Sulfonamides as multifunctional agents for Alzheimer's disease

Article abstract of DOI:10.1016/j.bmcl.2014.12.006

Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds

Full text of DOI:10.1016/j.bmcl.2014.12.006

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Sulfonamides as multifunctional agents for Alzheimer’s disease
Seema Bag a, , Rekha Tulsan a, , Abha Sood a, , Hyejin Cho a, , Hana Redjeb a, , Weihong Zhou a,
,
a,
Harry LeVine III b, Béla Török a, , Marianna Török
⇑
⇑
a Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA, USA
b Department of Molecular and Cellular Biochemistry, Chandler School of Medicine, and Center on Aging, University of Kentucky, Lexington, KY 40536, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with
the aim of producing multifunctional agents against several processes involved in the pathology of
Alzheimer’s disease (AD). The potency of the compounds were assessed in the inhibition of Ab
self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and
scavenging free radicals. Several compounds exhibited promising Ab self-assembly and cholinesterase
inhibition and in parallel, showed good free radical scavenging properties. The investigation of the
scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as
promising leads for the further design of multifunctional drug candidates for AD.
Received 29 October 2014
Accepted 3 December 2014
Available online xxxx
Keywords:
Alzheimer’s disease
Amyloid-b
Cholinesterase inhibition
Antioxidant
Ó 2014 Published by Elsevier Ltd.
Sulfonamides
Alzheimer’s disease (AD) is a complex neurodegenerative disor-
der of the central nervous system.1,2 In response to the pressing
need of an aging population several treatment strategies have been
explored.3–7 The most common approaches are related to the cho-
linerg8 and amyloid cascade hypotheses.9 The formation of Ab pep-
tide self-assemblies (oligomers and fibrils) and their neurotoxic
effects are believed to be major contributors to the development
of AD.10 Due to the potent effect of multiple Ab neurotoxic prod-
ucts on disease development, a broad range of Ab self-assembly
inhibitors have been identified.11 In addition, a low level of certain
neurotransmitters, such as acetylcholine (ACh), is also associated
with the disease.12 The first generation of AD drugs were acetyl-
cholinesterase (AChE) inhibitors with the goal of reducing ACh
breakdown and therefore increasing ACh concentration, to provide
symptomatic treatment.13 In addition to AChE another cholinester-
ase enzyme, butyrylcholinesterase (BuChE), also appeared to
negatively affect the level of neurotransmitters.14 Recent studies
indicate that the peripheral binding site of AChE may contribute
to the initiation of Ab self-assembly, as well.15 In vivo studies also
suggested elevated levels of both metals and oxidative stress are
present in the AD affected brain.16 There is a growing sentiment
that multitarget therapeutics may combat the complex
pathogenesis of the disease more effectively than single-target
approaches.17
Extending our recent efforts on the development of anti-
amyloidogenic compounds18–24 we describe the synthesis,
biochemical evaluation, and potential multifunctional application
of sulfonamide-based small molecule agents, including saccharin,
and other analogues. Sulfonamides exhibit a broad range of
biological effects and are well-tolerated in biomedical applications.
Their applications include use as early antibacterial agents25 or
saccharin, one of the most commonly sold artificial sweeteners.26
Sulfonamides have also been found to be beneficial in AD. Kumar
et al. proposed N-aryl sulfonamide substituted 3-morpholino arec-
oline derivatives for the symptomatic treatment of Alzheimer’s
dementia.27 Other reports include the inhibition of amyloid-b
formation from b-amyloid precursor protein (APP) or its
self-assembly by a series of sulfonamide derivatives.28–31 The
sulfonamide analogs reported in this study are either novel and
their synthesis never reported, or although commercially available
their testing as multifunctional anti-AD agents has not been
reported. We tested these compounds in a series of assays, including
the inhibition of Ab self-assembly, modulation of cholinesterase
activity, and assessment of potential antioxidant properties.
The above reports inspired the investigation of several small
commercially available sulfonamides (Fig. 1 and 1–6).
The commercial compounds were evaluated in the inhibition Ab
self-assembly, including fibrillogenesis and oligomer formation
inhibition, modulation of cholinesterase activity and free radical
scavenging. Some compounds showed promising results in these
assays and also pointed toward possible improvements. We
decided to synthesize additional derivatives focusing on the
extension of the length of the compounds.
⇑
Corresponding authors. Tel.: +1 617 287 6159; fax: +1 617 287 6030.
E-mail addresses: bela.torok@umb.edu (B. Török), marianna.torok@umb.edu (M.
Török).
