Synthesis of novel disulfide and sulfone hybrid scaffolds as potent β-glucuronidase inhibitor

Article abstract of DOI:10.1016/j.bioorg.2016.07.002

Novel series of disulfide and sulfone hybrid analogs (1 ?2 0) were synthesized and characterized through EI-MS and ¹H NMR and evaluated for β-glucuronidase inhibitory potential. All synthesized analogs except 13 and 15 showed excellent β-glucuronidase inhibitory potential with IC₅₀ value ranging in between 2.20–88.16 μM as compared to standard D-saccharic acid 1,4 lactone (48.4 ± 1.25 μM). Analogs 19, 16, 4, 1, 17, 6, 10, 3, 18, 2, 11, 14 and 5 showed many fold potent activity against β-glucuronidase inhibitor. Structure activity relationship showed that substitution of electron withdrawing groups at ortho as well as para position on phenyl ring increase potency. Electron withdrawing groups at meta position on phenyl ring showed slightly low potency as compared to ortho and para position. The binding interactions were confirmed through molecular docking studies.

Full text of DOI:10.1016/j.bioorg.2016.07.002

Accepted Manuscript
Synthesis of Novel Disulfide and Sulfone hybrid Scaffolds as Potent β-glucur-
onidase Inhibitor
Muhammad Taha, Nor Hadiani Immail, Syahrul Imran, Abdul Wadood, Fazal
Rahim, Laode Muhammad Ramadhan Al Muqarrabin, Hamizah Mohd Zaki,
Norizan Ahmat, Abdul Nasir, Fahad Khan
PII:
S0045-2068(16)30107-9
DOI:
http://dx.doi.org/10.1016/j.bioorg.2016.07.002
YBIOO 1922
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 May 2016
1 July 2016
4 July 2016
Please cite this article as: M. Taha, N.H. Immail, S. Imran, A. Wadood, F. Rahim, L.M.R. Muqarrabin, H.M. Zaki,
N. Ahmat, A. Nasir, F. Khan, Synthesis of Novel Disulfide and Sulfone hybrid Scaffolds as Potent β-glucuronidase
Inhibitor, Bioorganic Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bioorg.2016.07.002
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Synthesis of Novel Disulfide and Sulfone hybrid Scaffolds as Potent β-glucuronidase
Inhibitor
Muhammad Tahaa,b∗, Nor Hadiani Immaila,b, Syahrul Imrana,b, Abdul Wadoodc,
Fazal Rahimd, Laode Muhammad Ramadhan Al Muqarrabin a,b, Hamizah Mohd
Zaki, a,b Norizan Ahmata,b Abdul Nasirc, Fahad Khand
aAtta-ur-Rahman Institute for Natural Product Discovery, UniversitiTeknologi MARA,
PuncakAlam42300,Malaysia
bFaculty of Applied Science Universiti Teknologi MARA, Shah Alam 40450,Selangor D.
E., Malaysia
cDepatment of Biochemistry, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa,
Pakistan
dDepatment of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
Abstract
Novel series of disulfide and sulfone hybrid analogs (1-20) were synthesized and
1
characterized through EI-MS and H-NMR and evaluated for β-glucuronidase inhibitory
potential. All synthesized analogs except 13 and 15 showed excellent β-glucuronidase
inhibitory potential with IC50 value ranging in between 2.20-88.16 µM as compared to
standard D-saccharic acid 1,4 lactone (48.4 1.25 µM). Analogs 19, 16, 4, 1, 17, 6, 10, 3,
18, 2, 11, 14 and 5 showed many fold potent activity against β-glucuronidase inhibitor.
Structure activity relationship showed that substitution of electron withdrawing groups at
ortho as well as para position on phenyl ring increase potency. Electron withdrawing
groups at meta position on phenyl ring showed slightly low potency as compared to ortho
and para position. The binding interactions were confirmed through molecular docking
studies.
Keywords: Synthesis, Disulfide, sulfone, β-glucuronidase, SAR, molecular docking
∗ Correspondence and reprints
E-mail: taha_hej@yahoo.comand muhamm9000@puncakalam.uitm.edu.my, Tel: 0060193098141
1

1. Introduction
β-Glucuronidase is an enzyme that can be found in many mammalian and plant tissues
[1]. In prokaryotic and eukaryotic organisms, it is responsible for in vivo β-glucuronide
hydrolysis. In intestine the β-glucuronidase enzyme is mostly responsible for
detoxification of reactive metabolites that are interrelated to various disease and
development of cancer [2-4]. Bacterial β-glucuronidase (E.C.3.2.1.31) and β-glucosidase
(E.C.3.2.1.21) in human colon are responsible for activation and metabolism of
xenobiotic obtained from nutritional compounds. These enzymes are also known as
peacekeepers of colorectal cancer (CRC). Many endogenous (e.g; steroids, bile acids,
bilirubin) and exogenous (e.g; pesticides, drugs) and various carcinogenic compounds are
metabolized in liver. These metabolized compounds were then conjugated with
glucuronic acid before excreted with bile into small intestine. Conjugates are hydrolyzed
into activated hepatic metabolites in colon by bacterial β-glucuronidase enzyme [5]. It has
been reported that high level of fecal β-glucuronidase activity leads the population to
greater risk of having colorectal cancer and higher enzymes level than healthy controls in
case of CRC patient [5,6]. Besides that, β-glucuronidase is also associated with AIDS,
hepatic disorders and inflammatory joint diseases. It plays an important role in the
development of cholelithiasis in humans [7, 8]. Specific β G inhibitor, glucaro-1,5-
lactone alleviate CPT-11-induced mucosal damage in the small intestine in vivo [9].
However, glucaro-1, 5-lactone of the current treatments against CID is limited and not
effective, preferentially that inhibits human βG (hβG) activity [10], which may induce
mucopolysaccharidoses (MPS) [11, 12]. In past several naphthalenylidene-
benzenesulfonamide containing compound and steroids have been reported that possess
strong inhibitory activity against β-glucuronidase enzyme [13, 14].
Understanding evolution, folding, structural properties, angle constraints, imposing length
on backbone of protein the disulfide bonds play an essential role [15]. Disulfide
regulating the enzymatic activity, and also catalyze bond mediated thiol-disulfide
interchange reactions in protein substrates. Structural disulfide plays a vital role in the
stabilization and folding of proteins. Allosteric disulfide bonds, incontrast to catalytic
2

