1,3,4-Oxadiazol-2-ylbenzenesulfonamides as privileged structures for the inhibition of monoamine oxidase B

Article abstract of DOI:10.1016/j.bmcl.2019.126677

The present study investigates the monoamine oxidase (MAO) inhibition properties of a series of ten 5-aryl-1,3,4-oxadiazol-2-ylbenzenesulfonamides. The target compounds were synthesized by dehydration of the corresponding N,N′-diacylhydrazines with phosph

Full text of DOI:10.1016/j.bmcl.2019.126677

Bioorganic&MedicinalChemistryLetters29(2019)126677
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1,3,4-Oxadiazol-2-ylbenzenesulfonamides as privileged structures for the
inhibition of monoamine oxidase B
Anton Shetneva, Roman Shlenevb, Julia Efimovaa, Sergey Ivanovskiia, Alexey Tarasovb,
⁎
Anél Petzerc, Jacobus P. Petzerc,
a Pharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl 150000, Russian Federation
b Yaroslavl State Technical University, Yaroslavl 150023, Russian Federation
c Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa
A R T I C L E I N F O
A B S T R A C T
Keywords:
The present study investigates the monoamine oxidase (MAO) inhibition properties of a series of ten 5-aryl-1,3,4-
oxadiazol-2-ylbenzenesulfonamides. The target compounds were synthesized by dehydration of the corre-
sponding N,N′-diacylhydrazines with phosphorus oxychloride to yield the 1,3,4-oxadiazole cycle with con-
comitant transformation of the sulfonamide to the sulfonyl chloride group. Treatment with aqueous ammonia in
acetonitrile regenerated the target sulfonamides. The results of the enzymology document that these compounds
are potent and specific MAO-B inhibitors with the most potent compound exhibiting an IC50 value of 0.0027 µM.
An analysis of the structure-activity relationships shows that the 4-benzenesulfonamides are significantly more
potent MAO-B inhibitors than the corresponding 3-benzenesulfonamides, and that the corresponding N,N′-dia-
cylhydrazine synthetic precursors are weak MAO inhibitors. Although MAO inhibition by oxadiazole compounds
are known, this is the first report of nanomolar MAO inhibition potencies recorded for sulfonamide derivatives.
MAO-B specific inhibitors such as those discovered here may be of interest in the treatment of neurodegenerative
disorders such as Parkinson’s disease.
Monoamine oxidase
MAO
Inhibition
Sulfonamide
Zonisamide
Oxadiazole
Introduction
amines and are thus important targets for the treatment of neu-
ropsychiatric and neurodegenerative disorders.5 Inhibitors of the MAO-
Monoamine oxidase (MAO) exists as two isoforms, MAO-A and
MAO-B, that are products of distinct genes.1,2 The MAOs are bound to
the outer membrane of mitochondria and are found in most mammalian
tissues including brain, liver, intestine, heart, placenta and platelets.
The MAO-A isoform predominates in the intestinal and placental tissues
while platelets express exclusively MAO-B. The MAOs are approxi-
mately 70% similar on the amino acid sequence level and also have
similar three-dimensional structures with the active sites being highly
conserved.3,4 In spite of this, MAO-A and MAO-B exhibit different
substrate specificities. Serotonin is a specific substrate for MAO-A while
2-phenylethylamine and benzylamine are specific substrates for the
MAO-B isoform.5,6 Dopamine, adrenaline, noradrenaline and tyramine
are substrates for both isoforms. The MAOs also exhibit differing in-
hibitor specificities with clorgyline and selegiline being the classical
MAO-A and MAO-B specific inhibitors, respectively.5 Numerous ex-
perimental MAO inhibitors have been described, many of which exhibit
isoform specificity, while others are non-specific inhibitors.