Tel.: +1 617 287 6159; fax: +1 617 287 6030.
http://dx.doi.org/10.1016/j.bmcl.2014.12.006
0960-894X/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Bag, S.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.12.006

2
S. Bag et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
O
The data indicate that the compounds overall belong to two dif-
R
O
S
O
ferent groups. The commercially available sulfonamides (1–6) and
the rather compact saccharin derivatives (7–12) commonly pro-
mote fibril formation. In contrast, the long linear-shaped com-
pounds (13–28) exhibited moderate to good fibrillogenesis
inhibition. Compounds 14, 18, 19, 21 and 26 showed the most
significant effect (87%, 60%, 43%, 64% and 45%, respectively). To
confirm that inhibition was not due to THT displacement by
compounds during the above assays, complementary Atomic Force
Microscopy (AFM) experiments were performed.34 For example,
AFM images of the solvent treated control and the sample incu-
bated in the presence of compound 14 (Fig. 3), which showed the
best (87%) fibril inhibition are depicted in Figure 5.
The images confirm the interpretation of the THT results.
The control sample showed the expected well-developed mature
fibrils, while the image of the inhibitor-containing sample reflects
the high, although not complete, inhibition. The small amount
of remaining fibril-like assemblies were thinner and shorter in
appearance indicating the profound effect of 14 on the Ab
fibrillogenesis.
1
4-OCH3
2 4-NO2
2-CH3
4 2-Br
3-C4H4
6
saccharin
H2N
NH
S
R
O
3
O
5
Figure 1. Structure of the tested commercial sulfonamides.
(b)
(a)
O
OH
O
O
H
O
O
N
N
Figure 2. Structure of donepezil (a) and galanthamine (b).
We expected that compounds with longer alkyl chains might
The compounds were also tested for their activity in the inhibi-
tion of oligomer formation by the biotinyl-Ab(1–42) single-site
streptavidin-based assay.35 The samples were incubated for
act as better cholinesterase inhibitors, mimicking the structural
features of donepezil (Fig. 2a); a well-known AChE inhibitor with-
out decreasing the efficiency of the compounds in other assays.32
Therefore, several saccharin derivatives (7–12) were synthesized
as illustrated in Scheme 1.
30 min in the assays, using Ab/inhibitor = 0.0002 ratio at 0.01 lM
Ab concentration. The intensity of the inhibited samples was nor-
malized to the control sample containing Ab and the solvent. The
percentile values were calculated similarly to those of fibril inhibi-
tion as shown above. The data are illustrated in Figure 6.
After the preliminary assays further modifications were exe-
cuted on the scaffold. Instead of having the sulfonamide moiety
in a ring, a relatively long, linear chain was introduced to the scaf-
fold, positioning the sulfonamide group in the chain. Aromatic
head and tail groups were added as well. This design aims to pro-
vide more flexibility to the compounds and at the same time to
continue to have large flat end-units. The synthesis of these second
generation compounds (14–26) is summarized in Scheme 2a.
Two additional compounds; 27 and 28 were also prepared
(Scheme 2b) to determine how the activity would be affected if
the sulfonamide moiety was eliminated from the scaffold. Each
product was characterized by 1H and 13C NMR spectroscopy and
by LC–MS. The spectroscopic characterization of the new com-
pounds was in agreement with their structures (see Supporting
information). The complete list of the compounds synthesized in
this work, except 27 and 28 (Scheme 2b), is shown in Figure 3.
To determine the activity profile of the compounds they were
first subjected to Ab fibrillogenesis assays. The quantitative Thio-
flavin-T (THT) fluorescence assay was applied to determine the
antifibrillogenic potency of the compounds.33 All data were nor-
malized to the fluorescence of the inhibitor-free control (Icontrol).
The fibrillogenesis assay data are presented in Figure 4.
Comparing Figure 6 to Figure 4, indicates that compounds
active against oligomers were poorly active against fibrillogenesis
and vice versa. The small commercial sulfonamides and saccharin
derivatives (1–12) showed moderate inhibition (up to 54%, except
11) of oligomers while the long chain linker containing sulfona-
mides (13–26) were generally oligomer formation promoters.
Interestingly, 27 and 28 showed 50–100% inhibition of oligomer
formation. These compounds are similar to the long chain sulfona-
mides (13–26), however, they lack the sulfonamide moiety. Com-
paring the activity of the compounds in the two Ab self-assembly
inhibition assays one cannot fail to notice that the behaviour of
the compounds in the two assays are the opposite; a compound
is either a fibril inhibitor or an oligomer inhibitor. This observation
is in agreement with our earlier findings21–24 and literature data.10
Oxidative stress caused by free radicals also plays an important
role in development of AD. Thus, the potential antioxidant charac-
ter of the compounds was also assessed. The scavenging of the 2,2-
diphenyl-1-picrylhydrazyl (DPPH) free radical was measured by
the decrease of its absorbance The data are compared to those
obtained with reference compounds ascorbic acid36 and
resveratrol,37 both of which are well-known antioxidants. The data
are illustrated in Figure 7.