disulfides, control the functioning of proteins by triggering changes in either the intra-
molecular or intermolecular protein structure, acting essentially as switches for protein
function [16]. Disulfide usually not considered to take part in catalytic activities but they
reduces entropy due to internal motions, add structural stability and are usually concerned
in coordination with metal ions [17]. Synthesized disulfide compound showed
leishmanicidal [18], anticancer [19], herbicidal activity [20] and as PTP1B [21], urease
[22] and extracellular thioredoxin inhibitor [23].
Sulfone acts as valuable intermediates in organic synthesis [24] such as Julia olefination,
Ramberg Backlund rearrangement etc. It is also used for construction of building blocks
for biologically active compounds. Sulfone is a diverse structural class associated with
antifungal, antibacterial, antitumour agents [25] and for several enzyme act as inhibitor
such as HIV-1 reverse transcriptase [26], cyclooxygenase-2 (COX-2) [27], ATPase [28]
and intrgrin VLA-4 [29].
We are currently working on hybrid molecules [30-40] and we found that the hybrid
compounds are more potent than either of individual molecule. Keeping in view the great
biological importance of both these classes we have plan for synthesizing the hybrid
analogs of these two important scaffolds. Here in this study we are reporting synthesis of
hybrid analogs of these biologically important classes of compounds i.e. disulfide and
sulfone as β-glucuronidase inhibitors. The binding interactions were confirmed through
molecular docking studies.
2. Results and Discussion
2.1. Chemistry
In this study, disulfanediyldianiline had been synthesized by slowly adding H5IO6 and
NaHSO3 to 2-aminothiophenol in water during a period of 10 minutes [41]. This reaction
involves formation of hypoiodous acid that is easily generated through reaction between
H5IO6 with suitable reducing agent like sodium hydrogen sulfite. The mixture was stirred
at room temperature for 3 hours before being monitored through TLC. Upon completion,
the product was separated by extracting from water using ethyl acetate. Using
3

disulfanediyldianiline, which had been synthesized earlier, sulfone analogs (1-20) were
synthesized by reacting 2,2'-disulfanediyldianiline (1 equiv, 1 mmol) with sulfonyl
chlorides (2 equiv, 2 mmol) in pyridine. When the reaction completes, which was
confirmed via TLC, concentrated sulfuric acid was added in excess to neutralize pyridine
and allow the formation of sulfone (1-20). The crude products were further recrystallized
from methanol to afford pure compounds with the yield between 72-96% (scheme 1).
Scheme-1: Synthesis of disulfide and sulfone hybrid analogs (1-20)
Table-1: Synthesized various disulfide and sulfone hybrid analogs (1-20)
No
R
IC50 SEMaµM No
R
IC50 SEMaµM
1
11
12
8.18 0.35
28.38 0.65
2
25.02 0.50
59.25 1.20
3
4
5
13
14
15
15.20 0.35
6.23 0.10
34.45 0.65
N. A.
34.28 0.60
N. A.
4

6
7
8
16
17
18
13.20 0.28
58.55 1.20
75.06 1.40
3.34 0.10
11.30 0.30
16.20 0.40
9
19
20
88.16
1.56
2.20 0.05
10
14.20 0.40
56.30 1.15
D-Saccharic acid 1,4-lactoneb
48.4 1.25
aIC50 values are expressed as mean standard error of mean; bStandard inhibitor for β-glucuronidase; N.A = Not Active.
2.2. Biological activity
Disulfide and sulfone hybrid analogs (1-20) were evaluated for β-glucuronidase inhibitory
potential. It was found that, except for compounds 13 and 15, other analogs showed a
variable degree of β-glucuronidase inhibition with IC50 values ranging between 2.20-
88.16 µM when compared with standard D-Saccharic acid 1,4-Lactone (IC50, 48.4 1.25
µM). Thirteen analogs 19, 16, 4, 1, 17, 6, 10, 3, 18, 2, 11,14 and 5 exhibited potent β-
glucuronidase inhibitory potential with IC50 values 2.20 0.05, 3.34 0.10, 6.23 0.10,
8.18 0.35, 11.30 0.30, 13.20 0.28, 14.20 0.40, 15.20 0.35, 16.20 0.40, 25.02
0.50, 28.38 0.65, 34.28 0.60, and 34.45 0.65 µM respectively many fold better than
the standard. Analog 19 was found to be the most potent among the series having three
5