A isoform are established therapy for depressive illness and social
phobia, and act by increasing the levels of serotonin and noradrenaline
in the central nervous system.7 MAO-B inhibitors reduce the metabo-
lism of dopamine in the brain and are used for the treatment of Par-
kinson’s disease, particularly in combination with L-dopa, the metabolic
precursor of dopamine.8,9 By blocking the metabolism of amine sub-
strates, MAO inhibitors also reduce the formation of hydrogen peroxide
and aldehyde species, by-products of MAO catalysis.10 Since these by-
products may lead to neuronal cell damage, they have been implicated
in the pathogenesis of Parkinson’s disease, and MAO inhibitors have
been advocated as potential neuroprotective agents. MAO-B inhibitors
may be particularly relevant to neuroprotection in aged-related neu-
rodegenerative disorders since the density of the MAO-B isoform in-
creases in the brain with age while that of MAO-A remains un-
changed.11 MAO-A inhibitors may have a similar protective function in
the heart since MAO-A has been associated with hydrogen peroxide
formation in cardiac tissue.12 MAO-A inhibitors may thus have a po-
tential role in the treatment of cardiovascular diseases such as
The MAOs are key enzymes in the degradation of neurotransmitter
⁎ Corresponding author.
E-mail address: jacques.petzer@nwu.ac.za (J.P. Petzer).
https://doi.org/10.1016/j.bmcl.2019.126677
Received 6 August 2019; Received in revised form 5 September 2019; Accepted 8 September 2019
Availableonline10September2019
0960-894X/©2019ElsevierLtd.Allrightsreserved.

A. Shetnev, et al.
Bioorganic&MedicinalChemistryLetters29(2019)126677
Table 1
IC50 values for the inhibition of MAO by 1,3,4-oxadiazol-2-ylbenzenesulfonamides 1a–e and 2a–e, and N,N’-diacylhydrazines synthetic precursors 8a–e. The values
for reference inhibitors are also given for comparison.
№
Structure
IC50 (µM
MAO-A
SD)a
SIb
MAO-B
0.168
1a
63.9
23.1
0.019
0.010
380
O
S
N
O
N
NH2
O
1b
1c
1d
83.8
11.8
6.20
3.97
0.079
0.048
0.318
1061
1417
76
O
N
O
N
S
NH2
O
F
68.0
24.3
0.0043
0.0087
O
S
N
N
NH2
O
O
Cl
O
N
N
S
NH2
O
O
NC
1e
46.2
11.2
6.02
5.03
0.0027
0.00064
17,111
O
N
N
S
NH2
O
Cl
Cl
O
2a
2b
2c
34.4
0.975
0.571
0.439
0.014
0.083
0.027
35
N
N
O
O
S
O
NH2
F
61.4
108
N
O
N
O
S
O
NH2
> 100c
> 228
N
O
N
Cl
O
S
O
NH2
2d
2e
> 100c
> 100c
0.210
0.767
0.023
0.016
> 476
> 130
N
N
O
O
S
O
NH2
Cl
N
O
N
O
S
O
NH2
8a
8b
8c
8d
62.8
39.6
55.9
16.1
6.71
> 100c
> 100c
11.7
< 0.6
< 0.4
4.8
O
HN NH
S
NH2
O
O
O
0.354
7.20
1.97
O
S
HN NH
F
NH2
O
O
O
2.24
O
HN NH
Cl
NC
S
O
O
S
NH2
O
O
1.17
0.388
14
HN NH
NH2
O
O
O
(continued on next page)
2

A. Shetnev, et al.
Bioorganic&MedicinalChemistryLetters29(2019)126677
Table 1 (continued)
№
Structure
IC50 (µM
MAO-A
SD)a
SIb
MAO-B
8e
13.6
2.33
10.1
0.643
1.3
Cl
Cl
O
S
HN NH
NH2
O
O
O
Toloxatone
Lazabemide
3.92d
–
–
–
–
0.091d
a
b
c
All values are expressed as the mean
SD of triplicate determinations.
Selectivity index (SI) = IC50(MAO-A)/IC50(MAO-B).
No inhibition observed at maximum tested concentration of 100 µM.