1.NaH, DMF
RT, 1h
Three of our synthetic sulfonamides (19, 23 and 24) showed
higher free radical scavenging property than ascorbic acid, two
molecules (23 and 24) were even better than resveratrol.
2. X
O
O
Y
MW, 120oC, 5min
Y
With an aim to have multi-target functionality each compound
was assayed for the inhibition of cholinesterases. All of the synthe-
sized molecules were subjected to Ellman assay of the hydrolysis
of acetylthiocholine to determine their potency towards inhibition
of AChE and BuChE (Figs. 8 and 9). For AChE inhibition, the mole-
cules were assayed at 2 M; which is the IC50 of galanthamine
N
NH
S
S
O
O
O
O
6
7 8
-
Y = OH, N(C2H5)2
O
O
O
1. NaH, DMF
RT, 1h
2.
(Fig. 2b).38 Molecule 19 (Fig. 3) produced 88% inhibition at 2
lM,
+ R-NH2
N
NH
O
N
K2CO3, DMF,
S
O
while galanthamine at same concentration showed 54% inhibition.
Molecules 18 and 26 (Fig. 3) showed greater than 40% inhibition at
the same concentration. Due to solubility issues molecule 28
(Scheme 2) could not be tested in either assay. For BuChE inhibi-
Br-(CH2)3-Br
S
O
S
MW, 120oC,
MW, 120oC,
O
O
O
5min
Br
5min
NHR
9-12
6
R= alkyl, substituted alkyl
Scheme 1. Structure of the tested commercial sulfonamides.
tion, the molecules were assayed at 10
lM; which is the IC50 of
galanthamine against that enzyme.39 Nine out of 15 synthesized
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S. Bag et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
(a)
TEA,
dry CH2Cl2
RT, 24 h
Cl
H
N
O
O
1-Naph
Cl
1-Naph
NH3
S
O
N
H
S
N
H
(CH2)3
Cl
O
2HCl
13
R-NH2, dry ACN, MW
1-Naph = Naphth-1-yl
120 oC, 20-30 min
H
N
O
1-Naph
N
S
R
H
O
14-26
(b)
TEA,
CH2Cl2
O
H
N
H
COCl
COCl
NH2
N
HN
1-Naph
N
H
NH
2
2 HCl
RT, 3 h
1-Naph
O
1-Naph
27
TEA,
CH2Cl2
O
H
NH2
(CH)4
NH2
O
N
2-Naph
2-Naph
N
2
0-5 oC, 2 h
RT, 3 h
H
2-Naph
ClH
O
28
2-Naph = Naphth-2-yl
Scheme 2. Synthesis of second generation sulfonamides (a) and compounds 27 and 28 that lack the sulfonamide linker (b).
100
R
80
O
7 -CH2-CH2-OH
-CH2-CH2-N (C2H5)2
9 -CH2-CH2-CH2-N(C2H4OH)2
60
8
N
R
40
20
S
O
O
10
-CH2-CH2-CH2-N (C2H5)2
N
N
0
11
-20
-40
-60
-80
-100
OH
12
compounds
N
H
N
O
N
H
S
R
O
Figure 4. Inhibitory effect of sulfonamide derivatives on the Ab fibrillogenesis. The
assays were carried out at an Ab/inhibitor = 1:10 ratio at 100
except 26 where the ratio was 1:1.
lM Ab concentration,
R
R
13 -Cl
.
21
22
N
OH
N
HCl
14
N
Ph
Ph
.
(
a
)
(b)
N
N
HCl
15
N
N
N
O
N
OH
.
16
17
18
N
N
N
N
23
N
HCl
Ph
N
OH
OH
24
25
N
H
N
.
Ph
Ph
HCl
19
20
N
N
H
NH
H
N
.
26
HCl
Figure 5. Atomic Force Microscopy images of Ab(1–40) samples incubated (a)
without sulfonamides (control) and (b) with compound 14 for 4 days.
N
Ph
H
.
HCl
88% AChE inhibition at 2
For compound 14 (Fig. 3), which showed 58% BuChE inhibition at
10 M concentration, the IC50 was 5.08 M. In the case of molecule
6, which showed 73% BuChE inhibition at 10 M concentration, the
IC50 was 3.60 M. For compounds 19 and 26 (Fig. 2) with 90% and
99% BuChE inhibition, respectively, at 10 M concentration, the
IC50’s were 2.00 M and 930 nM. Molecule 19 showed >85% inhibi-
tion for both enzymes. However, molecule 18 and 26 also exhibited
lM concentration, the IC50 was 160 nM.