chloro groups on the phenyl ring. Presence of these chloro groups play a vital role in
inhibitory potential and might be involved in this inhibition. Similar is the case with other
chloro analogs like 1, 2, 3, 18 and 17 having chloro groups. It seems that increase in
number of chloro groups on phenyl group and especially on ortho and para position
increase the inhibitory potential. Analogs 10, 11, 12 and 16 were having the nitro
substituent on phenyl ring. Among these analogs it was also observed that position of
substituent as well as number of substituent’s greatly influence the inhibitory potential.
Similar patterns were observed as in case of chloro substituted analogs. The ortho
substituted analog showed more potency than para and meta and para showed more
potency than meta substituted analog. Analog 4, 5 and 6 were the fluoro substituted on the
substituted phenyl ring. It showed that ortho has more potency then para and meta
substituent analog and para showed more potency than meta analog. In methyl substituted
analogs 13, 14 and 15 only ortho substituted showed potency while meta and para
substituted analogs were found completely inactive.
It was concluded that electron withdrawing substituent’s on phenyl ring at ortho as well
as para position increase the inhibitory potential as compare to meta substituted.
Increasing the substitution of electron withdrawing groups also increases the inhibitory
potential. The size of substituents also play role in the inhibition study but this moment
we observe that electronic effect of substituents might be responsible.
2.3. Molecular Docking Simulation
Molecular docking of disulfide and sulfone hybrid analogs against β-glucuronidase
enzyme was performed to investigate their binding modes via molecular docking
technique using Molecular Operating Environment (MOE) (www.chemcomp.com). The
docking simulation results showed that all the compounds were accommodated well in
the binding cavity of β-glucuronidase enzyme. The predicted binding mode of the most
active compound 19 as shown in (IC50, 2.20
0.05) with a trichloro phenyl substituent
showed three interaction with the active site residues Asp 207, Tyr 205 and Arg 600 of
the enzyme. Asp 207 and Tyr 205 established two hydrogen bonds with the sulfonic
amide group of the compound while Arg 600 made an arene-cation-π interaction with one
of the phenyl ring of the compound. Additionally, several hydrophobic interactions were
6

observed between the compound and the active residues (Asp 207, Val 410 and Leu 412
etc.) of the enzyme (Figure 1a). The number and position of the substituent play key role
in the biological activity as well as their binding mode of the compound. For example
compound 1, 2 and 3 having single chorine substituent over the phenyl ring showed poor
biological activity as compared to compound 19. If we compare the position of the
substituents among the series of the compounds, the ortho position is more favorable for
interaction as compared to para and meta substituent. The docking conformation of
Compound 1 (ortho chloro analogue) established two interactions (arene-arene and arene-
cation) between chlorophenyl rings of the compound with the Tyr 508 and His 509 of the
enzyme, whereas the compound 3 showed single hydrogen bonds with the sulfonyl
oxygen of the compound (Figure 1b and 1c).
Figure-1: Docking conformation of Compounds 19 (a), 1 (b) and 3 (c) in active site of β-
glucuronidase enzyme.
The docking conformation of second most active compound 16 (IC50, 3.34 0.10) with a
dinitro substituent showed a good interaction pattern with active site residues (Asn 484,
Tyr 508 and Arg 600) of the enzyme (Figure 1a) as compared to compounds 10, 11, 12
having single nitro substitution. In case of compound 10 (IC50, 14.20 0.40), the NO2
group is present at ortho position over the benzene ring established a hydrogen bond and
an arene-arene interaction with Arg 600 and Tyr 508 residues of the enzyme (Figure
2b). When NO2 group present at meta position (Compound 12), the compound displayed
only an arene-arene interaction with Tyr 508 of the enzyme (Figure 2c). The interaction
7

patterns of these two analogs of NO2 demonstrate better inhibition for ortho position of
NO2 than meta position.
Figure-2: Docking conformation of compounds 16(a), 10(b) and 12(c) in active site of β-
glucuronidase enzyme.
The ortho fluoroaryl substituted compound 4, the third most active compound (IC50,
6.23 0.10) displayed two hydrogen bonds and an arene-cation interactions with active
site residue Tyr 508, His 509 and Arg 600 of the enzyme (Figure-3a). On the other hand,
fluorine group was present in the para position over the phenyl ring of compound 6 leads
to only one hydrogen bond and an arene-cation interaction with Tyr 508 and Arg 600
residues of the enzyme respectively (Figure-3b). Almost similar results were observed
for compound 7 (ortho Br) and 9 (meta Br) in which the ortho Br substituent was found
superior.
8

Figure-3: Docking conformation of compounds 4 and 6 in active site of β-glucuronidase
enzyme.
In case of least active compound (methyl substituted), the docking conformation of
compound 14 showed an arene-arene interaction with active site residue Tyr 508 of the
enzyme (Figure-4a). Whereas the para (Compound 15) and meta (Compound 13)
analogues displayed non active in the active site of the enzyme(Figure-4b).
Figure-4: Docking conformation of compounds 14 and 13 in active site of β-
glucuronidase enzyme.
3. Conclusion
In conclusion disulfide and Sulfone hybrid compounds (1-20) were synthesized and
evaluated for β-glucuronidase inhibitory potential. All analogs except 13 and 15 showed a
variable degree of β-glucuronidase inhibition with IC50 values ranging between 2.20
0.05 – 88.16 1.56 µM when compared with standard D-Saccharic acid 1,4 Lactone
(IC50, 48.4 1.25 µM). Among the series thirteen analogs 19, 16, 4, 1, 17, 6, 10, 3, 18, 2,
11,14 and 5 showed many fold better β-glucuronidase inhibitory potential than standard.
Analogs 7, 8, 9, 12 and 20 also showed good inhibitory potential. Structure activity
9

