Design, synthesis, and biological evaluation of oxindole derivatives as antidepressive agents

Article abstract of DOI:10.1016/j.bmcl.2015.09.048

The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of c

Full text of DOI:10.1016/j.bmcl.2015.09.048

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and biological evaluation of oxindole derivatives as
antidepressive agents
Sharad Kumar Suthar a, Sumit Bansal a, Md. Maqusood Alam b, Varun Jaiswal c, Amit Tiwari d,
Anil Chaudhary d, Angel Treasa Alex e, Alex Joseph a,
⇑
a Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal 576104, India
b Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130701, Republic of Korea
c Department of Computer Engineering and Bioinformatics, Shoolini University, Solan 173229, India
d Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal 576104, India
e Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal 576104, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant
activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results
of biological studies revealed that the majority of compounds exhibited potent to moderately potent
activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of
37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62
and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC50 of
18.27 lmol, whereas the reference drug moclobemide displayed an IC50 of 13.1 lmol. The SAR study dis-
closed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole deriva-
tives was critical for the antidepressant activity.
Received 16 January 2015
Revised 24 August 2015
Accepted 19 September 2015
Available online xxxx
Keywords:
Oxindole derivatives
Antidepressant activity
MAO-A inhibitors
Forced swimming test
Tail suspension test
Ó 2015 Elsevier Ltd. All rights reserved.
According to the World Health Organization, major depression
will become the second leading cause of death by the year 2020
because of the complications arising from cardiovascular system
and stress.1 There is a tremendous unmet need for new, safer,
and more effective antidepressant drugs, since currently used
antidepressants have significant side effects and about 30% of the
population does not respond to these current treatments.2,3 Mono-
amine oxidase (EC 1.4.3.4, MAO) is an integral protein of the outer
mitochondrial membrane, catalyses the oxidative deamination
reaction of neurotransmitters such as dopamine, norepinephrine,
and serotonin monoamines in central nervous system and periph-
eral tissues.4,5 Both the MAO-A and -B are present in the majority
of brain areas6 and have attracted considerable interest because of
their key roles in monoamine neurotransmitter metabolism and
involvement in various neuropsychiatric disorders.7 The MAO reac-
tion yields aldehydes and hydrogen peroxide (H2O2), which
induces apoptosis.8 The inhibition of MAO and subsequent H2O2
generation effectively prevents depression and various oxidative
stresses in the brain.9 However, classical MAO inhibitors have been
shown to have side-effects.10,11
Indoles, oxindoles, and isatins (2,3-dioxindoles) are nitrogen-
containing heterocyclic compounds, widely distributed in the liv-
ing world and in its chemical environment. Some indole amines,
such as tryptamine and serotonin (Fig. 1) are the substrates of
MAO. A recent study revealed that 5-hydroxyisatin selectively
inhibits MAO-A, while indole and other isatin analogs were less
potent inhibitors of MAO-A and -B.12 Audia et al. reported affinity
of indole derivatives toward 5HT2A, 5HT2B, and 5HT2C receptors,
which could be useful in the treatment of various disorders associ-
ated with these receptors, like migraine, anxiety, depression,
schizophrenia, tachygastria, ichlasia, and dyspepsia.13 Further-
more, indole moiety is present in a number of drugs currently in
the market and most of these belong to triptans, used for the treat-
ment of migraine headaches. Few of the new molecules reported in
the past few years sharing structure similarities with indole moiety
are the Wyeth’s compounds WAY-161503 and WAY-163909
(Fig. 2), both selective 5HT2C receptor agonists, claimed to be useful
Abbreviations: MAO, monoamine oxidase; FAD, flavin-adenine dinucleotide;
FST, forced swimming test; TST, tail suspension test; %DID, percentage decrease in
immobility duration; PDB, protein data bank.
for the prevention and treatment of depressive disorders.14–18
A
new drug PD-6735 (Fig. 2) too bears an indole moiety in its struc-
ture is a melatonin receptor agonist that has recently completed
⇑
Corresponding author. Tel.: +91 09448548060; fax: +91 0820 2571998.
