derivatives 1–9 were synthe-
sized and their inhibition effects on some esterase enzymes (CA I, CA II,
AChE and BChE) were determined.
Many previous studies have shown that cholinesterase enzymes
(AChE and BChE) have very important functions on cognition and
memory. These enzymes catalyze the hydrolysis of ACh and BCh, which
leads to reduced neural communication between nerve cells. This fact
slows down brain functions of individuals with subnormal ACh levels
and finally leads to AD. Therefore, the treatment of AH is to some extent
dependent on the rebalancing of the ACh level [32–35]. Many studies
have targeted cholinesterase inhibitors (ChEIs) for the treatment of
cognitive disorders. Due to the disadvantages of existing AD drugs such
as gastrointestinal disorders and bioavailability, many studies across
the world are constantly investigating new ChEIs. Therefore, in this
study, derivatives 1–9 were also screened for their inhibitory activities
on cholinesterase enzymes.
Considering the results obtained for CA isoenzymes, all tested
compounds 1–9 (Table 1) were capable of inhibiting CA II isoenzyme at
lower doses. High selectivity for CA II proves the potential utilization of
these compounds in the treatment of glaucoma. Inhibition values of
cholinesterase, which is a useful and specific inhibitor, were obtained
close to those of neostigmine; indicating that this series of substances
are likely to be used in the treatment of neurodegenerative diseases
such as neostigmine.
Sulfonamides are well known CA inhibitors, but recent studies have
shown that their molecules containing different functional groups have
3

BioorganicChemistry104(2020)104279
Fig. 2. Structure of tested compounds.
Fig. 3. Sulfonyl chlorides used in the synthesis of sulfonamide derivatives.
Fig. 4. The model of sulfonamides binding to the active site of the CA II isoenzyme (A) [12,41] and the estimated binding model of the derivative 2 to the active site
in the CA II isoenzyme (B).
as good inhibitory effects as sulfonamides [6–17,36–44]. In addition, it
has been determined in recent studies that the molecules which are
effective on CA isoenzymes also have effects on another esterase
enzyme group, AChE and BChE enzymes. These results indicate that N-
phenylsulfonamide derivatives exhibit both hCA I, II and AChE/BChE
inhibitory activity due to the presence of different functional groups.
4

BioorganicChemistry104(2020)104279
Fig. 5. A: The binding of acetylcholine with the active region of the hAChE enzyme (pdb: 4ey4) [4,42,43] B: The binding pattern of butyrylcholine with the active
site of the hBChE enzyme (pdb: 1p0i) [4,42–44]. C: The estimated AChE binding form of 2, D: The predicted BChE binding pattern of 2.
The proposed mechanisms for enzyme inhibition are given in Figs. 4
and 5.
The findings of this study provides multiple targets. Tested in-
hibitors of esterase enzymes are currently considered as effective drugs
in the treatment of several diseases. Since these N-phenylsulfonamide
derivatives (1–9) are effective cholinesterase inhibitors, they can be
used in the treatment of Alzheimer's disease, as well as in the treatment
of diseases such as glucoma, edema and cancer, since they are also
effective CAIs. In addition to comparing the synthesized N-phe-
nylsulfonamides with many other compounds, this study will expand
targets to determine the structure–activity relationship for N-phe-
nylsulfonamides 1–9. Thus, the synthesized N-phenylsulfonamides can
also be evaluated as drug precursors or building blocks in the pre-
paration of more effective drug molecules.
4. Discussion
The main goal of the present study was to synthesize and investigate
the inhibition effects on the CA I, CA II, AChE and BChE enzymes due to
the presence of different functional groups (-F, -CH3, -OCH3, -CF3,
naphthalene, pyridine, etc.) found in their molecular structures. The
synthesis of the target compounds was performed according to the
previously reported literature procedure as outlined in Fig. 3 [6]. Before
the sulfonation reaction of the aniline, H’s of aniline signals were ob-
served at 7.20 (t, 2H, J = 7.5 Hz), 6.81 (t, 1H, J = 7.5 Hz), 6.71 (d, 2H,
Declaration of Competing Interest
1
J = 7.5 Hz), 3.65 (br s, 2H, -NH2) ppm at the H NMR spectra. After
sulfonamide formation, it was observed that there were changes in the
peaks of benzylic aniline and disappear the broad singlet (2H, -NH2) of
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
1
aniline. All sulfonamide structures were confirmed by H NMR in lit-
erature. [23–26]
N-phenylsulfonamide derivatives 1–9 used in this study showed
different inhibition effects on CA I, CA II, AChE and BChE enzymes due
to the presence of different functional groups (-F, -CH3, -OCH3, -CF3,
naphthalene, pyridine, etc.) found in their particular molecular struc-
tures. Results of this study show that synthesized compounds are highly
effective on the tested esterase enzymes at nanomolar concentrations.
The data obtained from this study exhibit the potential usage of these
synthesized compounds for the production of strong CAIs or cholines-
terase inhibitors that target other CA isoforms that have not yet been
tested (Fig. 2).
Acknowledgments
This work was supported by Kilis 7 Aralik University, Scientific
Research Projects Coordinatorship (BAP 18-12191)
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⁎
Elif Akin Kazancioglua,b, , Murat Senturkc
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a Vocational High School of Health Services, Kilis 7 Aralik University,
79000 Kilis, Turkey
b Advanced Technology Application and Research Center, Kilis 7 Aralik
University, 79000 Kilis, Turkey
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E-mail address: eakazancioglu@kilis.edu.tr (E. Akin Kazancioglu).
⁎ Corresponding author at: Vocational High School of Health Services, Kilis 7 Aralik University, 79000 Kilis, Turkey.
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