relationship was also established. The binding interactions were confirmed though
molecular docking studies.
4. Experimental
4.1. General methods
NMR experiments were performed on Avance Bruker 500 MHz. Elemental analysis was
performed on Carlo Erba Strumentazion-Mod-1106, Italy. Electron impact mass spectra
(EI-MS) were recorded on a Finnigan MAT-311A, Germany. Thin layer chromatography
(TLC) was performed on pre-coated silica gel aluminum plates (Kieselgel 60, 254, E.
Merck, Germany). Chromatograms were visualized by UV at 254 and 365 nm.
4.2. Synthesis of 2,2′-disulfanediyldianiline
Periodic acid (1.5 equiv, 75 mmol) and sodium hydrogen sulfite (1.5 equiv, 75 mmol) in
H2O (200 mL) was added slowly to 2-aminothiophenol (1 equiv, 50 mmol) during a
period of 10 minutes and the mixture was stirred at room temperature for 3 hours. The
reaction was monitored through TLC and the product was extracted with water:ethyl
acetate (20 mL × 3). The collective organic layer was washed with aqueous Na2S2O3 and
dried over Na2SO4.
4.3. General procedure for synthesis of compounds (1–20)
Sulfone analogs (1-20) were synthesized by reacting of 2,2'-disulfanediyldianiline (1
equiv, 1 mmol) with sulfonyl chlorides (2 equiv, 2 mmol) in pyridine. Upon completion,
which was confirmed by using TLC, concentrated sulfuric acid was added to neutralize
pyridine and allow the formation of sulfone (1-20). The crude products were further
recrystallized from methanol to afford pure compounds with the yield between 72- 96%.
4.4 Biological Assay
From Sigma Chemical Co. (U.S.A.) the β-glucuronidase (E.C. 3.2.1.31, from bovine
liver, G-0251) and p-nitrophenyl-β-D-glucuronide (N-1627) were purchased. Na2CO3
anhydrous and all other reagents of standard grade were getting from E. Merck. The
10

anhydrous EtOH and CHCl3were used in experiment and these were dried by using the
standard methods. All other solvents and reagents were of standard grade like the benzoyl
chloride.
4.4.1. β-Glucuronidase assay
β-glucuronidase activity was determined by measuring absorbance at 405 nm of p-
nitrophenol formed substrate by spectrophotometric method. 250 µL was the volume of
total reaction. Reaction mixture containing 5 µL of test compound solution, 185 µL of
0.1M acetate buffer and 10 µL of enzyme solution were incubated for 30 minute at 37 °C.
At 405 nm the plates were recorded on multiplate reader (SpectaMax plus 384) after the
addition of 50 µL of 0.4mM p-nitrophenyl-β-D.Glucuronide. Experiments were
performed for triplicate [42-46]. To avoid precipitation compound concentration were
decreased and the volume of reaction was high (200 µL). Precipitation probability was
less thus addition of detergents was not needed.
4.5. Molecular Docking Simulation
The three dimensional structure of β-glucuronidase (PDB: ID 1BHG) an enzyme was
obtained from Protein Database. From the original protein data bank file, the B-chain of
protein and hetero-atoms including cofactors were removed. After 3D protonation of the
enzyme, the energy of the retrieved protein molecule was minimized using the default
parameters of MOE energy minimization algorithm (gradient: 0.05, Force Field:
MMFF94X). Energy minimization was terminated when the root mean square gradient
falls below the 0.05. The 3D structures of these newly synthesized derivatives were
constructed using MOE-Builder tool and hydrogens were added. Then, these molecules
were energy minimized using the default parameters of MOE energy minimization
algorithm (gradient: 0.05, Force Field: MMFF94X). All the minimized molecules were
saved in the mdb file format. The prepared ligands were used as input file for MOE-Dock
in the next step. MOE docking program was used to analyze the binding modes of the
ligands with the protein molecule. To find the correct conformations of the ligands and to
11