E-mail address: alex.joseph@manipal.edu (A. Joseph).
http://dx.doi.org/10.1016/j.bmcl.2015.09.048
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Suthar, S. K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.09.048

2
S. K. Suthar et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Figure 1. Chemical structures of indole amines.
phase II clinical trials for treating sleep disorders in blind individ-
uals.3 Oxindole is a neurodepressant tryptophan metabolite phys-
iologically present in mammalian brain and blood, and affects
brain functions.19–21 Like indole, several oxindole derivatives have
also been reported to possess antidepressant activity.3
Relying on the notion that some of the indole and oxindole
derivatives share structural similarity with neurotransmitters
and endogenous amines,3 such as MAO substrates serotonin and
tryptamine;22 we thought to synthesize oxindole derivatives as
possible antidepressants. Moreover, QSAR and in vitro study per-
formed by Chimenti et al. revealed that chalcones are valid scaf-
folds for the inhibition of MAO.23 In this study, some of the
chalcones showed a very high selectivity index when compared
to the standard antidepressants clorgyline, deprenyl, iproniazid,
and moclobemide. Based on this perception, we decided to synthe-
size derivatives of oxindoles in the form of chalcones. The synthe-
sized compounds were studied for antidepressant activity by
employing Porsolt’s forced swimming test (FST),24,25 tail suspen-
sion test (TST),26 and MAO-A inhibition assay.
The title compounds (3–20) were synthesized by Claisen–Sch-
midt condensation reaction of a ketone with various aldehydes.
The commercially available oxindole (indolin-2-one) (1) was stir-
red with appropriate aldehydes (2) in the presence of alcoholic
NaOH to afford 3-substituted oxindole derivatives (3–20)
(Scheme 1). All the compounds were obtained in excellent yield
(>81%) and their synthesis was confirmed by UV, IR, 1H NMR,
and mass spectroscopic techniques. The UV spectra of final com-
pounds (3–20) showed two typical chalcone bands between
312.60–368.40 nm (band-I) and 240.80–258.20 nm (band-II). The
IR spectra of compounds (3–20) exhibited peaks at 3138.26–
3186.51, 1690.14–1712.85, and 1587.47–1622.19 cmÀ1 character-
istic to the NAH, C@O, and C@C groups of compounds, respectively.
The 1H NMR spectra of synthesized products revealed that the
number of protons were consistent with the proposed structures.
All the synthesized products showed two singlets at 7.222–
7.755 ppm (1H) and 10.481–10.673 ppm (1H) distinctive to the
@CH and NH fragments of the compounds, respectively. Thus, syn-
Scheme 1. Synthesis of oxindole derivatives (3–20): (a) alcoholic NaOH; (b) stir 2 h.
bonyl group, along with the presence of molecular ion peaks
respective to the molecular weights of the synthesized compounds.
FST and TST are the most common animal models of antidepres-
sant drug screening. Both tests are based on the same principle of
measurement of the duration of immobility when rodents are
exposed to an inescapable situation. Testing of new substances in
above tests allows a simple assessment of their potential antide-
pressant activity by measurement of their effect on immobility.
In a comparative review of drug effects on immobility time in mice,
Borsini and Meli adopted a limit of 20% reduction of immobility to
consider drug as an effective antidepressant.27 Coming to our
experimental setup, Swiss strain of albino mice was chosen
because it is sensitive against almost all types of mechanisms
involved in the depression,28,29 and it is an economical option also.