Value obtained from reference.33
d
O
congestive heart failure.13–15 Interestingly, MAO-A activity has been
found to be increased in certain types of cancer, and MAO-A inhibitors
have thus been investigated as potential treatment of prostate cancer.16
Based on the therapeutic applications of MAO inhibitors and the
academic interest in the discovery of new classes of compounds that
may inhibit the MAOs, the present study investigates the MAO inhibi-
tion properties of a series of ten 5-aryl-1,3,4-oxadiazol-2-ylbenzene-
sulfonamides (1a–e; 2a–e) (Table 1). Oxadiazole derivatives are well
known to inhibit the MAOs, and numerous examples of high potency
inhibitors exist in literature. This is demonstrated by a recent report of
1,2,4-oxadiazole compounds with good potency MAO inhibition with,
for example, compound 3 exhibiting an IC50 value of 0.012 μM for the
inhibition of MAO-B (Fig. 1).17 In an earlier study, both 1,2,4-ox-
adiazole and 1,3,4-oxadiazole compounds were found to be potent and
specific MAO-A inhibitors as shown by example with compounds 4 and
5.18 As exemplified by zonisamide, sulfonamide compounds have also
been reported to inhibit the MAOs. This drug inhibits MAO-B with an
IC50 value of 24.8 µM.19 No sulfonamide compound has, however, been
reported to possess nanomolar MAO inhibition potency, and the sul-
fonamide functional group is not considered privileged for MAO in-
hibition. The present study will show that 5-aryl-1,3,4-oxadiazol-2-yl-
benzenesulfonamides are potent and specific inhibitors of MAO-B. In
this regard, molecular docking suggests that the sulfonamide functional
group forms key productive interactions in the substrate cavity, and
thus should be considered for the future design of MAO inhibitors.
Many clinical drugs are sulfonamide compounds and are used for the
treatment of a wide variety of disease states.20 Examples of such sul-
fonamide drugs are antimicrobial agents, diuretics, anticonvulsants and
antidiabetic agents.
O
S
O
O
S
O
HN NH
O
NH2
a
N
NH2
NH2
+
R
H
R
O
O
8a
HO
e
6
7
b
O
S
O
O
S
O
N
O
N
N
N
c
NH2
Cl
O
R
R
1a
e
9
Scheme 1. The synthesis of compounds 8a–e and 1a–e. Key: (a) EDC, DMF,
12 h, rt; (b) POCl3, 24 h, reflux; (c) NH3 (aq), CH3CN, 2 h, 50 °C.
the commercially available 3- and 4-sulfamoylbenzoic acids and ar-
ylhydrazide derivatives as building blocks represents a promising
strategy, and allows for the selective introduction of the sulfamoyl
moiety on position 4 of the aromatic ring of the intermediate N,N’-
diacylhydrazine. These compounds, under the action of acid catalysis in
the presence of dehydrating agents, can be converted to the corre-
sponding 1,3,4-oxadiazoles in a good yield. It should be noted that the
presence of the primary sulfonamide moiety makes it difficult to form a
1,3,4-oxadiazole ring because of the low solubility of the corresponding
N,N’-diacylhydrazine in most common solvents (THF, toluene, acet-
onitrile). Also, the reaction is complicated by the lability of the sulfa-
moyl moiety when heated in an acidic medium. However, the problem
of synthesizing such structures was successfully solved and is reported
in literature,22 where the practical and transition metal-free one-pot
synthesis of (1,3,4-oxadiazol-2-yl)anilines have been developed via
reaction of isatins with hydrazides in the presence of molecular iodine.
Scientists at Novartis company, as well as others followed an ap-
proach that was based on the use of Burgess reagent.23 Researchers
have used thionyl chloride as a dehydrating agent for a N,N’-dia-
cylhydrazines containing a sulfonamide moiety, which generally re-
sulted in relatively low yields (40–50%) of the desired 1,3,4-ox-
adiazoles.24
A significant number of works are devoted to the synthesis of 1,3,4-
oxadiazoles containing the 1,3- and 1,4-arylidene sulfonamide
moiety.21–24 It was shown that the direct chlorosulfonation of 3,5-
diaryl-1,3,4-oxadiazoles leads to the introduction of the sulfonyl
chloride moiety in position 3 of the selected aromatic ring.21 Therefore,
for the selective synthesis of 2-(4-sulfonylamidophenyl)-5-aryl-1,3,4-
oxadiazoles, a convergent approach is required. For this purpose, using
In this work, we used the classical and effective approach for the
N
O
O
S
O
HN NH
a
N
R2
NH2
R1
R2
O
+
Cl
N
H
N
Cl
O
N
O
O
H
N
O
R1
N
S
S
Cl
O
O
11
O
10
7
Cl
Cl
3
4
N
N
b
O
O
N
N
O
N
O
N
O
O
S
O
c
R2
R2
NH2
O
O
N
S
S
O
O
O
NH2
Cl
R1
R1
Zonisamide
5
2a
e
12
Fig. 1. Examples of known oxadiazole-based MAO inhibitors and the structure
Scheme 2. “One pot” synthesis of compounds 2a–e. Key: (a) Pyridine, CH3CN,
of zonisamide.