obtain minimum energy structures, ligands were allowed to be flexible. The default
parameters of MOE-Dock program were used for the molecular docking of the ligands.
The top ranked pose of each compound was selected for docking analysis.
4.5. Characterization of compound (1-20)
4.5.1. N,N'-(disulfanediylbis(2,1-phenylene))bis(2-chlorobenzenesulfonamide) (1)
Brown solid. Yield: 76 %. m.p.: 264-265 °C; 1H NMR (500 MHz, DMSO-d6): δ 12.15 (s,
2H), 8.20 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H), 7.50-7.45 (m, 4H), 7.40 (t, J = 7.5
Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.10-7.05 (m, 4H); 13C NMR (150 MHz, DMSO-d6): δ
139.7, 133.4, 132.1, 131.6, 131.2, 130.4, 130.1, 129.6, 129.0, 128.3, 127.2, 122.4; HR-
ESI-MS: m/z calcd for C24H18Cl2N2O4S4, [M]+ 595.9526; Found 595.9529; Anal. Calcd:
C, 48.24; H, 3.04; N, 4.69; Found C, 48.22; H, 3.03; N, 4.67.
4.5.2. N,N'-(disulfanediylbis(2,1-phenylene))bis(3-chlorobenzenesulfonamide) (2)
1
White solid. Yield: 87%. m.p.: 261-262 °C; H NMR (500 MHz, DMSO-d6): δ 12.11 (s,
2H), 7.91 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0, 2H), 7.48-7.43 (m, 2H), 7.35 (t, J = 7.0 Hz,
2H), 7.28-7.22 (m, 4H), 7.18 (dd, J = 8.0, 2.0 Hz, 2H), 6.62 (dd, J = 7.0, 2.0 Hz, 2H); 13C
NMR (150 MHz, DMSO-d6): δ 139.6, 139.6, 134.4, 134.4, 133.2, 133.2, 132.1, 132.1,
131.6, 131.6, 131.2, 131.2, 130.5, 130.5, 130.1, 130.1, 130.1, 129.0, 129.0, 129.0, 127.6,
127.6, 127.2, 127.2, 122.4, 122.4; HR-ESI-MS: m/z calcd for C24H18Cl2N2O4S4, [M]+
595.9526; Found 595.9522; Anal. Calcd: C, 48.24; H, 3.04; N, 4.69; Found C, 48.22; H,
3.03; N, 4.67.
4.5.3. N,N'-(disulfanediylbis(2,1-phenylene))bis(3-chlorobenzenesulfonamide) (3)
Light yellow. Yield: 83%. m.p.: 272-271 °C; 1H NMR (500 MHz, DMSO-d6): δ 12.05 (s,
2H), 7.78-7.70 (m, 6H), 7.60 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 4H), 7.32 (t, J = 7.5
Hz, 2H), 7.18 (t, J = 7.5 Hz, 2H); 13C NMR (150 MHz, DMSO-d6): δ 139.6, 139.6, 134.4,
134.4, 133.2, 133.2, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 130.5, 130.5, 130.1, 130.1,
129.0, 129.0, 127.6, 127.6, 127.2, 127.2, 122.4, 122.4; HR-ESI-MS: m/z calcd for
C24H18Cl2N2O4S4, [M]+ 595.9526; Found 595.9534; Anal. Calcd: C, 48.24; H, 3.04; N,
4.69; Found C, 48.23; H, 3.02; N, 4.68.
4.5.4. N,N'-(disulfanediylbis(2,1-phenylene))bis(2-fluorobenzenesulfonamide) (4)
12

1
Brown. Yield: 81%. m.p.: 281-280 °C; H NMR (500 MHz, DMSO-d6): δ 12.10 (s, 2H),
8.51 (m, 2H), 7.80 (dd, J = 8.0, 2.0 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.31-7.26 (m, 6H),
7.26-7.19 (m, 4H);13C NMR (150 MHz, DMSO-d6): δ 158.4 (J = 251.8 Hz), 136.4, 136.4,
132.5, 132.5, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 129.7, 129.7, 129.0, 129.0, 127.2,
127.2, 126.8, 126.8, 122.4, 122.4, 117.2, 117.2; HR-ESI-MS: m/z calcd for
C24H18F2N2O4S4, [M]+ 564.0117; Found 564.0117; Anal. Calcd: C, 51.05; H, 3.21; N,
4.96; Found C, 51.04; H, 3.20; N, 4.94.
4.5.5. N,N'-(disulfanediylbis(2,1-phenylene))bis(3-fluorobenzenesulfonamide) (5)
1
White solid. Yield: 84%. m.p.: 278-277 °C; H NMR (500 MHz, DMSO-d6): δ 11.90 (s,
2H), 7.96 (d, J = 8.0 Hz, 2H), 7.83 (t, J = 8.0, 2H), 7.68(d, J = 8.0 Hz, 2H), 7.45-7.39 (m,
6H), 7.26 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.0 Hz, 2H); 13C NMR (150 MHz, DMSO-d6): δ
162.3 (d, J = 251.8 Hz, H, 17, 28), 138.5, 138.5, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2,
130.9, 130.9, 129.0, 129.0, 127.8, 127.8, 127.2, 127.2, 122.4, 122.4, 121.0, 121.0, 115.7,
115.7; HR-ESI-MS: m/z calcd for C24H18F2N2O4S4, [M]+ 564.0117; Found 564.0124;
Anal. Calcd: C, 51.05; H, 3.21; N, 4.96; Found C, 51.04; H, 3.20; N, 4.93.
4.5.6. N,N'-(disulfanediylbis(2,1-phenylene))bis(4-fluorobenzenesulfonamide) (6)
1
White solid. Yield: 79%. m.p.: 291-290 °C; H NMR (500 MHz, DMSO-d6): δ 11.91 (s,
2H), 7.82 (m, 6H), 7.60 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.29-7.22 (m, 4H),
13
7.15 (t, J = 7.0 Hz, 2H); C NMR (150 MHz, DMSO-d6): δ 153.9 (d, J = 252.7 Hz),
137.2, 137.2, 134.2, 134.2, 134.2, 134.2, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 130.2,
130.2, 130.2, 130.2, 129.0, 129.0, 127.2, 127.2, 122.4, 122.4; HR-ESI-MS: m/z calcd for
C24H18F2N2O4S4, [M]+ 564.0117; Found 564.0109; Anal. Calcd: C, 51.05; H, 3.21; N,
4.96; Found C, 51.03; H, 3.20; N, 4.95.
4.5.7. N,N'-(disulfanediylbis(2,1-phenylene))bis(2-bromobenzenesulfonamide) (7)
1
Light yellow solid. Yield: 87%. m.p.: 276-275 °C; H NMR (500 MHz, DMSO-d6): δ
11.60 (s, 2H), 8.02 (dd, J = 8.0, 2.0 Hz, 2H), 7.78 (dd, J = 8.0, 2.0 Hz, 2H), 7.71 (d, J =
8.0 Hz, 2H), 7.56 (d, J = 2.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H),
7.11-7.08 (m, 4H); 13C NMR (150 MHz, DMSO-d6): δ 141.1, 141.1, 135.6, 135.6, 133.4,
133.4, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 130.8, 130.8, 129.0, 129.0, 128.4, 128.4,
13