The original description of the FST by Porsolt et al.24 explains that
6 cm of water is sufficient; though, mice can sense the bottom of
the cylinder with this level of water. Thus, we performed FST at
10 cm of water level.30 Hypothermic exposure in FST may be prob-
lematic, especially if a targeted gene is involved in thermoregula-
tory processes.31 Also, selective serotonin reuptake inhibitors
(fluoxetine, paroxetine, sertraline),32 and drugs enhancing motor
activity may give false positive effects in FST. Therefore, we
thought to perform; TST parallel with FST to minimize the false
positive results. The TST is a dry land version of the FST29 and it
is based on the observation that rodents after initial escape-ori-
ented movements develop an immobile posture when placed in
an inescapable stressful situation. In case of the TST, stressful situ-
ation involves the hemodynamic stress of being hung in an uncon-
trollable fashion by their tail. An obvious advantage of this test is
its ability to detect a broad spectrum of antidepressants irrespec-
tive of their mechanisms and it is inexpensive, methodologically
unsophisticated, and easily amenable to automation.29
thesis of
(3-substituted oxindoles) was confirmed by the presence of IR
and NMR peaks distinctive to the ,b-unsaturated bond and car-
a,b-unsaturated carbonyl compounds, that is chalcones
a
All the synthesized 3-substituted oxindole derivatives (3–20)
were tested in vivo for antidepressant activity employing FST and
TST models. Imipramine was used as the standard drug. Results
are expressed as immobility time in seconds and percentage
decrease in immobility duration (%DID) (Tables 1, 2 and Figs. 3,
4). As listed in Tables 1 and 2, bromo substituted compounds
demonstrated higher activity than compounds substituted with
other groups at the analogous positions. The compounds 9, 11,
12, and 19 with 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl,
and 5-bromothienyl substitutions showed promising activity in
both the test models with compound 12 exhibiting the highest %
DID of 37.95 and 44.84, in the FST and TST, respectively. The com-
pound 9 showed %DID of 36.43 and 44.09, whereas the reference
drug imipramine displayed %DID of 43.62 and 50.64 in the FST
and TST, respectively. The compounds bearing 3-phenyl ring
(3–14) were more active than the compounds bearing 3-thienyl
ring (18–20), while compounds possessing 3-furanyl ring (15–17)
were least active. The position of groups on the phenyl ring exerted
Figure 2. Indole and related derivatives under development for depressive
(WAY-161503 and WAY-163909) and sleep disorders (PD-6735).
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S. K. Suthar et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 1
ring was substituted with 5-bromo group. The activity pattern of
furanyl substituted compounds was also repeated in the thienyl
substituted compounds, wherein activity order observed was:
5-bromothienyl substitution > 5-methylthienyl substitution >
thienyl substitution. Based upon above findings, one can conclude
that compounds possessing bromo group demonstrated superior
antidepressant activity.
Based on the results obtained in the FST and TST models, the
most active compounds 9, 11, 12, and 19 those showed immobility
time 100 or less seconds, were further studied to find out their
activity against MAO-A and compare it against the clinically used
drugs moclobemide and clorgyline. The outcome of test com-
pounds 9, 11, 12, and 19 against the bovine MAO-A is presented
in Table 3. The 4-bromophenyl substituted oxindole derivative 12
displayed the highest inhibition of MAO-A activity with an IC50
Antidepressant activity of test compounds and imipramine in the forced swimming
test
Compound
Dose (mg/kg) Immobility
time (s)
% immobility %Decrease in
immobility
mean SEM
duration
(%DID)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120.6 2.9⁄⁄⁄
137.3 2.4⁄
79.44
90.44
86.16
84.25
74.17
69.03
63.57
73.38
65.67
62.05
96.77
95.65
91.43
75.69
82.74
82.08
66.46
71.27
56.38
20.56
09.56
13.84
15.75
25.83
30.97
36.43
26.62
34.33
37.95
03.23
04.35
08.57
24.31
17.26
17.92
33.54
28.73
43.62
—
130.8 2.1⁄⁄⁄
127.9 2.5⁄⁄⁄
112.6 4.0⁄⁄⁄⁄
104.8 3.2⁄⁄⁄
96.5 2.9⁄⁄⁄
111.4 2.3⁄⁄⁄
99.7 2.4⁄⁄⁄
94.2 3.4⁄⁄⁄
146.9 2.8ns
145.2 2.9ns
138.8 1.5ns
114.9 1.9⁄⁄⁄
125.6 2.8⁄⁄⁄
124.6 3.1⁄⁄⁄
100.9 2.4⁄⁄⁄
108.2 2.5⁄⁄⁄
85.6 2.3⁄⁄⁄
of 18.27
mophenyl) and 19 (5-bromothienyl) also showed encouraging
IC50s of 27.2 and 35.1 mol, respectively against MAO-A. Along
lmol. Other bromo group bearing compounds 11 (3-bro-
l
with these compounds, another promising lead compound 9 that
has 4-chlorophenyl moiety in its structure also exhibited the note-
worthy IC50 of 29.5 lmol against the MAO-A. Interestingly, the
potency of our test compound 12 was similar to that of the clini-
cally used reversible MAO-A inhibitor moclobemide. However,
another clinically used irreversible and selective MAO-A inhibitor
clorgyline exhibited activity far superior to our test compounds
with an IC50 of 3.65 nmol against MAO-A. Relying on these prelim-
inary results against bovine MAO-A, we can propose that the test
compound 12 is a potential antidepressant that warrants further
explorations.