1 h, 25 °C; (b) POCl3, toluene, 6 h, reflux; (c) NH3 (aq), CH3CN, 2 h, 50 °C.
3

A. Shetnev, et al.
Bioorganic&MedicinalChemistryLetters29(2019)126677
MAO-B
100
75
50
25
0
-3
-2
-1
0
1
2
Log[I], µM
Fig. 2. Sigmoidal plots for the inhibition of MAO-B by compounds 1c (open
circles), 1b (filled circles) and 1e (triangles). Each data point represents the
mean
SD of triplicate measurements.
100
75
50
25
0
Fig. 4. Predicted binding orientation of 1e in the active sites of MAO-B (top)
and MAO-A (bottom).
NI
1e sel
dialyzed
1e
undialyzed
Fig. 3. Reversibility of MAO-B inhibition by 1e. MAO-B and the test inhibitor
(at a concentration of 4 × IC50) were incubated for 15 min, dialyzed for 24 h
and the residual enzyme activity was measured (1e – dialyzed). Similar in-
cubation and dialysis of the enzyme in the absence of inhibitor (NI – dialyzed)
and presence of the irreversible inhibitor, selegiline (sel – dialyzed), were also
carried out. The residual activity of undialysed mixtures of MAO-B and the test
inhibitor was also recorded (1e – undialyzed).
cyclization of N,N’-diacylhydrazines, which consists of in situ dehy-
dration of the corresponding N,N’-diacylhydrazines 8a–e with an excess
of phosphorus oxychloride for 24 h under reflux (Scheme 1). Together
with the formation of the 1,3,4-oxadiazole cycle, we observed the
transformation of the sulfamoyl group to the sulfonyl chloride group;
therefore, after the dehydration of N,N’-diacylhydrazines, the reaction
mass was treated with aqueous ammonia in acetonitrile to regenerate
the target sulfonamides 1a–e. Synthesis of the key reagents 8 was
carried out according to literature by reaction of commercially avail-
able hydrazides with carboxylic acids in DMF using EDC as a dehy-
drating agent.25
Fig. 5. The predicted binding orientation of 1e in the active site of MAO-B
compared to the orientation of zonisamide in the crystal structure (PDB entry:
3PO7).
To determine the inhibition potencies of the synthesized com-
pounds, the recombinant human MAO enzymes were used as enzyme
sources, and kynuramine served as the non-selective substrate.28 Ky-
nuramine is oxidized by MAO to ultimately yield 4-hydroxyquinoline, a
metabolite which may conveniently be measured by fluorescence
spectrophotometry. By thus measuring MAO activity in the presence of
various test inhibitor concentrations, sigmoidal curves of enzyme cat-
alytic rate versus the logarithm of inhibitor concentration may be
constructed, from which IC50 values are estimated. Examples of sig-
moidal curves for the inhibition of MAO-B are given in Fig. 2.