127.2, 127.2, 122.4, 122.4, 118.0, 118.0; HR-ESI-MS: m/z calcd for C24H18Br2N2O4S4,
[M]+ 683.8516; Found 683.8511; Anal Calcd: C, 41.99; H, 2.64; N, 4.08; Found C,
41.98; H, 2.63; N, 4.07.
4.5.8. N,N'-(disulfanediylbis(2,1-phenylene))bis(4-bromobenzenesulfonamide) (8)
1
White solid. Yield: 81%. m.p.: 288-287 °C; H NMR (500 MHz, DMSO-d6): δ 11.70 (s,
2H), 7.90 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 8.0 Hz, 4H), 7.65 (d, J = 8.0 Hz, 2H), 7.55 (d,
J = 8.0 Hz, 4H), 7.32 (t, J = 7.5 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H); 13C NMR (150 MHz,
DMSO-d6): δ 139.0, 139.0, 132.4, 132.4, 132.4, 132.4, 132.1, 132.1, 131.6, 131.6, 131.2,
131.2, 129.7, 129.7, 129.7, 129.7, 129.2, 129.2, 129.0, 129.0, 127.2, 127.2, 122.4, 122.4;
HR-ESI-MS: m/z calcd for C24H18Br2N2O4S4, [M]+ 683.8516; Found 683.8519; Anal
Calcd: C, 41.99; H, 2.64; N, 4.08; Found C, 41.97; H, 2.62; N, 4.05.
4.5.9. N,N'-(disulfanediylbis(2,1-phenylene))bis(3-bromobenzenesulfonamide) (9)
1
White solid. Yield: 82%. m.p.: 272-271 °C; H NMR (500 MHz, DMSO-d6): δ 11.80 (s,
2H), 8.14 (d, , J = 2.0 Hz, 2H), 7.82 (dd, J = 8.0, 2.0 Hz, 2H), 7.62-7.56 (m, 4H), 7.37-
7.31 (m, 4H), 7.18-7.15 (m, 4H); 13C NMR (150 MHz, DMSO-d6): δ 139.6, 139.6, 136.3,
136.3, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 130.9, 130.9, 130.5, 130.5, 129.4, 129.4,
129.0, 129.0, 127.2, 127.2, 122.9, 122.9, 122.4, 122.4; HR-ESI-MS: m/z calcd for
C24H18Br2N2O4S4, [M]+ 683.8516; Found 683.8521; Anal Calcd: C, 41.99; H, 2.64; N,
4.08; Found C, 41.96; H, 2.62; N, 4.06.
4.5.10. N,N'-(disulfanediylbis(2,1-phenylene))bis(2-nitrobenzenesulfonamide) (10)
Yellow solid. Yield: 84%. m.p.: 295-294 °C; 1H NMR (500 MHz, DMSO-d6): δ 12.20 (s,
2H), 8.38 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 8.5 Hz, 2H), 7.18-7.12
(m, 4H), 7.04-7.00 (m, 4H), 6.96-6.93 (m, 2H); 13C NMR (150 MHz, DMSO-d6): δ 148.3,
148.3, 133.6, 133.6, 133.1, 133.1, 133.0, 133.0, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2,
129.0, 129.0, 128.9, 128.9, 127.2, 127.2, 125.0, 125.0, 122.4, 122.4; HR-ESI-MS: m/z
calcd for C24H18N4O8S4, [M]+ 618.0007; Found 618.0014; Anal Calcd: C, 46.59; H, 2.93;
N, 9.06; Found C, 46.58; H, 2.92; N, 9.05.
4.5.11. N,N'-(disulfanediylbis(2,1-phenylene))bis(4-nitrobenzenesulfonamide) (11)
14