All the eighteen compounds were docked into the active site of
human MAO-A using Autodock tools 1.5.4. Results of molecular
docking studies are expressed in terms of estimated free energy
of binding (kcal/mol). The estimated free energy of binding of all
the docked eighteen molecules ranged between À4.95 and
À3.69 kcal/mol and is presented in Table 4. The docked complexes
of ligands (3–20) within the active site of MAO-A revealed that the
secondary amine (ANHA) and carbonyl (C@O) groups of synthe-
sized derivatives were involved in hydrogen bonding with the
Asn-181, Tyr-407, and Tyr-444 residues of the MAO-A. The most
active compound (12) of in vivo study showed lowest estimated
free energy of binding (À4.95 kcal/mol). The hydrogen atom of a
secondary amine group of 12 was involved in hydrogen bond for-
mations with the Tyr-444 of MAO-A (NAHÁ Á ÁOAH: 1.941 Å) (Figs. 5
Imipramine 10
Control
—
151.8 2.1 100.00
n = 6. Test compounds and imipramine (reference) were administered orally,
60 min before the test. ***P <0.00, **P <0.01, *P <0.05, ns: not significant versus
control. Data were analyzed by one way ANOVA followed by Tukey’s test.
an important effect on the pharmacological activity. The sub-
stituents present at the 4-position of phenyl ring imparted highest
activity followed by the substituents present at the 3-position of
the phenyl ring. The introduction of substituent on the 2-position
of phenyl ring resulted in decreased activity. The size of the sub-
stituent also affected the activity. Substitution of bromo group
imparted superior activity than activity imparted by chloro and
fluoro substitutions present at the analogous positions. Substitu-
tion of the nitro group on the phenyl ring caused a dramatic loss
of activity. Compounds bearing 3-furanyl ring produced inactive
compound (15), while substitution of 5-methylfuranyl ring
increased the activity, which was further enhanced, when furanyl
Table 2
Antidepressant activity of test compounds and imipramine in the tail suspension test
Compound
Dose
(mg/
kg)
Immobility
time (s)
mean SEM
%
%Decrease in
Immobility immobility duration
(%DID)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
102.3 1.6⁄⁄⁄
115.3 2.8⁄⁄⁄
114.5 1.9⁄⁄⁄
113.4 2.5⁄⁄⁄
93.0 2.2⁄⁄⁄
81.9 1.9⁄⁄⁄
75.2 2.9⁄⁄⁄
91.6 2.4⁄⁄⁄
76.8 2.5⁄⁄⁄
74.2 3.8⁄⁄⁄
124.7 3.1ns
120.5 2.2⁄
119.7 2.1⁄⁄
95.8 2.7⁄⁄⁄
109.6 2.8⁄⁄⁄
107.1 1.6⁄⁄⁄
78.7 1.1⁄⁄⁄
88.4 1.9⁄⁄⁄
66.4 2.7⁄⁄⁄
134.5 3.1
76.05
85.72
85.13
84.31
69.14
60.89
55.91
68.10
57.10
55.16
92.71
89.59
88.99
71.22
81.48
79.62
58.51
65.72
49.36
23.95
14.28
14.87
15.69
30.86
39.11
44.09
31.90
42.90
44.84
07.29
10.41
11.01
28.78
18.52
20.38
41.49
34.28
50.64
—
Imipramine 10
Control
—
100
n = 6. Test compounds and imipramine (reference) were administered orally,
60 min before the test. ***P <0.001, **P <0.01, *P <0.05, ns: not significant versus
control. Data were analyzed by one way ANOVA followed by Tukey’s test.
Figure 3. Percentage decrease in immobility duration by force swimming test. All
the data are mean SEM of six mice. ***P <0.001, **P <0.01, *P <0.05, ns: not
significant versus control.
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S. K. Suthar et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 4
Estimated free energy of binding of synthesized compounds in the target MAO-A
Compound
Estimated free energy of binding (kcal/mol)
3
4
5
6
7
À4.27
À4.05
À4.03
À4.14
À4.39
À4.44
À4.88
À4.31
À4.87
À4.95
À3.68
À3.90
À3.69
À4.62
À4.29
À4.17
À4.66
À4.41
8
9
10
11
12
13
14
15
16
17
18
19
20
Figure 4. Percentage decrease in immobility duration by tail suspension test. All
the data are mean SEM of six mice. ***P <0.001, **P <0.01, *P <0.05, ns: not
significant versus control.
and 6) and at the same time, a nitrogen atom of secondary amine
was 2.654 Å away from the hydroxyl hydrogen of the Tyr-444.