To obtain isomeric 1,3,4-oxadiazoles 2a–e, an alternative one-pot
synthetic approach was developed (Scheme 2). In our previous
works,26,27 it was shown that reactions of equimolar amounts of 3-
chlorosulfonylbenzoyl chlorides 10 with amidoximes and aromatic
amines lead to the corresponding O-acylated amidoximes and benza-
mides, with the SO2Cl moiety remaining unmodified. In the present
work, it is shown that compounds 10 can successfully be reacted in a
similar manner with equimolar amounts of hydrazides 7, yielding
corresponding compounds 11. The sulfonyl chlorides 11 thus obtained
were subjected without isolation to cyclocondensation in a mixture of
POCl3-toluene to yield the corresponding oxadiazoles 12. After the
solvent was replaced with acetonitrile, 12 was treated, without isola-
tion, with an aqueous solution of ammonia to form the 1,3,4-ox-
adiazoles 2a–e in good yields (69–78%).
The IC50 values are given in Table 1, and show that the 5-aryl-1,3,4-
oxadiazol-2-ylbenzenesulfonamides (1a–e; 2a–e) are specific inhibitors
of MAO-B with SI values > 35. In this regard, 1a–e and 2a–e are weak
MAO-A inhibitors with IC50 > 24.3 µM. In contrast, these compounds
are good potency MAO-B inhibitors with all compounds exhibiting
IC50 < 1 µM. The most potent MAO-B inhibition was observed for 1e
which exhibit an IC50 of 0.0027 µM. This compound is therefore ap-
proximately 33-fold more potent than the reference MAO-B inhibitor,
lazabemide. Substitution of the sulfonamides on position 4 of the
4

A. Shetnev, et al.
Bioorganic&MedicinalChemistryLetters29(2019)126677
phenyl yielded significantly higher MAO-B inhibition compared to
substitution on position 3 (e.g. 1b vs. 2a; 1c vs. 2d). Furthermore,
halogen substitution as observed with 1b–c and 1e further enhanced
MAO-B inhibition (compare with 1a and 1d). Compared to the 1,3,4-
oxadiazole compounds, the N,N’-diacylhydrazines synthetic precursors
are weak MAO inhibitors, which demonstrates the requirement for the
oxadiazole functionality for MAO-B inhibition. Finally, ortho substitu-
tion to the 3-benzenesulfonamides reduced MAO-B inhibition (e.g. 2c
and 2e vs. 2d).
moiety is placed towards to the entrance of the active site. The sulfo-
namide undergoes hydrogen bonding with the backbone carbonyl
groups of Gly-110 and Ala-111, while pi-pi interactions are established
between the benzenesulfonamide ring and Phe-208, and between Tyr-
407 and the dichlorophenyl ring. Pi-sulfur interactions are present be-
tween the oxadiazole ring and Cys-323 and Met-350. Of significance is a
steric conflict between Leu-97 and the sulfonamide group, which in-
dicates that 1e does not fit well in the MAO-A active site. The or-
ientation of binding in MAO-A also may be less favorable since it would
be expected that the polar sulfonamide will bind in the polar region of
the active site, in front of the FAD.
The reversibility of MAO-B inhibition was investigated for the most
potent inhibitor of this study, 1e. For this purpose, dialysis experiments
were carried out. MAO-B and 1e were pre-incubated (at a concentration
of 4 × IC50) and subsequently dialyzed. The incubation mixtures were
diluted twofold to yield an inhibitor concentration of 2 × IC50, and the
residual MAO-B activity was recorded. For comparison, a similar ex-
periment was carried out with the exception that the pre-incubations
were not dialyzed. As negative and positive controls, respectively,
dialysis experiments were carried out in the absence of test inhibitor
and presence of the irreversible MAO-B inhibitor, selegiline. The results
of the dialysis experiments show that 1e is a reversible MAO-B inhibitor
since, after dialysis, MAO-B activity is recovered to 60% of the negative
control value (100%) (Fig. 3). As expected, inhibition of MAO-B persists
in non-dialysed pre-incubations with the residual activity at 44%. For
the positive control selegiline, dialysis does not restore catalytic activity
with the residual activity at 7%. It may thus be concluded that 1e is a
reversible inhibitor of MAO-B, but may exhibit tight-binding to the
MAO-B active site since dialysis does not completely (100%) restore
catalytic activity.