1
Dark brown solid. Yield: 82%. m.p.: 301-300 °C; H NMR (500 MHz, DMSO-d6): δ
12.21 (s, 2H), 8.22 (d, J = 8.0 Hz, 4H), 8.05 (d, J = 8.0, 4H), 7.84 (d, J = 7.0, 2H), 7.73 (t,
J = 8.0, 2H), 7.40 (t, J = 7.5, 2H), 7.21 (t, J = 7.5, 2H); 13C NMR (150 MHz, DMSO-d6):
δ 150.0, 150.0, 141.0, 141.0, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 129.0, 129.0,
129.0, 129.0, 127.2, 127.2, 124.5, 124.5, 124.5, 124.5, 124.1, 124.1, 122.4, 122.4; HR-
ESI-MS: m/z calcd for C24H18N4O8S4, [M]+ 618.0007; Found 618.0012; Anal Calcd: C,
46.59; H, 2.93; N, 9.06; Found C, 46.57; H, 2.91; N, 9.04.
4.5.12. N,N'-(disulfanediylbis(2,1-phenylene))bis(3-nitrobenzenesulfonamide) (12)
1
White solid. Yield: 84%. m.p.: 292-291 °C; H NMR (500 MHz, DMSO-d6): δ 12.05 (s,
2H), 8.01 (d, J = 8.0 Hz, 2H), 7.85-7.80 (m, 6H), 7.66-7.60 (m, 4H), 7.40 ( t, J = 8.0 Hz,
13
2H), 7.22 (t, J = 8.5 Hz, 2H); C NMR (150 MHz, DMSO-d6): δ 148.8, 148.8, 138.0,
138.0, 136.6, 136.6, 133.2, 133.2, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 129.2, 129.2,
129.0, 129.0, 127.3, 127.3, 127.2, 127.2, 122.4, 122.4; HR-ESI-MS: m/z calcd for
C24H18N4O8S4, [M]+ 618.0007; Found 618.0011; Anal Calcd: C, 46.59; H, 2.93; N, 9.06;
Found C, 46.58; H, 2.91; N, 9.05.
4.5.13. N,N'-(disulfanediylbis(2,1-phenylene))bis(3-methylbenzenesulfonamide) (13)
Brownish solid. Yield: 76%. m.p.: 244-245 °C; 1H NMR (500 MHz, DMSO-d6): δ 11.60
(s, 2H), 7.80 (d, J = 7.0 Hz, 2H), 7.60 (d, J = 8.0, 2H), 7.48-7.45 (m, 2H), 7.35-7.32 (m,
2H), 7.25-23 (m, 4H), 7.16(d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 2.40 (s, 6H); 13C
NMR (150 MHz, DMSO-d6): δ 138.7, 138.7, 138.0, 138.0, 132.6, 132.6, 132.1, 132.1,
131.6, 131.6, 131.2, 131.2, 129.0, 129.0, 128.7, 128.7, 128.7, 128.7, 128.3, 128.3, 127.2,
127.2, 122.4, 122.4, 21.3, 21.3; HR-ESI-MS: m/z calcd for C26H24N2O4S4, [M]+
556.0619; Found 556.0627; Anal Calcd: C, 56.09; H, 4.35; N, 5.03;Found C, 56.08; H,
4.34; N, 5.02.
4.5.14. N,N'-(disulfanediylbis(2,1-phenylene))bis(2-methylbenzenesulfonamide) (14)
1
Dark brown solid. Yield: 81%. m.p.: 251-250 °C; H NMR (500 MHz, DMSO-d6): δ
11.70 (s, 2H), 7.84 (dd, J = 8.0, 2.0 Hz, 2H), 7.73 (t, J = 8.0 Hz, 2H), 7.44 (dd, J = 8.0,
7.0 Hz, 2H), 7.36 (d, J = 7.5 Hz, 2H), 7.26-7.21 (m, 4H), 7.12-7.08 (m, 4H), 2.42 (s, 6H);
13C NMR (150 MHz, DMSO-d6): δ 147.1, 147.1, 143.3, 143.3, 136.6, 136.6, 134.2, 134.2,
15

134.2, 134.2, 132.1, 132.1, 131.6, 131.6, 131.6, 131.6, 131.2, 131.2, 129.0, 129.0, 127.2,
127.2, 122.4, 122.4, 26.2, 26.2; HR-ESI-MS: m/z calcd for C26H24N2O4S4, [M]+
556.0619; Found 556.0624; Anal Calcd: C, 56.09; H, 4.35; N, 5.03;Found C, 56.07; H,
4.33; N, 5.01.
4.5.15. N,N'-(disulfanediylbis(2,1-phenylene))bis(4-methylbenzenesulfonamide) (15)
Yellow solid. Yield: 83%. m.p.: 254-255 °C; 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s,
2H), 7.82-7.79 (m, 2H), 7.69 (d, J = 8.0Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H), 7.34 (d, J =
13
7.0 Hz, 4H), 7.18 (d, J = 7.0 Hz, 4H), 7.12 (t, J = 8.0 Hz, 2H), 2.37 (s, 6H); C NMR
(150 MHz, DMSO-d6): δ 141.7, 141.7, 137.2, 137.2, 132.1, 132.1, 131.6, 131.6, 131.2,
131.2, 129.3, 129.3, 129.3, 129.3, 129.0, 129.0, 127.3, 127.3, 127.3, 127.3, 127.2, 127.2,
122.4, 122.4, 21.6, 21.6; HR-ESI-MS: m/z calcd for C26H24N2O4S4, [M]+ 556.0619;
Found 556.0614; Anal Calcd: C, 56.09; H, 4.35; N, 5.03;Found C, 56.08; H, 4.33; N,
5.02.
4.5.16. N,N'-(disulfanediylbis(2,1-phenylene))bis(2,4-dinitrobenzenesulfonamide) (16)
Brown solid, Yield: 68%. m.p.: 310-309 °C; 1H NMR (500 MHz, DMSO-d6): δ 12.60 (s,
2H), 8.10 (d, J = 2.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.54-7.50 (m, 4H), 7.30-7.25 (m,
2H), 7.20 (t, J = 8.0 Hz, 1H), 6.92-6.90 (m, 2H), 3.90 (s, 3H); 13C NMR (150 MHz,
DMSO-d6): δ 152.9, 152.9, 140.0, 140.0, 136.1, 136.1, 132.1, 132.1, 131.6, 131.6, 131.2,
131.2, 129.0, 129.0, 128.2, 128.2, 127.2, 127.2, 124.3, 124.3, 123.0, 123.0, 122.4, 122.4;
HR-ESI-MS: m/z calcd for C24H16N6O12S4, [M]+ 707.9709; Found 707.9714; Anal
Calcd: C, 40.68; H, 2.28; N, 11.86;Found: C, 40.67; H, 2.26; N, 11.85.
4.5.17. N,N'-(disulfanediylbis(2,1-phenylene))bis(2,4-dichlorobenzenesulfonamide) (17)
1
Light brown solid. Yield: 75%. m.p.: 298-297 °C; H NMR (500 MHz, DMSO-d6): δ δ
12.40 (s, 2H), 7.90 (d, J = 2.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.50-7.46 (m, 4H), 7.32-
7.27 (m, 2H), 7.18 (t, J = 8.0 Hz, 2H), 6.96-6.93 (m, 2H);13C NMR (150 MHz, DMSO-
d6): δ 140.0, 140.0, 137.0, 137.0, 132.6, 132.6, 132.1, 132.1, 131.6, 131.6, 131.2, 131.2,
130.5, 130.5, 129.7, 129.7, 129.0, 129.0, 127.2, 127.2, 126.5, 126.5, 122.4, 122.4; HR-
ESI-MS: m/z calcd for C24H16Cl4N2O4S4, [M]+ 663.8747; Found 663.8753; Anal Calcd:
C, 43.25; H, 2.42; N, 4.20; Found C, 43.24; H, 2.41; N, 4.20.
16