The distance between the carbonyl group of 12 and Asn-181 was
found to be 5.032 Å. Apart from hydrogen bonding, 4-bromophenyl
portion of the lead compound 12 displayed strong hydrophobic
and van der Waals interactions with the Phe-177, Ile-180, Phe-
208, and Ile-335 residues of the MAO-A. Additionally, oxindole
scaffold of 12 demonstrated hydrophobic and van der Waals inter-
actions with the Ile-207 and Phe-352 residues of the target protein.
The activity of the most active compound 12 can be attributed
to strong hydrogen bond formation of 1.941 Å between the hydro-
gen of secondary amine and hydroxyl oxygen of Tyr-444. The
hydrogen atom of the OAH group in Tyr-444 is attached to the oxy-
gen by a covalent bond and the lone pair of electrons at oxygen (of
OAH in Tyr-444) is still available to form a hydrogen bond with the
hydrogen atom of secondary amine of 12. Here, Tyr-444 acts as the
hydrogen bond acceptor, while 12 acts as the hydrogen bond
donor. As we know, hydrogen bonding takes place between the
most electronegative atom and the comparatively electropositive
hydrogen atom. The nitrogen atom of secondary amine is less elec-
tronegative due the amide-delocalization. We consider it as an
amide, because the C@O functionality is adjacent to it. In this case,
the oxygen atom of C@O in oxindole moiety of 12 is the better
hydrogen bond acceptor but polar hydrogens are present nowhere
nearby up to a distances of 2.5–2.6 Å. Therefore, the only possibil-
ity of hydrogen bond formation remained was with the polar
hydroxyl oxygen of Tyr-444. Based on these observations, we can
conclude that hydrogen bond formation between the secondary
amine of 12 and the Tyr-444 of MAO-A was quite obvious and
was responsible for the activity of the lead compound 12.
Figure 5. Docking of compound 12 in the active site of human MAO-A. The amino
acids involved in the hydrogen, hydrophobic, and van der Waals interactions with
12, are highlighted.
In conclusion, a series of 3-substituted oxindole derivatives
were designed and synthesized in search of potent antidepres-
sants. The pharmacological results revealed that synthesized com-
pounds showed significant activity and compound 12 was found to
be the most active with a potency comparable to that of the imi-
pramine in the in vivo models and similar to the moclobemide in
the in vitro MAO-A inhibition assay. The preliminary structure-ac-
tivity relationship (SAR) study revealed that the substitution of
bromo atom on phenyl, furanyl, and thienyl rings was critical for
the activity and imparted superior activity when bromo atom
was placed at the 4-position of the phenyl (12), 3-position of the
phenyl (11), and 5-positions of the furanyl (16), and thienyl rings
(19). Additionally, the electronegative nature of the halogen sub-
stituents also affected the activity. It was found that the com-
pounds possessing the least electronegative halogen atom
(bromine atom) were reasonably more active than the compounds
bearing atoms of higher electronegativity, such as chloro and flu-
oro atoms at the analogous positions. Although, when the chlorine
Table 3
In vitro MAO-A inhibition assay results
Compound
MAO-A inhibition activity (IC50 lmol SEM)
9
11
12
19
29.5 0.68
27.2 1.12
18.27 0.81
35.1 1.88
13.1 0.96
3.65⁄ 0.27
Moclobemide
Clorgyline
⁄
Activity in nmol.
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S. K. Suthar et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
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Acknowledgments
The authors thank the Indian Institute of Science, Bangalore and
SAIF labs of Central Drug Research Institute, Lucknow and Punjab
University, Chandigarh for NMR, mass and CHN analyses. We are
also grateful to Principal, Manipal College of Pharmaceutical
Sciences, and Head, Dept. of Pharmaceutical Chemistry, Manipal
College of Pharmaceutical Sciences, Manipal University for provid-
ing necessary research facilities.
Supplementary data
Supplementary data (1H NMR spectra of all the compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2015.09.048.
Please cite this article in press as: Suthar, S. K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.09.048