This study shows that 5-aryl-1,3,4-oxadiazol-2-ylbenzenesulfona-
mides are potent and specific inhibitors of MAO-B, with IC50 values as
low as 0.0027 µM for the most potent inhibitor. Although MAO in-
hibition by oxadiazole compounds is known, this is the first report of
nanomolar MAO inhibition potencies recorded for sulfonamide deri-
vatives. Molecular docking studies show that the sulfonamide of the
most potent inhibitor, 1e, undergoes hydrogen bonding in the MAO-B
substrate cavity, while the oxadiazole and benzenesulfonamide phenyl
rings forms pi-pi stacking interactions. The dichlorophenyl binds in the
entrance cavity where interactions are mostly hydrophobic in nature.
This large inhibitor thus fills the MAO-B active site and forms numerous
productive interactions, which may explain its highly potent inhibition
of this enzyme. In this regard, the sulfonamide moiety undergoes ex-
tensive hydrogen bonding, and is likely a key contributor to inhibitor
stabilization. In contrast, the MAO-A active site is more restricted and
does not accommodate larger inhibitors as well as MAO-B. In particular,
Phe-208 prevents larger inhibitors from binding to MAO-A, while the
side chain of the analogous residue in MAO-B, Ile-199, is able to rotate
from the active site cavity, thus increasing the space available for in-
hibitors to bind.32 This may, at least in part, explain the specificity of
these compounds. In conclusion, MAO-B specific inhibitors such as
those discovered here may be of interest in the treatment of neurode-
generative disorders such as Parkinson’s disease.
Possible binding orientations and interactions of 1e, the most potent
inhibitor of this study, in the MAO-B active site were predicted using
molecular docking experiments. For comparison, this inhibitor was also
docked into the MAO-A active site. For this purpose, the Discovery
Studio 3.1 modelling software (Accelrys) was used, and the X-ray
crystal structures of human MAO-A co-crystallised with harmine (PDB
entry: 2Z5X) and human MAO-B co-crystallised with safinamide (PDB
entry: 2V5Z) served as protein models.3,29 The docking experiments
were carried out as described previously with the CDOCKER application
of Discovery Studio.30 In the first step, the pKa values and protonation
states of the amino acid residues were calculated for the protein models,
and an energy minimization, with the protein backbone constrained,
was carried out. The structure of 1e was drawn in Discovery Studio, and
after docking with CDOCKER, the docked orientations (ten solutions
generated) were refined using in situ ligand minimization.
Declaration of Competing Interest
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.
Acknowledgements
The results of the docking study show that 1e binds to the MAO-B
active site with the sulfonamide group in proximity to the FAD, the
polar region of the MAO-B active site (Fig. 4). The sulfonamide group of
1e binds in the same region as that of zonisamide as reported in the
crystal structure of this compound in complex with MAO-B (Fig. 5).31
The inhibitor extends towards the entrance of the active site with the
dichlorophenyl bound in the entrance cavity, the space beyond the Ile-
199 gating residue. Hydrogen bonding occurs between the sulfonamide
functional group and an active site water and Gln-206. Pi-pi stacking
interactions occurs between the oxadiazole ring and Tyr-326, and be-
tween Tyr-398 and the benzenesulfonamide phenyl ring. Pi-sulfur in-
teractions are present between the sulfonamide and Tyr-60, and be-
tween Cys-172 and the oxadiazole and benzenesulfonamide rings. In
the entrance cavity, the dichlorophenyl undergoes hydrophobic inter-
actions. The finding that the dichlorophenyl binds within the entrance
cavity may explain the 17-fold difference in the MAO-B inhibition ac-
tivities of 1e (IC50 = 0.0027 µM) versus 1c (IC50 = 0.048 µM). The
substitution of 1e with an additional chloro group would increase the
hydrophobic interaction between the inhibitor and the entrance cavity
leading to the observed increase in inhibition potency. No unfavorable
interactions have been recorded.
Support was obtained from the National Research Foundation of
South Africa [Grant specific unique reference numbers (UID) 85642 and
96180]. The Grantholders acknowledge that opinions, findings and
conclusions or recommendations expressed in any publication gener-
ated by the NRF supported research are that of the authors, and that the
NRF accepts no liability whatsoever in this regard.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2019.126677.
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