4.5.18. N,N'-(disulfanediylbis(2,1-phenylene))bis(2,5-dichlorobenzenesulfonamide) (18)
Brown solid. Yield: 88%. m.p.: 289-288 °C; 1H NMR (500 MHz, DMSO-d6): δ 12.20 (s,
2H), 7.96 (d, J = 2.0 Hz, 2H), 7.66-7.60 (m, 6H), 7.30-7.26 (m, 2H), 7.16 (t, J = 8.0 Hz,
13
2H), 6.94-6.90 (m, 2H); C NMR (150 MHz, DMSO-d6): δ 136.2, 136.2, 133.1, 133.1,
132.1, 132.1, 131.6, 131.6, 131.2, 131.2, 131.1, 131.1, 130.7, 130.7, 129.7, 129.7, 129.0,
129.0, 128.4, 128.4, 127.2, 127.2, 122.4, 122.4; HR-ESI-MS: m/z calcd for
C24H16Cl4N2O4S4, [M]+ 663.8747; Found 663.8741; Anal Calcd: C, 43.25; H, 2.42; N,
4.20; Found C, 43.23; H, 2.40; N, 4.20.
4.5.19.
N,N'-(disulfanediylbis(2,1-phenylene))bis(2,4,5-trichlorobenzenesulfonamide)
(19)
1
Dark brown solid; Yield: 75%; %. m.p.: 254-255 °C; H NMR (500 MHz, DMSO-d6): δ
12.40 (s, 2H), 8.05 (d, J = 2.0 Hz, 2H), 7.80 (d, J = 2.0 Hz, 2H), 7.44 (dd, J = 8.0, 2.0
Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 6.94-6.91 (m, 2H), 3.90 (s, 3H); 13C NMR (150 MHz,
DMSO-d6): δ 136.7, 136.7, 133.7, 133.7, 132.1, 132.1, 131.9, 131.9, 131.7, 131.7, 131.6,
131.6, 131.6, 131.6, 131.2, 131.2, 130.7, 130.7, 129.0, 129.0, 127.2, 127.2, 122.4, 122.4;
HR-ESI-MS: m/z calcd for C24H14Cl6N2O4S4, [M]+ 731.7968; Found 731.7971; Anal
Calcd: C, 39.20; H, 1.92; N, 3.81;Found; C, 39.20; H, 1.91; N, 3.80.
4.5.20. N,N'-(disulfanediylbis(2,1-phenylene))bis(4-methoxybenzenesulfonamide) (20)
Brown solid. Yield: 83%. m.p.: 254-255 °C; 1H NMR (500 MHz, DMSO-d6): δ 12.10 (s,
2H), 7.79 (d, J = 8.0 Hz, 4H), 7.64 (d, J = 8.0 Hz, 4H), 7.55 (dd, J = 8.0, 2.0 Hz, 2H),
7.31 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 7.5 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 3.78 (s, 6H);
13C NMR (150 MHz, DMSO-d6): δ 163.6, 163.6, 134.9, 134.9, 132.1, 132.1, 131.6, 131.6,
131.2, 131.2, 129.2, 129.2, 129.2, 129.2, 129.0, 129.0, 127.2, 127.2, 122.4, 122.4, 115.5,
115.5, 115.5, 115.5, 115.5, 55.3, 55.3; HR-ESI-MS: m/z calcd for C26H24N2O6S4, [M]+
588.0517; Found 588.0523; Anal Calcd: C, 53.04; H, 4.11; N, 4.76;Found; C, 53.03; H,
4.10; N, 4.75.
Acknowledgements
17

The authors would like to acknowledge Universiti Teknologi MARA for the
financial support under the Research Intensive Faculty grant scheme with reference
number UiTM 600-RMI/DANA 5/3/LESTARI (54/2015).
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Research Highlights
ꢀ Synthesis of 20 disulfide sulfone derivatives
ꢀ In-vitro β-glucuronidase inhibitory activity.
ꢀ Docking studies were carried out to confirm binding of active compounds with enzyme
22

*Graphical Abstract
Graphical Abstract
Synthesis of Novel Disulfide and Sulfone hybrid Scaffolds
As Potent β-glucuronidase Inhibitor
Muhammad Tahaa,b, Nor Hadiani Immaila,b, Syahrul Imrana,b, Abdul Wadoodc, Fazal Rahimd, Laode
Muhammad Ramadhan Al Muqarrabin a,b, Hamizah Mohd Zaki, a,b Norizan Ahmata,b Abdul Nasirc,
Fahad Khand
aAtta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam 42300,
Malaysia
bFaculty of Applied Science Universiti Teknologi MARA, Shah Alam 40450, Selangor D. E., Malaysia
cDepatment of Biochemistry, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
dDepatment of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
Synthesis and β-glucuronidase Inhibition Activity of Sulfone Derivatives