Figure 3. Structure of sulfonamides synthesized in this work.
l
l
l
molecules showed more than 40% inhibition at 10 lM. Compounds
19, 25, and 26 (Fig. 3) exhibited more than 80% inhibition at this
concentration.
Several of the compounds showed lower IC50 values than the
galanthamine standard. For compound 19 (Fig. 3), which showed
l
l
l
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4
S. Bag et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
120
100
80
100
80
60
40
20
60
40
0
-20
-40
-60
-80
20
0
-20
compounds
compound
s
Figure 6. Inhibitory effect of sulfonamide derivatives on the Ab oligomer forma-
tion. The assays were carried out at Ab/inhibitor = 0.0002 ratio at 0.01 lM Ab
concentration.
Figure 9. Inhibition of BuChE activity by commercial and synthetic sulfonamides
tested at 10 M concentration.
l
45
40
35
30
25
20
15
10
5
0
-5
-10
compounds
Figure 10. Superimposition of molecule 19 (green, ball and stick) with donepezil
(brown, ball and stick) and galanthamine (magenta, ball and stick) in the active site
of AChE (PDB code: 1EVE).
Figure 7. Radical scavenging activity of the sulfonamides (10 lM) determined as
the% decrease of the DPPH radical absorbance at k = 519 nm after
a 60 min
incubation.
active site occupying both the catalytic site and the peripheral
anionic site. Its position is similar to that of donepezil (brown)
and significantly different from that of galanthamine (green). The
interactions shown by the docked conformation of molecule 19
were studied in detail. Both nitrogens of the benzyl piperazine ring
in 19 formed two cation– interactions with Phe330 residue (cen-
100
80
60
40
20
0
troid: centroid = 4.67 Å and 4.48 Å) of the active site. One
p–p
interaction was seen between the benzyl ring of benzyl piperazine
with Trp84 residue (centroid: centroid = 4.28 Å) of the active site.
The aliphatic-N of benzyl piperazine formed a hydrogen bond with
Phe330 of 1EVE. These interactions further stabilized the molecule
in the active site accounting for the improved potency.
-20
Most of the synthesized molecules (13–26, Fig. 3) have an
extended linear structure with a sulfonamide moiety. In order to
observe whether the sulfonamide plays any role in the activity
measured in our different assays, two more compounds (27, 28,
Scheme 2b), which also have an extended linear structure but lack
the sulfonamide moiety, were synthesized. These two new mole-
cules had little or no effect on the inhibition of fibril formation,
cholinesterase inhibition and free radical scavenging. In contrast,
one of these compounds (28) exhibited 99% oligomer assembly
inhibition. In all 26 sulfonamides have been synthesized and tested
in a variety of assays related to AD pathology and neurochemical
abnormalities of the disease. The compounds can be categorized
into three groups: commercially available, sulfonamides with lim-
ited length and size (1–5); cyclic sulfonamides (6–12) and open-
chain sulfonamides (13–26) with a head and tail group that was
linked with a long chain in order to span the active center of the
cholinesterases. The structure–activity relationship in the different
assays reveals significant information for future design. The cyclic
sulfonamides (saccharin derivatives), while promoting the fibril
-40
compounds
Figure 8. Inhibition of AChE activity by commercial and synthetic sulfonamides
tested at 2 M concentration.
l
notable inhibition for AChE and nearly complete inhibition for
BuChE at 10 M. This is significant, in view of the renewed interest
in dual AChE and BuChE inhibitors as symptomatic therapeutics for
l
AD.
With the aim of understanding the cholinesterase inhibition
property of these new molecules, they were docked in the active
site of AChE (PDB code: 1EVE). The superimposition of compound
19 with donepezil and galanthamine (known AChE inhibitors) in
the active site of 1EVE is as shown in the Figure 10.
From the superimposition of molecule 19 (green) with donepe-
zil (brown) in the active site of 1EVE (Fig. 10) it is evident that the
19 occupies the active site (magenta), and extends throughout the
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S. Bag et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
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pounds with cholinesterase and Ab self-assembly inhibitory and
promising antioxidant properties for AD treatment. While the
small and cyclic derivatives (saccharins) were largely inactive in
the assays, the open chain sulfonamides showed potency and effi-
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linkers have potential as leads for development of new drug candi-
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Acknowledgments
Financial support provided by the University of Massachusetts
Boston through the 2013 Joseph P. Healey Research Grant and
National Institute of Health (R21AG028816-01 to H.L.) is gratefully
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Please cite this article in press as: Bag, S.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.12.006